entecavir and adefovir

Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into "simultaneous" combination ("de novo" strategy); "sequential" combination, which involved starting with one therapy followed by the other ("switch-to" strategy); "add-on" combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Genotype; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Interferon-alpha; Lamivudine; Organophosphonates; Randomized Controlled Trials as Topic; Reproducibility of Results; Tenofovir; Treatment Outcome; Viral Load

We aimed to evaluate the efficacy of five oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of hepatitis B virus (HBV) reactivation and HBV-related complications in chronic hepatitis B virus (CHB) infected patients with hematological malignancies receiving chemotherapy or hematopoietic stem cell transplantation (HSCT) by network meta-analysis.. The search identified 28 articles involving 5 different prophylactic regimens covering 1478 participants.. Among five prophylactic regimes, tenofovir (predicted probability, 90%), was the most effective intervention followed by entecavir (88%) in preventing HBV reactivation. There was no significant difference between tenofovir and entecavir for preventing HBV reactivation. With regards to other outcomes, tenofovir and telbivudine was not included to evaluate due to lack of relevant studies. Entecavir was the most effective intervention in reducing the risk of HBV related hepatitis (100%), HBV related death (61%) and all other causes of hepatitis (98%).. Tenofovir and entecavir might be the most potent regimes in prevention of HBV reactivation for CHB infected patients with hematological malignancies undergoing chemotherapy or HSCT.

Topics: Adenine; Antiviral Agents; Controlled Clinical Trials as Topic; Guanine; Hematologic Neoplasms; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunocompromised Host; Lamivudine; Organophosphonates; Survival Analysis; Telbivudine; Tenofovir; Thymidine; Treatment Outcome; Virus Activation

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Carcinoma, Hepatocellular; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Neoplasms; Organophosphonates; Retrospective Studies; Survival Analysis; Telbivudine; Tenofovir; Thymidine

The primary goal of therapy for chronic hepatitis B (CHB) is to prevent liver disease progression. Hepatitis B surface antigen (HBsAg) seroclearance or seroconversion is regarded as an optimal endpoint to discontinue treatment. However, HBsAg seroclearance occurs very rarely with nucleos(t)ide analog (NUC) treatment, and long-term, almost indefinite, NUC treatment is required for the majority of patients. In patients with drug-resistant hepatitis B virus (HBV), a combination of tenofovir disoproxil fumarate (TDF) and entecavir (ETV), which is currently regarded as the strongest combination therapy against HBV, would be potentially safe to prevent the emergence of additional HBV resistance mutations. However, long-term tolerance data are lacking, and cost may be an issue for combination therapies. Several recent, well-designed, randomized controlled trials have shown that TDF monotherapy provides similar antiviral efficacy compared with the combination of TDF and ETV. Furthermore, no additional HBV resistance mutations emerged during TDF monotherapy for up to 96 weeks. Considering a comparable antiviral efficacy, extremely low risk of TDF-resistance, lower cost, and better safety potential, TDF monotherapy would be a reasonable choice for the treatment of drug-resistant patients with CHB.

Topics: Adenine; Antiviral Agents; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Tenofovir

Currently, no consensus exists regarding the optimal oral prophylactic regimens for hepatitis B surface antigen seropositive patients undergoing chemotherapy. We aimed to compare the efficacy of oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of chemotherapy-induced hepatitis B virus (HBV) reactivation and its related morbidity and mortality in patients with chronic HBV (CHB) infection.. Fifty-two eligible articles consisting of 3892 participants were included. For HBV reactivation, prophylactic treatment with NAs were all significantly superior to no prophylaxis, with odds ratio (OR) from 0.00 (95% confidence interval [CI] 0.00~0.04) for the most effective intervention (tenofovir) to 0.10 (95% CI 0.06~0.14) for the least effective intervention (lamivudine). For secondary outcomes, prophylaxis with NAs also significantly outperformed observation. The results suggested that entecavir reduced the risk of HBV related hepatitis (predicted probability, 83%), HBV related death (68%) and all causes of hepatitis (97%) most efficaciously. It ranked second in decreasing all causes of death (34%).. PubMed, Embase and Cochrane Library database were searched for controlled trials up to March 31, 2015. Primary outcome was the incidence of HBV reactivation. Secondary outcomes included the incidence of HBV-related hepatitis and death, all causes of hepatitis and death. Network meta-analysis combined direct and indirect evidence to estimate ORs for the clinical outcomes. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment based on clinical outcomes.. Available evidence suggests that prophylatic therapy with tenofovir and entecavir may be the most potent interventions in prevention of HBV reactivation and HBV-related morbidity and mortality for CHB infection patients undergoing chemotherapy.

Topics: Adenine; Antineoplastic Agents; Antiviral Agents; Controlled Clinical Trials as Topic; Guanine; Hepatitis B; Hepatitis B virus; Host-Pathogen Interactions; Humans; Lamivudine; Organophosphonates; Telbivudine; Thymidine; Virus Activation

The aim of the present study was to compare the efficacy of interferon (IFN) with or without different nucleos(t)ide analogues (NAs).. The PubMed, Wan Fang and CNKI databases were searched to identify relevant trials up to May 2015. Meta-analysis was performed with Review Manager 5.0. The stability and reliability were evaluated by publication bias tests.. Fifty-six studies fulfilled the criteria for the meta-analysis. Compared with IFN monotherapy, combination therapy were superior in HBV DNA undetectable rate (Risk Ratio (RR) = 1.55, 95% confidence interval (CI): 1.44-1.66, p < 0.00001), HBeAg and HBsAg loss rate (RR = 1.38, 95% CI: 1.22-1.56, p < 0.00001; RR = 1.69, 95% CI: 1.03-2.78, p = 0.04, respectively) at the end of week 48 treatment. Sub-analysis showed the RRs of virological response for entecavir (ETV), adefovir (ADV), and lamivudine (LAM) were 1.64, 1.61 and 1.52, respectively; RRs of HBeAg loss rate were 1.34, 1.71 and 1.34, respectively. However, at the end of follow-up, IFN plus NAs therapy was better than IFN monotherapy only in terms of HBV DNA undetectable rate (p = 0.0007).. Combination therapy was better than IFN monotherapy in virological and serological responses at the end of treatment. After follow-up, only HBV DNA undetectable rate was superior for combination therapy.

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Odds Ratio; Organophosphonates; Treatment Outcome

Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver-related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications.

Topics: Adenine; Animals; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Liver Neoplasms; Organophosphonates; Telbivudine; Thymidine; Treatment Outcome

The treatment of chronic hepatitis B (CHB) in patients with chronic kidney disease (CKD) is based on nucleoside (lamivudine, telbivudine, entecavir) or nucleotide (adefovir, tenofovir) analogues (NAs), but it may be complex and the information is scarce. Entecavir and tenofovir represent the currently recommended first-line NAs for NA-naive CHB patients, while tenofovir is the NA of choice for CHB patients with resistance to nucleosides.. To review the efficacy and safety of NAs in adult CHB patients with CKD and to provide reasonable recommendations for their optimal management.. Literature search in PubMed/Medline and manual search of relevant articles, reviews and book chapters.. NAs are cleared by kidneys and their dosage should be adjusted in patients with creatinine clearance <50 mL/min. There are concerns about nephrotoxic potential of the nucleotides, particularly adefovir, while improvements of creatinine clearance have been reported under telbivudine. Most existing data in CHB patients with CKD are for lamivudine and, less frequently, for other NAs, mostly entecavir. Besides CHB, NA should be used in case of immunosuppressive therapy in any HBsAg-positive patient with CKD including renal transplant (RT) recipients and in anti-HBs-positive recipients of kidney grafts from HBsAg-positive donors.. Chronic hepatitis B patients with chronic kidney disease receiving nucleoside analogues should be followed carefully for treatment efficacy and renal safety. Despite the absence of strong data, entecavir and telbivudine seem to be the preferred options for nucleoside analogue-naive CHB patients with chronic kidney disease, depending on viraemia and severity of renal dysfunction. More studies are certainly needed in this setting.

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Renal Insufficiency, Chronic; Telbivudine; Tenofovir; Thymidine

The ultimate goal of therapy for hepatitis B virus (HBV) infection is to obtain a clinical benefit for the patient by reducing infection-related complications, including hepatocellular carcinoma (HCC). Two main types of antiviral agents have been approved to treat patients in the immune clearance phase: interferon (IFN) and nucleos(t)ide analogues (NAs). NAs are used in most HBeAg-positive chronic hepatitis B patients for several reasons. They are oral drugs that are taken once a day and can be prescribed to all chronic hepatitis B patients, even those with contraindications for IFN. The current first-line NA options, entecavir (ETV) and tenofovir (TDF), have minimal or no risk of long-term resistance, and the sustained virological response is achieved in almost 100% of adherent HBeAg-positive patients. Tolerance is excellent and the safety profile is good, whereas IFN can be associated with adverse events that affect the patients' quality of life. There is considerable evidence to show that NAs modify the natural history of chronic hepatitis B, and increasing evidence that they reduce the risk of developing HCC. The need for long-term, perhaps indefinite treatment in patients who do not achieve anti-HBe seroconversion is the main limitation of NAs, but this is offset by their excellent tolerance and safety profile.

Topics: Adenine; Age Factors; Antiviral Agents; Biomarkers; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Polyethylene Glycols; Precision Medicine; Recombinant Proteins; Sex Factors; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Hepatocellular carcinoma (HCC) is a frequent, long term complication of chronic infection with hepatitis B virus (HBV) with an annual incidence ranging from 2 to 5%, often independent from the histological stage of underlying liver disease and serological status. Nevertheless, HCC is more often seen in older patients in whom HBV has been asserting its pro-oncogenic properties through both indirect and direct mechanisms. In Europe, HBV-related HCC is associated with cirrhosis in most patients, whereas this is not true in Asia and Africa where the tumour is also common among carriers with mild hepatic fibrosis, probably because of the coexistence of environmental co-carcinogens (aflatoxin) and long standing infection that is often acquired perinatally. Since hepatitis B-related carcinogenesis develops independently of the onset of cirrhosis, antiviral treatments such as nucleo(t)side analogues (NAs) that may result in the regression of fibrosis, prevent clinical decompensation and variceal bleeding, often fail to prevent HCC. Studies enrolling patients treated with lamivudine or rescued with adefovir, i.e. regimens characterized by limited potency and a low to moderate genetic barrier, have clearly been shown to help prevent HCC in patients with chronic hepatitis but not in those with cirrhosis, and in general not in patients that cannot achieve a sustained virological response. More potent anti-HBV drugs, such as entecavir and tenofovir, have been shown to improve the prevention of HCC in responders with cirrhosis, although HCC may still occur even in low risk patients. To attenuate HCC related outcomes, HBV replication must permanently be suppressed and HCC surveillance by abdominal ultrasound should be maintained even in responder patients.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Tenofovir

The goal of chronic hepatitis B (CHB) treatment is to achieve seroclearance of HBsAg. Nucleos(t)ide analogues (NAs) are one of the first-line treatments for CHB. NAs produce a potent suppression of viral replication but are associated with a low rate of HBsAg seroclearance and a high risk of virological relapse after discontinuation. Because of these reasons, long-term treatment is needed. They are well-tolerated oral drugs, and it seems they do not produce important side-effects in long-term administration. The duration of NA treatment remains unclear, nevertheless, in some patients NAs can be stopped with a low rate of relapse. HBeAg-positive patients could discontinue NA therapy if they achieved HBeAg seroclearance and maintain undetectable HBV DNA. For HBeAg-negative patients, to stop NA treatment is not recommended. In addition to other factors, serum HBsAg titres during treatment have recently been proposed to guide NA-based therapy duration in selected patients. All patients could be stopped from taking treatment if they achieve HBsAg loss.

Topics: Adenine; Algorithms; Antiviral Agents; Biomarkers; DNA, Viral; Drug Therapy, Combination; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine

Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included "Hepatitis B virus infection," "children," "HBV," "interferon," "lamivudine," "adefovir," "entecavir," and "tenofovir." Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Carrier State; Child; Databases, Bibliographic; Guanine; Hepatitis B, Chronic; Humans; Immune Tolerance; Incidence; Interferons; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Risk; Tenofovir

To determine whether adefovir (ADV) in combination with entecavir (ETV) is more effective than with lamivudine (LAM) in patients with lamivudine-resistant chronic HBV infection, electronic databases were searched through May 10th, 2013 to obtain relevant trials which met the inclusion criteria. Meta-analysis was performed on randomized controlled trials (RCTs) and non-randomized studies. Four trials containing a total of 323 patients were included. Serum HBV DNA reductions after 3 and 6 months of treatment in the ETV + ADV group were greater than that of LAM + ADV group (mean difference (MD) = 0.90, 95% confidence interval (CI): 0.74-1.07, P < 0.00001; MD = 0.81, 95% CI: 0.57-1.06, P < 0.00001). The rate of 6 months HBV DNA undetectability with ETV and ADV was higher than that of LAM and ADV (relative risk (RR) = 1.63, 95% CI: 1.14-2.34, P < 0.007). There were higher rates of serum ALT normalization than those in LAM + ADV group after 6 months of treatment (RR = 1.40, 95% CI: 1.11-1.77, P < 0.005). The ETV + ADV group had lower viral breakthrough and genotypic mutation rates than LAM + ADV group after 12 months of treatment (RR = 0.24, 95% CI: 0.10-0.58, P = 0.002). The combination of ETV plus ADV is a more effective rescue therapy than LAM add-on ADV in patients with LAM-resistant HBV.

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Treatment Outcome

Five oral nucleos(t)ide analogues are available to treat chronic hepatitis B (CHB). With the availability of newer agents, their efficacy on incidence of hepatocellular carcinoma (HCC) is not well described.. To determine the efficacy of oral anti-viral agents in reducing HCC risk in relationship with other known factors.. Published studies of at least 20 CHB patients treated with an oral anti-viral agent and followed for >2 years were analysed for incidence of HCC per 100 person years follow-up.. Pooled homogeneous data from six studies showed lamivudine (LAM) treatment (n = 3306) to reduce HCC risk by 51% compared with no treatment (n = 3585) (3.3 vs. 9.7 per 100 person years, P < 0.0001). Pooled data from 49 studies (23 with LAM; 16 with adefovir; and 10 with entecavir, tenofovir or telbivudine) of 10 025 treated patients showed HCC incidence of 1.3 per 100 person years, independent of the agent used. Patient age >50 years and hepatitis B virus-DNA detectability at HCC diagnosis increased risk of HCC by twofold with a 10-fold higher risk among patients with cirrhosis compared with chronic hepatitis. Meta-regression showed patient age, study location (Eastern vs. Western) and type of study (randomised or not) contributed to heterogeneity.. Lamivudine treatment significantly reduces the incidence of HCC compared with no treatment. However, HCC still develops at a rate of 1.3 per 100 patient years in CHB patients receiving an oral anti-viral agent. This finding highlights the need for continued HCC surveillance, particularly in CHB patients with inadequate viral suppression, older age and cirrhosis.

Topics: Adenine; Administration, Oral; Age Factors; Antiviral Agents; Carcinoma, Hepatocellular; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Neoplasms; Organophosphonates; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Hepatitis B virus infection is a significant health problem worldwide. The prevalence of HBsAg positivity is about 0.5-0.7% in Hungary. Liver cirrhosis and/or hepatocellular carcinoma develops in 15-40% of chronic hepatitis B virus infected patients without treatment. The ultimate goal of treatment would be to clear the virus from the infected subject; however, in practice, we can usually achieve long term suppression of viral replicaton with consequent prevention of the progression of liver disease, and reduction of the risk of the development of liver cirrhosis and hepatocellular carcinoma. Currently, there are two different treatment strategies for patients with chronic hepatitis B virus infection: therapy of finite duration with interferon or long-term treatment with nucleot(s)ide analogues. Entecavir and tenofovir are the two most effective nucleot(s)ide analogues with high barrier to resistance, thus, they can be confidently used as first-line treatments. Lamivudine engenders very high rates of resistance; adefovir is less efficacious than entecavir or tenofovir, and also engendering higher rates of resistance, thus none of them are recommended for initiation of a new treatment. Tenofovir is the treatment option in cases with lamivudine resistance, because entecavir has an unfavourable resistance-profile in this group of patients. Interferon is contraindicated during pregnancy. Should treatment of chronic hepatitis B virus infection be necessary during pregnancy, tenofovir, listed by the FDA as pregnancy category B drug, is to be preferred. Nucleot(s)ide analogues may be used to reduce the risk of intra-uterine and perinatal transmission of hepatitis B virus, which may occur in a proportion of newborns from highly viremic mothers, despite active and passive immunization. Similarly, tenofovir is recommended in the last trimester of pregnancy for women with high viremia. The risk of reactivation of chronic hepatitis B virus infection is high in HBsAg positive patients, and in patients with occult hepatitis B virus infection during and after chemotherapy or immunosuppressive treatment, including biological response modifiers (particularly related to rituximab therapy). Therefore, all candidates for these treatments should be screened for HBsAg and anti-HBc. Pre-emptive nucleot(s)ide analogues therapy should be initiated in patients with HBsAg positivity, and patients with occult hepatitis B virus infection. The role of general practitioners and occupat. A krónikus hepatitis B-vírus-fertőzés igen jelentős, globális közegészségügyi probléma. Hazánkban a HBsAg-pozitivitás prevalenciája 0,5–0,7%. Kezelés nélkül a fertőzöttek 15–40%-ában fejlődik ki májcirrhosis és/vagy hepatocellularis carcinoma. A kezelés célja a vírusreplikáció megszüntetése vagy csökkentése, amely a májbetegség progressziójának és így a májcirrhosis és a hepatocellularis carcinoma kialakulásának kockázatát is csökkenti. Jelenleg két különböző kezelési stratégia áll rendelkezésre: a határozott idejű interferon- vagy nukleoz(t)idanalóg-kezelés, illetve a hosszú távú nukleoz(t)idanalóg-terápia. A nukleoz(t)idanalóg-csoport két leghatékonyabb, igen kedvező rezisztenciaprofilú, már hazánkban is elérhető képviselője az entecavir és a tenofovir, amelyeket a hazai és a nemzetközi szakmai ajánlások is az interferonkezeléssel egyenrangúként, első választandó kezelési módnak ajánlják. A korábban széles körben alkalmazott lamivudin igen kedvezőtlen rezisztenciaprofilja miatt ma már új kezelésként nem indítható. Hasonlóan nem ajánlott az adefovir sem új kezelés indítására. Lamivudinrezisztencia esetén egyértelműen tenofovirra váltás szükséges, mert ezekben az esetekben az entecavir rezisztenciaprofilja lényegesen kedvezőtlenebb. Terhesség alatt lehetőség szerint kezelést nem végzünk. Ilyenkor az interferon ellenjavallt, azokban az esetekben, amikor a krónikus hepatitis B-vírus-fertőzés kezelése terhesség alatt szükséges, az FDA B osztályba tartozó tenofovir adható. Magas anyai vírustiter esetén a perinatalis átvitel megelőzésére – a kötelező aktív és passzív immunizáláson túl – a harmadik trimeszterben nukleoz(t)idanalóg-kezelés is szükséges lehet, ilyen esetekben is tenofovir választandó. Kemoterápia, immunszuppresszív vagy biológiai kezelés, csontvelő- vagy őssejt-transzplantáció esetén (különösen, ha rituximabot kap a beteg) a krónikus hepatitis B-vírus-fertőzés fellángolása, az okkult hepatitis B-vírus-fertőzés reaktivációja fordulhat elő, ezért minden ilyen kezelés előtt hepatitis B-vírus-szerológiai vizsgálat szükséges. HBsAg-pozitivitás vagy okkult hepatitis B-vírus-fertőzés esetén nukleoz(t)idanalóg-kezelés indokolt. Az alapellátásban és a foglalkozás-egészségügyben dolgozó kollégáknak alapvető szerepük van a hepatitis B-vírus-fertőzés felismerésében, illetve a pre- és posztexpozíciós profilaxisban. A szerző ismerteti a hepatitis B-vírus-fertőzés szempontjából veszélyeztetettek, illetve az immunizálandóak körét, valamint az aktív és passzív im

Topics: Adenine; Antiviral Agents; Comorbidity; Drug Interactions; Drug Therapy, Combination; Female; Gastroenterology; Guanine; Hematology; Hepatitis B, Chronic; Humans; Hungary; Infant, Newborn; Infant, Newborn, Diseases; Infectious Disease Transmission, Vertical; Interdisciplinary Communication; Interferons; Lamivudine; Medical Oncology; Organophosphonates; Pregnancy; Pregnancy Complications, Infectious; Rheumatology; Tenofovir

Hepatitis B virus infection remains 1 of the major health threats worldwide. Currently, lamivudine plus adefovir combination therapy or entecavir monotherapy is usually used for the treatment of patients with lamivudine-resistant chronic hepatitis B (CHB). However, there are few systematic comparisons between the efficacy of lamivudine plus adefovir and the efficacy of entecavir in the treatment of these patients.. The goal of this systematic study and meta-analysis was to assess the efficacy of lamivudine plus adefovir compared with entecavir for the treatment of patients with lamivudine-resistant CHB.. A comprehensive literature search of PUBMED, Web of Science, WANFANG database, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Review, were screened to obtain citations from January 1990 to January 2012 in this study. Data analysis was done by using the Review Manager Software 5.1.. Eight studies were suitable for analysis. A total of 696 patients with lamivudine-resistant CHB were studied and grouped according to treatment: 341 patients in the entecavir group and 355 patients in the lamivudine plus adefovir group. The results found that the rates of undetectable hepatitis B virus DNA levels, alanine aminotransferase normalization, hepatitis B e antigen loss, and hepatitis B e antigen seroconversion were not significantly different between the lamivudine plus adefovir group and the entecavir group. Moreover, the rate of adverse reactions was also not significantly different between the 2 groups. However, virologic breakthrough for the patients with lamivudine resistance was higher in the entecavir group than in the lamivudine plus adefovir group.. For these CHB patients with lamivudine resistance, lamivudine plus adefovir was a better treatment option than entecavir alone.

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Organophosphonates; Treatment Outcome

The optimal oral anti-viral agent to use in patients with decompensated HBV cirrhosis remains unclear.. We performed a meta-analysis of the oral nucleos(t)ide analogues in patients with decompensated HBV cirrhosis.. One year efficacy and safety outcomes in 22 studies published in English between '95 and 2010 were analysed.. Substantial heterogeneity was noted in the inclusion/exclusion criteria, controls, and sensitivity of the HBV DNA assay used. Pooled 1-year data showed benefit favouring lamivudine (LAM) vs. untreated controls for Child-Turcotte-Pugh (CTP) score improvement by ≥2 (OR: 117 (15 921), P ≤ 0.0001) and transplant-free survival (OR: 3.2 (1.2, 9), P = 0.022). Adefovir (ADV) led to undetectable HBV DNA at 1-year in 41% compared to 83% with LAM and 80% with entecavir (ETV). Overall, 1-year transplant-free survival rates varied from 78% with LAM to 95% and 94% with Tenofovir (TDF) and Telbivudine (TBV), respectively. The 1-year incidence of drug resistant HBV was 0% with ADV, ETV and TDF and 11% with LAM although TBV was associated with a 29% incidence at 2 years. Drug-related adverse events were infrequently reported.. All the oral anti-viral agents were associated with improved virological, biochemical and clinical parameters at 1-year. However, the efficacy of lamivudine and telbivudine is limited by drug resistance, and adefovir is limited by its potency and slower onset of action. Additional studies of tenofovir and entecavir are needed to determine the optimal agent(s) for treatment naïve patients and in those with drug-resistant decompensated HBV cirrhosis.

Topics: Adenine; Administration, Oral; Adult; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Nucleosides; Organophosphonates; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Time Factors; Treatment Outcome; Viral Load

Treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogs is often required over a prolonged period to achieve durable virologic suppression. One barrier to the success of long-term therapy is the emergence of drug-resistant mutants. Current guidelines therefore recommend the most potent drugs with optimal resistance profiles, that is, entecavir and tenofovir are used as first-line monotherapies in CHB. Characteristics of the hepatitis B virus, the disease, the patient and the drug can influence the response to antiviral treatment and risk of relapse. This review discusses factors to consider maximizing the chances of successful long-term treatment of CHB, and provides an overview of the long-term efficacy and safety data that have become available over the 4-5 years since entecavir and tenofovir were first approved for the treatment of CHB. Recent findings on whether and under what circumstances long-term therapy of CHB might be stopped are also discussed.

Topics: Adenine; Age Factors; Antiviral Agents; Comorbidity; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Life Style; Organophosphonates; Severity of Illness Index; Telbivudine; Tenofovir; Thymidine; Time Factors

Nucleos(t)ide analogues (NA) are a breakthrough in the treatment and management of chronic hepatitis B. NA could suppress the replication of hepatitis B virus (HBV) and control the progression of the disease. However, drug resistance caused by their long-term use becomes a practical problem, which influences the long-term outcomes in patients. Liver transplantation is the only choice for patients with HBV-related end-stage liver disease. But, the recurrence of HBV after transplantation often caused by the development of drug resistance leads to unfavorable outcomes for the recipients. Recently, the multi-drug resistance (MDR) has become a common issue raised due to the development and clinical application of a variety of NA. This may complicate the antiviral therapy and bring poorly prognostic outcomes. Although clinical evidence has suggested that combination therapy with different NA could effectively reduce the viral load in patients with MDR, the advent of new antiviral agents with high potency and high genetic barrier to resistance brings hope to antiviral therapy. The future of HBV researches relies on how to prevent the MDR occurrence and develop reasonable and effective treatment strategies. This review focuses on the diagnostic and therapeutic progress in MDR caused by the anti-HBV NA and describes some new research progress in this field.

Topics: Adenine; Antiviral Agents; Drug Resistance, Multiple; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Liver Transplantation; Mutation; Nucleosides; Nucleotides; Organophosphonates; Prognosis; Tenofovir; Viral Load

HBeAg seropositivity is a marker for active viral replication. In the natural history of chronic hepatitis B infection, HBeAg marks the first two of the four phases, namely the immune tolerant phase and the immune clearance phase, and is associated with highly replicative activity of the hepatitis B virus (HBV). Most HBV consensus reports and guidelines recommend antiviral therapy if the immune clearance phase is prolonged and if there is evidence of significant necroinflammation and fibrosis. Two main types of antiviral agents have been approved for treating patients in the immune clearance phase: interferon and nucleos(t)ide analogues (NUCs). The endpoints of therapy are viral suppression with HBeAg seroconversion, undetectable serum HBV DNA, normalization of serum alanine transaminase and improvement in the histological necroinflammatory and fibrosis scores. The ultimate goal of therapy is to obtain clinical benefit for the patient by reducing complications including hepatocellular carcinoma (HCC). The choice between interferon-based immune modulators or NUCs that target the HBV DNA polymerase must be carefully weighed on an individual basis. Therapy with NUCs is often preferred by doctors and patients because it is easy to administer, with predictable efficacy and minimal side-effects. In specific patient subgroups such as those with decompensated disease, poor predictors of response or lack of response to interferon-based therapy and/or significant comorbidities that cannot tolerate interferon-induced side effects, NUCs therapy is the obvious choice. Entecavir and tenofovir are the treatments of choice because their efficacy and safety profile are better than lamivudine, adefovir and telbivudine. More importantly, there is a minimal risk of drug resistance during long-term therapy with these agents.

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide. According to World Health Organization estimates, more than 300 million people are chronically infected and exposed to the risk of developing severe complications including cirrhosis and hepatocellular carcinoma (HCC). Major progress in the treatment of chronic hepatitis B (CHB) has been made during the last decade with the development of antivirals that inhibit viral polymerase activity. Antiviral drug resistance is an important factor in determining the success of long-term therapy for CHB. The development of resistance to nucleoside analogues (NUCs) has been associated with exacerbations of liver disease. Sequential therapy increases the risk of the emergence of multidrug resistance. The selection of a potent antiviral with a high barrier to resistance as a first-line therapy provides the best chance of achieving long-term treatment goals and should be used whenever possible. This has led to a significant decrease in drug resistance in countries where this strategy is affordable. However, the barrier to resistance of a given antiviral agent is influenced by the genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, the drug mechanisms of action and cross resistance. Furthermore, because of specific viral kinetics, prolonged treatment with NUCs does not result in the clearance of the viral genome from the infected liver. It is therefore important to continue research to identify new viral and immune targets and develop novel antiviral strategies for controlling viral replication as well as preventing drug resistance and its complications in the long term.

Topics: Adenine; Antiviral Agents; Capsid; Clinical Protocols; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Virus Internalization; Virus Replication

The combination of antiretroviral (ARV) therapies introduced at the end of the 1990s profoundly changed the natural history of human immunodeficiency virus (HIV) infection. Liver diseases are one of the three primary causes of 'non-AIDS-related' death in people living with HIV for three reasons: the high prevalence of hepatotropic viral co-infections, the hepatotoxicity of ARV drugs and new emerging liver diseases, including nodular regenerative hyperplasia and hepatitis E virus infection. The impact of HIV infection on the natural history of hepatitis C virus (HCV) or hepatitis B virus (HBV)/HIV co-infection has markedly changed in the past few decades with the progress made in ARV treatment and the improved definition of therapeutic strategies for HCV or HBV. Initially, HIV had a negative impact on hepatotropic infections. Today, HIV does not appear to significantly modify the natural history of HCV and HBV infection. This is associated with fair immune restoration, viral suppression associated with analogues having dual activity against HBV and HIV and with the increasing efficacy of antiviral treatments against HCV. A significant decline is expected in the morbidity and mortality associated with chronic liver infection in co-infected patients. Nevertheless, today, there are three major issues: (i) improving preventive measures including vaccination and risk reduction; (ii) screening patients infected with HBV or HCV and evaluating the impact of chronic infection on the liver and finally; (iii) early screening of hepatocellular carcinoma whose occurrence is higher and that evolves more rapidly in co-infected than in mono-infected patients.

Topics: Adenine; Antiviral Agents; Deoxycytidine; Disease Progression; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B; Hepatitis C; Hepatitis Viruses; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates

Although entacavir and adefovir were widely used in most Asian countries, there were few conclusions drawn from a meta-analysis for comparing the efficacy between entecavir and adefovir in nucleos(t)ide-naïve Asian patients with chronic hepatitis B (CHB). The aim of this study was to evaluate the 48-week efficacy between the two drugs in HBeAg-positive nucleos(t)ide-naïve Asian CHB patients with the method of Meta analysis, which was generally accepted by the international as the best evidence for evaluating the efficacy of drugs.. We searched all data documented in Pubmed, Embase, Wanfang Database and CNKI (China National Knowledge Infrastructure) before November 30, 2010. Heterogeneity was examined by Chi-square test, the relative risk calculated and forest plot drawn. Rates of undetected serum HBV DNA, serum alanine aminotransferase (ALT) normalization, HBeAg clearance and HBeAg seroconversion were analyzed. A total of 6 articles was included. Meta analysis showed that the rate of undetected serum HBV DNA (relative risk, 1.73; 95% confidence interval, 1.38-2.17; P < 0.00001) and that of serum ALT normalization (relative risk, 1.25; 95% confidence interval, 1.06-1.49; P = 0.009) in the entecavir group were higher than those in the adefovir group. However, no statistic significance existed between the two groups in the rate of HBeAg clearance (relative risk, 0.77; 95% confidence interval, 0.44-1.35; P = 0.36), or the rate of HBeAg seroconversion (relative risk, 0.74; 95% confidence interval, 0.28-1.94; P = 0.53).. Entecavir is superior to adefovir in decreasing serum HBV DNA and normalizing ALT but similar with adefovir in clearing HBeAg and encouraging HBeAg seroconversion for the HBeAg-positive nucleos(t)ide-naive Asian patients with chronic hepatitis B. Adefovir can be still used for first-line therapy in these patients.

Topics: Adenine; Antiviral Agents; Asia; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Organophosphonates; Randomized Controlled Trials as Topic

In Japan there are four approved anti-hepatitis B virus drugs available. Interferon has both antiviral and immune-modulatory effects. When it is effective, the durable treatment responses can be obtained. Three nucleoside and nucleotide analogues, lamivudine, adefovir, and entecavir, are potent oral inhibitors of HBV replication and well-tolerable. Though these drugs have greatly improved clinical course of chronic hepatitis B, it is still difficult to eradicate HBV from carriers. Several trials of combination of nucleoside analogues and interferon have been reported and some showed improved treatment responses. Further studies are needed to explore the best way to combine several drugs or to discover new anti-HBV drugs.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Guanine; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Organophosphonates

Chronic hepatitis B virus (HBV) infection represents a serious global health problem and resistance to lamivudine (LAM) has become a serious clinical challenge. Previous rescue therapy for the treatment of chronic LAM-resistant hepatitis B infected patients included switching to entecavir (ETV) and adding adefovir (ADV) or tenofovir (TFV). At present, switching to ETV is not recommended for rescue therapy for LAM-resistant chronic hepatitis B (CHB). The aim of this report was to determine whether add-on ADV was a superior rescue strategy in the treatment of CHB patients with LAM resistance.. We searched Medline/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library. Relative risks (RRs) of virologic response, virologic breakthrough, normalization of serum alanine aminotransferase (ALT) levels and HBeAg seroconversion rates were studied. Factors predicting virologic response, standardized mean differences (SMD) in HBV DNA levels and safety were reviewed.. Six eligible trials (451 patients in total) were included in the analysis. The rate of virologic breakthrough in the ETV group was higher than that in the LAM plus ADV group. There were no statistical differences in virologic response, ALT normalization and HBeAg seroconversion in either group 48 weeks post treatment. LAM plus ADV combination therapy produced faster and greater HBV DNA reduction rates 24 weeks post therapy compared to ETV monotherapy. HBV DNA baseline levels and the initial virologic response (IVR) were predictive of the virologic response. Additionally, combination therapy or monotherapy were both well tolerated.. LAM plus ADV combination therapy was more effective and produced longer-lasting effects than switching to ETV monotherapy in treating CHB patients with LAM resistance. However, considering the practical benefits and limitations of ADV, individualized therapy will be needed in patients with prior history of LAM resistant infections.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Function Tests; Organophosphonates; Salvage Therapy; Time Factors; Treatment Outcome; Viral Load

Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M(2) protein or the enzyme neuraminidase. Combination therapy with Interferon-α and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti-human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M(2) inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.

Topics: Acyclovir; Adenine; Amantadine; Antiviral Agents; Comorbidity; Drug Therapy, Combination; Foscarnet; Ganciclovir; Guanine; Hepatitis; Hepatitis B, Chronic; Hepatitis C; Herpesviridae Infections; HIV Infections; Humans; Influenza, Human; Interferons; Lamivudine; Nucleosides; Oligopeptides; Organophosphonates; Oseltamivir; Proline; Protease Inhibitors; Pyrimidinones; Ribavirin; Telbivudine; Thymidine; Valacyclovir; Valganciclovir; Valine; Virus Replication; Zanamivir

Topics: Adenine; Adult; Antiviral Agents; Guanine; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Organophosphonates; Practice Guidelines as Topic

Since its approval for the treatment of chronic hepatitis B in 1998, lamivudine (LAM) has been used extensively throughout the world, because of its relatively low costs and favourable tolerability. However, clinical trials and cohort studies have demonstrated that a high rate of resistance to this drug develops and, as a result, it is no longer included as a first-line therapy in most current treatment guidelines. Nevertheless, because of its low cost, this drug continues to be used in many countries and the pool of patients who have developed resistance to LAM continues to increase. Thus, there is a clear need to develop coherent management strategies to treat such patients as well as limit the emergence of resistance in the first instance. The purpose of this review is to highlight the need to aim for long-term treatment success while limiting the emergence of drug resistance and its consequences for the future. In addition to add-on/switch strategies with other nucleos(t)ide analogs, currently available data suggest that interferon-based therapies, with their potential to induce a sustained response, are worthy of consideration not only for reducing de novo resistance but as an option for the management of those patients in whom drug resistance has already developed.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir

Five nucleoside/nucleotide treatments are now available for chronic hepatitis B (CHB). This meta-analysis aimed to assess the relative efficacy of adefovir, entecavir, lamivudine, telbivudine, tenofovir disoproxil fumarate (TDF), and nucleos(t)ide combinations in the treatment of CHB.. A systematic review of MEDLINE and the Cochrane library was conducted to identify all studies evaluating these nucleos(t)ides in adults with CHB. Randomized controlled trials were included in the meta-analysis if they reported the proportion of patients with undetectable hepatitis B virus (HBV) DNA or hepatitis B e antigen (HBeAg) loss/seroconversion at 1 year. Bayesian mixed treatment comparison meta-analyses were conducted in WinBUGS to assess relative efficacy.. A random-effects meta-analysis of trials on treatment-naive patients with HBeAg-positive CHB demonstrated that 94% of patients will achieve HBV DNA < 300 copies/ml after 1 year with TDF, compared with 73% for entecavir, 50% for adefovir, and 38% for lamivudine. There was a 97.7% probability that TDF enabled a greater proportion of patients to achieve HBV DNA < 300 copies/ml at 1 year than all other treatments considered in the analysis. TDF was significantly superior to all nucleos(t)ides for this outcome at the 0.05 level. There were no statistically significant differences between nucleos(t)ides in HBeAg seroconversion at 1 year, based on a fixed-effects meta-analysis in the same population. More trials on HBeAg-negative and drug-resistant patients are required to facilitate meta-analyses for these subgroups.. In nucleos(t)ide-naive patients with HBeAg-positive CHB, TDF is associated with the highest probability of achieving undetectable HBV DNA at 1 year of all nucleos(t)ides considered.

Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Nucleotides; Organophosphonates; Tenofovir; Treatment Outcome; Viral Load

Combination therapy includes the use of two or more antivirals for the treatment of chronic hepatitis B. No study has shown that combination therapy is superior to monotherapy in naive patients for achieving treatment end points, but combination appears to result in a lower incidence of resistance. Moreover, the higher-potency compounds have not yet been studied. Consideration should be given to treating lamivudine-resistant patients with combination therapy, preferably with a nucleotide analogue in conjunction with a nucleoside analogue. Combination therapy should be considered in patients with decompensated cirrhosis who are unable to achieve an undetectable viral level on monotherapy and in naive patients who still have a detectable viral level 6 to 12 months after starting therapy.

Topics: Adenine; Antiviral Agents; Deoxycytidine; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Organophosphonates; Salvage Therapy; Treatment Outcome

Antiviral therapy is aimed to persistently suppress hepatitis B virus (HBV) to prevent liver complications and improve survival and long-term administration of nucleos(t)ide analogues represents an attractive treatment strategy. Five oral analogues are available, and all inhibit viral replication in most patients during the first year of therapy. By converse, long-term monotherapy is associated to high rates of resistance with lamivudine, and intermediate rates with Adefovir and Telbivudine. Third-generation analogues such as Entecavir and Tenofovir may efficiently inhibits viral replication in most patient for many years as they couple potency and high genetic barrier. In patients developing drug-resistance, specific rescue protocols based upon 'early add-on' have been developed to rapidly and efficiently control viral replication. In cirrhotics, long-term effective analog-based therapy prevented clinical decompensation for many years, but not liver cancer development. Long-term administration of NUCs, either as a monotherapy or as a sequential combination, inhibits HBV replication in most HBeAg-negative patients for at least 5 years, preventing clinical decompensation in cirrhotics.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Virus Replication

Chronic viral hepatitis B still remains serious diagnostic and therapeutic problem, that is mostly related to insufficient efficacy of available treatment options. This is the main reason of search for new recommendations and algorithms for optimizing procedures of patients selection and treatment. In this article we summarize informations collected from published recommendations of hepatologic scientific societies (EASL, AASLD, APASL) and independent groups of hepatologists, as well as therapeutic programs of Polish National Health Fund (NFZ). Principal criteria for patients selection include sera HBV-DNA concentration and alanine aminotransferase activity, but in some cases additional evaluation of histologic activity in liver biopsy can be necessary. Currently available medication used for HBV infection treatment are: adefovir, entecavir, lamivudine and pegylated interferon alfa 2a. The last two are most frequently prescribed in Poland, whereas use of adefovir and entecavir is limited due to lack of appropriate therapeutic programs covered by NFZ.

Topics: Adenine; Antiviral Agents; Disease Management; Drug Therapy, Combination; Guanine; Health Planning Guidelines; Health Services Accessibility; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; National Health Programs; Organophosphonates; Poland; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Hepatitis B virus is a significant cause of liver cirrhosis and hepatocellular carcinoma in patients with chronic infection. Higher levels of viral load are associated with increased risk of developing liver-related complications. The current available oral therapies suppress viral replication through their action on the hepatitis B virus polymerase. As treatment with oral nucleoside/nucleotide analogues is associated with the development of drug-resistant mutations, there is continuing research for newer and more potent antiviral agents to reduce the chance of drug resistance. LB80380, a prodrug, is an oral nucleotide analogue that inhibits viral replication by incorporation into the viral DNA. Antiviral activity against wild-type virus and virus with drug-resistant mutations was demonstrated in Phase II trials, with significant reduction of viral load in patients treated with LB80380. LB80380 was also shown to be safe and well tolerated.

Topics: Adenine; Alanine Transaminase; Antiviral Agents; DNA, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Immunologic Factors; Organophosphonates; Practice Guidelines as Topic

Hepatitis B virus (HBV) infection is a worldwide public health problem. There are an estimated 350 million persons with chronic HBV infection that could progress to cirrhosis and hepatocarcinoma with nearly one million deaths per year. In the last few years the therapeutic options in chronic hepatitis B have increased and currently six treatments are authorized: standard interferon (IFN)-alpha, pegylated interferon-alpha (PEG-IFNalpha), lamivudine, adefovir, entecavir, and telbivudine. For the last 25 years, conventional IFNalpha has been used as the treatment of chronic hepatitis B (CHB) and currently PEG-IFNalpha is indicated due to its greater effectiveness. Both drugs are first line options for HBeAg(+) and HBeAg(-) CHB. The advantages of IFNalpha and PEG-IFNalpha are that these drugs are administered for a limited time period, they achieve a higher sustained response rate and do not induce HBV mutants with antiviral resistance. These drugs achieve greater HBeAG and HBsAG clearance due to their antiviral and immunomodulatory activity. PEG-IFNalpha induces sustained biochemical and virological response in approximately one third of patients with HBeAg(+) CHB. The best response to IFNalpha and PEG-IFNalpha is obtained in patients with elevated transaminase levels, moderate viral load and HBV genotypes A and B. The disadvantages of IFNalpha and PEG-IFNalpha are their adverse effects and contraindications. These drugs cannot be administered in patients with decompensated cirrhosis. The combination of nucleos(t)ide analogs with PEG-IFNalpha could achieve much higher sustained response rates; however, which treatment constitutes the most suitable therapeutic strategy requires investigation.

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Genotype; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Multicenter Studies as Topic; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Randomized Controlled Trials as Topic; Recombinant Proteins; Telbivudine; Thymidine; Treatment Outcome

The development hepatitis B virus (HBV) polymerase inhibitors has revolutionised the treatment of chronic HBV infection. However, the emergence of resistance mutations can compromise their clinical efficacy and it is mandatory to know the mechanisms of these resistances, its clinical implications, strategies for prevention and how to deal with the rescue. Since HBV has a high degree of replication and a high error rate, during their life cycle it will produce a large number of punctual mutations in individuals with active replication. Due to the large size of the HBV genome, all the possible changes may occur daily and should be screened before starting any antiviral therapy. Therefore, in individuals infected with HBV there is a mixture of similar viruses that evolves over time (quasispecies), some of which are carriers of resistance mutations to antivirals, which explains why they can be selected quickly after exposure to drug. Of the five drugs approved in Europe for the treatment of hepatitis B, three of them (lamivudine, adefovir and entecavir) are likely to be affected directly by these mutations, as well as other active drugs, such as telbivudine, tenofovir and the emtricitabine. The characterization of the resistance mutations is helpful for the prevention and the optimization of antiviral therapies.

Topics: Adenine; Antiviral Agents; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Gene Products, pol; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Models, Molecular; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome; Virus Replication

Studies in the past decades have shown that active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression, and thus sustained viral suppression is of paramount importance in the management of chronic HBV infection. The nucleos(t)ide analogues lamivudine, adefovir, entecavir, telbivudine and tenofovir are potent inhibitors of HBV polymerase/reverse transcriptase activity and are highly effective in the suppression of HBV replication, but rarely eliminate the virus. Long-term therapy is usually required to achieve sustained hepatitis B e antigen seroconversion, HBV DNA suppression, ALT normalization and fibrosis reversal. Maintained long-term therapy has been demonstrated to significantly lower the rate of hepatic decompensation and development of cirrhosis or hepatocellular carcinoma. However, drug resistance is a serious risk on prolonged nucleos(t)ide analogue therapy, and this poses a critical challenge. Prevention and proper management of drug resistance are crucial to ensure long-term success.

Topics: Adenine; Adenine Nucleotides; Alanine Transaminase; Carcinoma, Hepatocellular; DNA, Viral; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Treatment Outcome; Virus Replication

The practising clinician is currently faced with a number of effective treatment options for chronic hepatitis B, including two formulations of interferon (standard IFN and pegylated IFN) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir). Treatment strategies can be divided into those aiming for sustained response after discontinuation of therapy and those that need to be maintained by prolonged antiviral therapy. Sustained response is particularly achieved with interferon-based therapy, while treatment-maintained response can be achieved with long-term nucleos(t)ide analogue therapy in the majority of patients. Of currently available drugs for the treatment of chronic hepatitis B, PEG-IFN seems to result in the highest rate of off-treatment sustained response after a 1-year course of therapy. Sustained transition to the immune-control phase (inactive HBsAg carrier state) can be achieved in 30-35% of HBeAg-positive patients and 20-25% of HBeAg-negative patients. Loss of HBsAg has been observed in 11% of both HBeAg-positive and HBeAg-negative patients after 3-4 years. Since hepatitis B virus (HBV) genotype is an important predictor of response to PEG-IFN, determination of HBV genotype is essential in patients in whom sustained off-treatment response is pursued. Aiming for sustained response is of particular interest because many HBV-infected patients are in need of antiviral therapy at a young age and may otherwise require indefinite antiviral therapy.

Topics: Adenine; Antiviral Agents; DNA, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Polyethylene Glycols; Practice Guidelines as Topic; Pyrimidinones; Randomized Controlled Trials as Topic; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

HBV cannot be fully eradicated from the body because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. True cure is infrequent, but persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Treatment options for chronic hepatitis B include pegylated interferon and 4 licensed oral nucleosides/nucleotides (lamivudine, adefovir entecavir and tenofovir). Interferon is the only drug with a defined duration of treatment. It is effective in 30% to 40% of patients but is poorly tolerated. In contrast to interferon, nucleotide/nucleoside analogs have only minor adverse effects. However, a resurgence of the infection may occur when these drugs are withdrawn, implying that treatment may have to continue indefinitely. The onset of viral resistance to these agents also limits their long-term use but can be minimized by ensuring potent suppression of viral replication.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Disease Progression; Guanine; Hepatitis B Vaccines; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Humans; Immunotherapy, Active; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Neoplasms; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir; Treatment Outcome

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Time Factors; Treatment Outcome

Several anti-viral treatments are now available for HBeAg-negative chronic hepatitis B (CHB), but the clinical and economic outcomes of potential treatment strategies and durations are unclear.. To examine the clinical and economic outcomes of potential treatment strategies and durations for HBeAg-negative CHB.. We conducted a cost-utility analysis from a payer perspective over a lifetime time horizon. Disease progression probabilities, costs and quality of life data were derived from the literature. We evaluated 5-year, 10-year, lifetime and 5 on-1 off treatment durations. For each of these treatment durations, we evaluated initial therapy with entecavir, lamivudine or adefovir, with addition of adefovir or entecavir for patients who developed virological breakthrough because of resistance (12 strategies total).. Increasing treatment duration improved quality-adjusted life-years (QALYs) and was generally cost-effective for all three drugs. However, a 5 on-1 off strategy was the most cost-effective: lifetime vs. 5 on-1 off entecavir had an ICER of $148,200/QALY. In probabilistic sensitivity analyses, entecavir 5 on-1 off was the preferred strategy over the range of commonly reimbursed cost-effectiveness thresholds. Lifetime treatment was preferred to a 5 on-1 off strategy, if treatment durability was < 10%.. The results of our analysis suggest that in HBeAg-negative CHB infection, a 5 on-1 off treatment strategy with entecavir improves health outcomes in a cost-effective manner compared to alternative strategies.

Topics: Adenine; Antiviral Agents; Cost-Benefit Analysis; Epidemiologic Methods; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates

Lamivudine and adefovir were approved for treatment of chronic hepatitis B virus (HBV) infection based on placebo-controlled trials, and entecavir was recently approved on the basis of its superiority over lamivudine in phase II/III trials; however, to date, these three therapies have not been compared head to head.. To evaluate the relative efficacy of these therapies, we applied a predefined protocol of established statistical techniques to compare data from phase III entecavir trials with published clinical trial results with lamivudine, adefovir and placebo in nucleoside-naive hepatitis B e antigen (HBeAg)-positive and -negative populations.. A comprehensive literature search identified 612 publications/data sources, of which 28 satisfied predefined inclusion criteria. Independent reviewers extracted week 48-52 histological, virological, biochemical and serological endpoints from these sources, which were analysed with a fixed-effects model. For each of the three histological endpoints in HBeAg-positive patients (Histological Improvement, Ranked Assessment of Necroinflammation [RA-N] and Ranked Assessment of Fibrosis [RA-F]), entecavir was superior to adefovir. Entecavir was superior to lamivudine for Histological Improvement and comparable to lamivudine for RA-N and RA-F. With respect to reducing HBV DNA levels, entecavir (-6.98 log(10) copies/mL) was more effective than lamivudine (-5.46 log(10) copies/mL, p < 0.0001) and adefovir (-3.60 log(10) copies/mL, p < 0.0001), and lamivudine was more effective than adefovir (p < 0.0001). The parallel goals of HBV DNA reduction below the limit of quantitation (LOQ) [by polymerase chain reaction] and ALT normalisation were achieved more often with entecavir (69% and 67% of patients, respectively) than with lamivudine (38% and 59%, respectively; p < 0.0001 and p < 0.05, respectively) or adefovir (21% and 48%, respectively; both p < 0.0001), and more often with lamivudine than with adefovir (p < 0.0001 and p < 0.05, respectively). HBeAg seroconversion rates were higher with entecavir (21% of patients) and lamivudine (18%) than with adefovir (12%, p < 0.01 and p < 0.05, respectively). For each of the three histological endpoints in the HBeAg-negative population, entecavir was comparable to adefovir. Entecavir was superior to lamivudine for Histological Improvement, and comparable to lamivudine for RA-N and RA-F, and all three antivirals were superior to placebo. Entecavir proved superior to lamivudine and adefovir in lowering HBV DNA levels (-5.20 vs -4.66 vs -3.91 log(10) copies/mL, respectively; p < 0.0005 and p < 0.0001, respectively) and in suppressing HBV DNA below the LOQ (91% vs 73% vs 51% of patients, respectively; both p < 0.0001); in the latter respect, lamivudine was in turn superior to adefovir (p < 0.0001). Entecavir was also superior to lamivudine in normalising ALT (76% vs 69% patients, respectively; p < 0.05).. Over a 12-month treatment period, this analysis predicts that the antiviral efficacy of entecavir would be superior to that of lamivudine, which in turn would be superior to that of adefovir, in nucleoside-naive patients with chronic HBV infection.

Topics: Adenine; Administration, Oral; Algorithms; Antiviral Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis C; Humans; Lamivudine; Mutation; Oligopeptides; Organophosphonates; Proline; Ribavirin; Serine Proteinase Inhibitors

The primary goal of treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB) is potent and durable suppression of hepatitis B virus (HBV) replication. It results in biochemical and histological remission of CHB and is the prerequisite for the prevention of cirrhosis, its life-threatening complications and hepatocellular carcinoma. Responses that are durable after the cessation of treatment are referred to as sustained virological responses, whereas those persisting under therapy are referred to as treatment-maintained virological responses. Treatment paradigms of sustained virological response in HBeAg-negative CHB are practically restricted to conventional IFN-alpha and pegylated interferons (peg-IFNs), and are limited only to patients with compensated liver disease. Long-lasting maintained virological responses without HBV resistance in HBeAg-negative CHB are achievable by all approved nucleos(t)ide analogues (lamivudine, adefovir and entecavir) in highly variable rates, depending on their potency, rapidity of virological response and genetic barrier to resistance. The maintenance of response under 5 years of adefovir treatment represents the most effective treatment paradigm for HBeAg-negative CHB, whereas such long-term data with entecavir and tenofovir monotherapy may become available in the near future. In patients with lamivudine-resistant HBV mutants, the recommended treatment strategy is to add adefovir at the same time as continuing treatment with lamivudine. There are no treatment paradigms as yet of combination therapy from the very outset with two nucleoside analogues for use in treatment-naive patients.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Thymidine

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

Chronic hepatitis B virus (HBV) infection is a significant public health problem in the United States, with 1.25 million people infected with the virus. The long-term risks of chronic HBV infection include cirrhosis and hepatocellular carcinoma, which occur in 15% to 30% of those infected at birth or early in life and may lead to liver transplantation or death. During the past few years, the development and increased availability of oral antiviral agents have made treatment simpler, safer, and more tolerable for these patients. This article focuses on 3 of these drugs--lamivudine, adefovir, and entecavir--and their use in patients with chronic HBV infection and advanced hepatic fibrosis or cirrhosis.

Topics: Adenine; Antiviral Agents; Disease Progression; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Organophosphonates

Topics: Adenine; Antiviral Agents; Biomarkers; Carrier State; Consensus Development Conferences as Topic; DNA, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferons; Japan; Lamivudine; Organophosphonates; Societies, Medical

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Organophosphonates

Topics: Adenine; Adenosine; Antiviral Agents; Comorbidity; Drug Therapy, Combination; Genotype; Guanine; Guanosine; Hepatitis B; Hepatitis B virus; HIV Infections; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors; Sexually Transmitted Diseases, Viral

Strong suppression of viral replication and normalization of alanine aminotransferase is feasible with nucleos(t)ide analogues. It is estimated viral replication and liver inflammation can be controlled in 90% of patients with chronic hepatitis B with the current available treatments.. To review the studies currently available on the management of chronic hepatitis B with nucleos(t)ide analogues.. Although very potent, nucleos(t)ide analogues are not effective in every patient. Some factors are known to influence treatment outcome, but many host and viral factors are still unknown. Stopping rules have to be defined to assess treatment efficacy in an early stage and change the regimen. Discontinuation of nucleos(t)ide analogues is often followed by reactivation of HBV. Data on the risk factors for relapse are necessary in order to decide if treatment can be safely discontinued. Another major drawback of nucleos(t)ide analogues is the emergence of resistance. The efficacy of compounds for the treatment of mutant virus and the impact of cross-resistance is largely unknown. The use of combination therapy to prevent resistance looks promising, but has to be proven.. HBV has become a treatable disease, however much research is needed to optimize treatment for individual patients and treatment failures.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Nucleotides; Organophosphonates; Reverse Transcriptase Inhibitors; Risk Factors; Virus Replication

Chronic hepatitis B develops in 3 phases: immune tolerance, where viral replication is strong and there is little or no fibrosis; immune activity phase with low viral replication and rapidly developing fibrosis as well as an elevated risk of cirrhosis; low viral replication and remission, with a risk, nonetheless, of reactivation. Antiviral treatment is indicated in patients with moderate or severe levels of either fibrosis or activity (necrotic and inflammatory lesions). Standard interferon treatment produces a prolonged response rate on the order to 20-40%; side effects are frequent but generally mild and reversible when treatment stops. Pegylated interferon (standard interferon conjugated with polyethylene glycol) has substantially better efficacy and comparable tolerance. Lamivudine (a nucleoside analog) has several advantages over interferon: oral administration, excellent tolerance, and rapid antiviral effect. Its principal disadvantage is the frequency of resistant mutations. Adefovir and entecavir have oral administration, are well tolerated and associated with a low incidence of resistance. They induce a sustained response after withdrawal of therapy in only a minority of patients and therefore the treatment needs to be indefinitely administered in the majority of patients.

Topics: Adenine; Administration, Oral; Antiviral Agents; Biopsy; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Drug Tolerance; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Lamivudine; Liver; Mutation; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Reverse Transcriptase Inhibitors; Time Factors; Virus Replication

In the absence of prophylaxis, there is an elevated risk of virus recurrence after liver transplantation required because of chronic hepatitis B. Regardless of prophylaxis, the risk of recurrence is associated with pre-graft viral load. Long-term prophylaxis by hepatitis B immune globulin (HBIG) significantly reduces the risk of recurrence, especially if there was no pre-graft viral replication. Use of antiviral agents such as lamivudine, adefovir, tenofovir, and entecavir, control HBV replication in patients with decompensation of cirrhosis while awaiting transplantation and in patients with HBV recurrence post-graft. The risk of emergence of resistant strains limits the use of these antiviral agents. The choice of one or several combined antiviral agents depends on their resistance profiles. Combining antiviral agents and HBIG after transplantation can reduce the risk of HBV recurrence to less than 10%, even in patients with viral replication pre-graft. If there was no detectable viral load pre-graft, withdrawal of HBIG should be considered at some point, while continuing an antiviral agent or after anti-HBV vaccination.

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Follow-Up Studies; Guanine; Hepatitis B Vaccines; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunoglobulins; Lamivudine; Liver Cirrhosis; Liver Transplantation; Mutation; Organophosphonates; Recurrence; Reverse Transcriptase Inhibitors; Tenofovir; Time Factors; Vaccination; Viral Load; Virus Replication

The Hepatitis B virus (HBV) is a DNA virus that can cause both acute and chronic liver disease in humans. Approximately 350-400 million people are affected worldwide and up to one million deaths occur annually from cirrhosis and hepatocellular carcinoma. When cirrhosis and liver failure develop, the definitive treatment of choice remains orthotopic liver transplantation (OLT). In the past, an unacceptable HBV recurrence rate with a high rate of graft loss was noted. The use of Hepatitis B immunoglobulin (HBIG) has resulted in improved patient and graft survival rates. The addition of the nucleoside analog Lamivudine (LAM) to HBIG has improved these survival curves to an even greater degree. Prolonged use of LAM will almost invariably lead to the development of viral mutations resistant to the drug. There are now several other nucleoside and nucleotide analogs (Adefovir, Entecavir, Tenofovir, and Truvada) available for the clinician to utilize against these resistant strains. It should be possible to prevent recurrence in most, if not all, post-transplant patients and also to significantly reduce viral loads with normalization of transaminases in those who have developed recurrent infection. The antiviral regimen should be robust and minimize the risk of breakthrough mutations. A prudent approach may be the implication of combination antiviral therapy. This review summarizes the efficacy of previous regimens utilized to prevent and treat recurrent HBV following OLT. Particular attention will be paid to the newer nucleoside and nucleotide analogs and the direction for future strategies to treat HBV in the post transplant setting.

Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B; Humans; Immunoglobulins; Lamivudine; Liver Transplantation; Nucleosides; Nucleotides; Organophosphonates; Recurrence; Tenofovir

Significant progress has been made during the last 2 years in the treatment of chronic hepatitis B (CHB). Treatment decisions differ significantly depending on whether patients are HBeAg+ or HBeAg-, treatment-naive or nucleoside/nucleotide-resistant, and in early or advanced stages of liver disease. Courses of finite duration, aiming to achieve sustained off-therapy responses, are practically restricted to HBeAg+ patients with compensated chronic liver disease, whereas long-term therapy aiming to achieve maintained on-therapy remission is mostly applicable to HBeAg- individuals either with early or advanced liver disease. A course of finite duration with pegylated (PEG)-IFN-alpha-2a offers the highest probability of sustained off-therapy response in HBeAg+ individuals, as well as in some HBeAg- individuals. Long-term therapy with nucleoside/nucleotide analogues, both in HBeAg+ and HBeAg- CHB, has most favourable effects on patient outcome, provided that virological and biochemical remission is maintained without development of viral resistance. The best results are achievable with potent analogues suppressing serum hepatitis B virus (HBV) DNA to non-detectability by most sensitive techniques. The best 2-year resistance profile has hitherto been reported with entecavir monotherapy, and the best long-term resistance profile was seen with adefovir of 5-year duration. Adefovir is effective in most lamivudine (LAM)-resistant patients, but should be administered as an add-on rather than as a substitute for LAM. Combination therapies have entered the treatment arena of CHB by the side doors of LAM-resistance and of end-stage liver disease, and the most recent results suggest that treatment with combinations of two strong nucleosides/nucleotides with different resistance profiles may turn out to be the optimal first-line/first choice option in CHB.

Topics: Adenine; Animals; Antiviral Agents; Clinical Trials as Topic; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Organophosphonates; Patient Selection; Polyethylene Glycols; Recombinant Proteins

Coinfections with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are common globally. HIV infection modifies the course of HBV infection by increasing rates of chronicity, prolonging HBV viremia, and increasing liver-related morbidity. To minimize the emergence of HIV and/or HBV resistance, as well as the emergence of liver enzyme flares, the treatment of both infections should be coordinated. Lamivudine or emtricitabine monotherapy readily selects resistant strains in the YMDD motif of the polymerase gene. Adefovir and tenofovir are fully active in the presence of YMDD mutations [corrected] If HBV treatment can be deferred until combination antiretroviral therapy for HIV infection is needed, the combination of tenofovir plus lamivudine or emtricitabine provides potent HBV therapy and a solid backbone for HIV combination antiretroviral therapy, and it likely decreases the emergence of HBV resistance.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Antiviral Agents; Deoxycytidine; Drug Combinations; Emtricitabine; Guanine; Hepatitis B; Hepatitis B virus; HIV Infections; HIV-1; Humans; Lamivudine; Organophosphonates; Preventive Medicine; Tenofovir

In the last years there was a continuous improvement in the therapy of hepatitis B virus infection. Meanwhile different therapeutic options are available. Therefore the indication for the different treatment options can be chosen dependent on clinical, biochemical, virological and histological parameters. Therapy with interferon alpha or PEG-interferon alpha should be started if positive prognostic parameters and lack of contraindications are present in a patient. Especially therapy with PEG-interferon alpha in recent studies showed good response rates. As an alternative nucleosides/nucleotides like lamivudine, adefovir or entecavir are available. During lamivudine therapy there is an increased risk for the selection of resistant strains, while the selection of resistant strains is less frequent during the medication of adefovir or entecavir. However at present the end of treatment for all nucleosides/nucleotides--especially in HBeAg negative patients--is not clearly defined. In patients with liver cirrhosis (Child B and C) only nucleos(t)ides should be used. In the future combination therapy for the treatment of chronic HBV infection seems very attractive. However at present combination therapy is not approved yet and therefore these options should only be used in clinical studies. Especially, as it seems possible that synergistic, but also antagonistic effects may exist between different drugs.

Topics: Adenine; Antiviral Agents; Drug Antagonism; Drug Resistance, Viral; Drug Synergism; Drug Therapy, Combination; Forecasting; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Organophosphonates; Polyethylene Glycols; Prognosis; Recombinant Proteins; Reverse Transcriptase Inhibitors; Time Factors

Topics: Adenine; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferon-beta; Lamivudine; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Treatment Outcome

Hepatitis B virus (HBV)-infected health care workers (HCWs) can infect patients undergoing exposure prone procedures. Until now reviews have focused on the problem of the HBeAg-positive HCWs. After transmission of HBV by HBeAg-negative surgeons, the focus of Public Health Policy in the UK and the Netherlands has changed from HBeAg status to serum HBV DNA level. Viral load and the volume of blood transmitted determine the transmission risk of HBV. We have estimated the number of infectious particles transmitted by needlesticks, in comparison with those attributed in maternal-fetal transfusion. The blood volume transmitted by needlestick is roughly 1-30% of that of delivery. As vertical transmission with maternal HBV DNA levels below 10(7) g Eq./ml is rarely documented, HBV transmission by needlesticks is, according to our assumptions, unlikely to occur with HBV DNA levels below 10(7) g Eq./ml. Sera of transmitting HCWs contained HBV DNA levels between 5.0 x 10(9) and 6.35 x 10(4) g Eq./ml. Interpretation of these levels is hampered as the sera were taken at least 3 months after transmission. To prevent both loss of expertise and nosocomial infection, highly viremic HCWs can be offered antiviral therapy. Lamivudine and alpha-interferon can now be complemented with adefovir, tenofovir and entecavir to provide effective new therapies for chronic HBV-infected HCWs.

Topics: Adenine; Antiviral Agents; DNA, Viral; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; Humans; Infectious Disease Transmission, Professional-to-Patient; Interferon-alpha; Lamivudine; Organophosphonates; Organophosphorus Compounds; Physicians; Risk Factors; Risk Management; Tenofovir; Viral Load

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Deoxycytidine; Emtricitabine; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Nucleosides; Organophosphonates

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Deoxycytidine; Emtricitabine; Guanine; Hepatitis B; Humans; Lamivudine; Organophosphonates

Hepatitis B virus replicates inside the hepatocyte through an intermediate step of reverse transcription mediated by the viral polymerase. We describe five nucleoside/nucleotide analogues that interfere with the replication mechanisms of the hepatitis B virus. The resemblance of nucleoside analogues to natural nucleosides may lead to direct cytotoxicity. Therefore, antiviral activity should always be interpreted in the light of cellular toxicity. In addition, prolonged therapy with a nucleoside analogue may induce mutations in the viral polymerase, causing structural and configurational changes of the polymerase resulting in a decreased affinity for the nucleoside analogue. Subsequently, the mutated virus is capable of renewed replication during continued antiviral pressure of the nucleoside analogue. The best antiviral strategy in the future is probably combination therapy, either with several nucleoside analogues or with a nucleoside analogue and interferon.

Topics: 2-Aminopurine; Adenine; Antiviral Agents; Famciclovir; Ganciclovir; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors

Our study purpose was to evaluate mitochondrial (mt)DNA and RNA in peripheral blood mononuclear cells (PBMCs) and body shape changes (BSC) in HBV-infected patients. mtDNA and mtRNA were measured in PBMCs. The presence of BSC was evaluated through a questionnaire and clinical evaluation. A total of 157 subjects were enrolled, of these 107 were HBV-infected patients, 54 receiving nucleoside analogues (NAs, Group A), 53 naive to antivirals (Group B) and 50 age-sex matched controls (Group C). All HBV-treated patients had negative HBV-DNA. Twenty (37,0%) received lamivudine + adefovir, 20 (37.0%) tenofovir, 2 (3.7%) lamivudine and 12 (22.2%) entecavir. Therapy median duration was 38 months (IQR 20-60) in NA-treated patients. Group A showed significantly higher mtDNA/nuclear (n) DNA ratio (p = 0.000008) compared to Group C and Group B (p = 0.002). Group B showed significantly higher mtDNA/nDNA ratio compared to Group C (p = 0.017). Group A and B had significantly lower mtRNA/nRNA ratio compared to Group C (p = 0.00003 and p = 0.00006, respectively). Tenofovir and entecavir showed less impact compared to lamivudine + adefovir. mtDNA/nDNA ratio positively (Rho = 0.34, p < 0.05) and mtRNA/nRNA ratio negatively (Rho = -0.34, p < 0.05) correlated with therapy duration. BSC were significantly more frequent in Group A [10/54 (18.5%)] compared to Group B [3/53 (5.6%, p = 0.04)] and Group C [0/50, (p = 0.0009)]. In conclusion, long-term NA therapy was associated both to mitochondrial toxicity and BSC, showing significant differences in mtDNA and mtRNA levels. Tenofovir and entecavir showed lower impact on alterations, compared to 1

Topics: Adenine; Adiposity; Antiviral Agents; Cross-Sectional Studies; DNA, Mitochondrial; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Organophosphonates; RNA, Mitochondrial; Tenofovir

Suboptimal responses to lamivudine or telbivudine plus adefovir (LAM/LdT+ADV) rescue therapy are common in patients with LAM-resistant hepatitis B virus (HBV) infections. We compared patients switched to entecavir plus tenofovir (ETV+TDF) to those maintained on LAM/LdT+ADV.. This prospective randomized controlled trial examined 91 patients whose serum HBV DNA levels were greater than 60 IU/mL after at least 24 weeks of treatment with LAM/LdT+ADV for LAM-resistant HBV. Patients were randomized to receive a new treatment (ETV+TDF, n=45) or maintained on the same treatment (LAM/LdT+ADV, n=46) for 48 weeks. Patients with baseline ADV resistance were excluded.. Compared to LAM/LdT+ADV group, ETV+TDF group had more patients with a virologic response (42/45 [93.33%] vs. 3/46 [6.52%], P<0.001) and had a greater mean reduction in serum HBV DNA level from baseline (-4.16 vs. -0.37 log10 IU/mL, P<0.001). Multivariate analysis indicated that high baseline HBV DNA level (P=0.005) and LAM/LdT+ADV maintenance therapy (P=0.001) were negatively associated with virologic response. At week 48, additional ADV- or ETV-associated mutations were cleared in ETV+TDF group, but such mutations were present in 4.3% of patients in LAM/LdT+ADV group (P=0.106). The two groups had similar rates of adverse events.. ETV+TDF combination treatment led to a significantly higher rate of virologic response compared to LAM/LdT+ADV combination treatment in patients with LAM-resistant HBV who had suboptimal responses to LAM/LdT+ADV regardless of HBV genotypic resistance profile (NCT01597934).

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Prospective Studies; Sustained Virologic Response; Telbivudine; Tenofovir

Efficacy of sequential therapy with nucleos(t)ide analogues and interferons versus monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remains unexplored. We aimed to assess efficacy and safety of sequential therapy with adefovir (ADV) or entecavir (ETV) followed by peginterferon (PEG-IFN) alfa-2a in Taiwanese patients with HBeAg-positive.. This randomized, placebo-controlled, double-blind trial was conducted at nine sites in Taiwan from April 2010 to October 2013. Patients (N = 280) were randomized 1:1:1 to receive placebo, ETV or ADV alone for four weeks, combined with PEG-IFN alfa-2a for two weeks, then PEG-IFN alfa-2a alone for 46 weeks. The primary efficacy end point was HBeAg seroconversion at 48 weeks post-treatment.. No significant differences were observed among groups for HBeAg seroconversion (PEG-IFN alfa-2a+placebo, 36.3%; PEG-IFN alfa-2a+ETV, 29.5%; and PEG-IFN alfa-2a+ADV, 27.4%), HBeAg loss (37.4%, 32.2%, and 28.6%, respectively) or change in hepatitis B surface antigen (HBsAg) levels from baseline (-0.56 IU/mL, -0.60 IU/mL, and -0.41 IU/mL, respectively). However, hepatitis B virus DNA levels were higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa+ETV at week 64 (p = 0.0412), 76 (p = 0.0311), and 88 (p = 0.0113), and alanine aminotransferase (ALT) normalization rate was higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa-2a+ADV (p = 0.0283) or PEG-IFN alfa-2a+ETV (p = 0.0369) at week 88. Sub-analysis of results revealed an association between on-treatment HBsAg and ALT levels and efficacy 48 weeks post-treatment. Safety was comparable among treatment groups.. Pre-therapy with ADV or ETV followed by PEG-IFN alfa-2a is not superior to PEG-IFN alfa-2a monotherapy in Taiwanese patients with HBeAg-positive CHB.. NCT: 00922207.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; DNA, Viral; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Taiwan

Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV.. In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1 mg/day) combination therapy (TDF/ETV, n=52) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks.. Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (-3.03 log10 IU/mL vs -3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96 weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups.. In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96 weeks.. NCT01639066.

Topics: Adenine; Adult; Aged; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Republic of Korea; Tenofovir; Treatment Outcome

Treatment of patients with chronic hepatitis B (CHB) with nucleos(t)ide analogues (NAs) suppresses hepatitis B virus (HBV) DNA production but does not affect the synthesis of the RNA pregenome or HBV messenger RNA. Whether HBV RNA-containing particles continue to be secreted into the bloodstream remains controversial.. We developed a sensitive polymerase chain reaction (PCR) assay to quantify the HBV RNA load in a supernatant of NA-treated HepG2-2.2.15 cells and in plasma specimens from 20 patients with CHB who were receiving NA therapy and 86 patients treated with pegylated interferon alfa (Peg-IFN) and adefovir.. Treatment of HepG2-2.2.15 cells with NAs for 9 days reduced HBV DNA levels (by 1.98 log10 copies/mL), whereas HBV RNA levels increased (by 0.47 log10 copies/mL; P < .05). During long-term NA treatment of patients with CHB, HBV RNA levels remained higher than HBV DNA levels. Peg-IFN-based treatment induced a stronger decrease in the HBV RNA load than NA monotherapy, and this decline was more pronounced in responders than in nonresponders. In HBV e antigen-negative patients, a lower baseline plasma HBV RNA level was independently associated with response to Peg-IFN and adefovir (odds ratio, 0.44; P = .019). Immunoprecipitation with HBV core antigen-specific antibodies after removal of the HBV surface antigen envelope demonstrated the association of plasma HBV RNA with virions.. HBV RNA is present in virions in plasma specimens from patients with CHB. HBV RNA levels vary significantly from those of established viral markers during antiviral treatment, which highlights its potential as an independent marker in the evaluation of patients with CHB.

Topics: Adenine; Adult; Amantadine; Antiviral Agents; Biomarkers; DNA, Viral; Drug Therapy, Combination; Female; Guanine; Hep G2 Cells; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Reproducibility of Results; RNA, Viral; Tenofovir; Virion

Entecavir (ETV) added to adefovir (ADV) is recommended in the consensus for management of patients with ADV resistance. However, little attention has been focused on the delayed reduction of HBV DNA and dynamics of ADV-resistant variants during ADV-ETV combination rescue therapy in the clinical setting. We characterized the dynamics of viral load and resistant variants in nucleos(t)ide analogues (NAs)-naïve chronic hepatitis B (CHB) patients during antiviral treatment with ADV monotherapy followed by ADV-ETV combination therapy.. A cohort of 55 CHB patients was enrolled in this study. Three NAs-naïve patients developed ADV-resistant variants during 24-33 months of ADV monotherapy, and then switched to ADV-ETV combination therapy. Thirty-five serial serum samples from these three patients were regularly collected during treatment. Ten mutants associated with commonly used antiviral drugs were detected by pyrosequencing.. HBV DNA decreased to the lowest level during ADV monotherapy at 6-18 months, with a decrease of 0.95-5.51 log10 copies/mL, whereas rtA181V or rtN236T gradually increased with extended therapy. HBV DNA decreased to below the detectable level during ADV-ETV combination therapy at 21-24 months, with a decrease of 4.19-4.65 log10 copies/mL. Resistant rtA181V and rtN236T were undetectable after 21-24 months of combination therapy. Moreover, no LAM-resistant rtM204I/V or ETV-resistant variants were detected during the 27-36 months of combination therapy.. Although ADV-resistant variants were suppressed, viral load reduction was delayed during ADV-ETV combination rescue therapy in patients with ADV-resistant HBV. The quantification of resistant variants by pyrosequencing may facilitate monitoring of antiviral therapy.

Topics: Adenine; Adult; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Mutation; Organophosphonates; Treatment Outcome; Viral Load; Young Adult

To evaluate the efficacy and safety of 4 treatment options for HBeAg-positive chronic hepatitis B (CHB) patients following a suboptimal response to 24-week interferon monotherapy.. The data of 193 HBeAg-positive CHB patients with suboptimal response to 24-week interferon monotherapy were collected from Nanfang Hospital between September, 2010 and January, 2013. According to the subsequent treatments, the patients were divided into group A with additional entecavir or adefovir, group B with further interferon monotherapy, group C with conversion to NAs therapy, and group D with direct therapy withdrawal, and the biochemical and virological results at weeks 24, 48 and 72 were analyzed in the 4 groups.. At week 48, the HBV DNA negative rates and serum alanine aminotransferase (ALT) normalization rates were both significantly higher in group A and C than in group B (P<0.05); in group A, ETV therapy subgroup had a significantly higher HBV DNA negative rate than ADV therapy subgroup at week 48 (90.3% vs 59.5%, Χ=8.255, P=0.004). At week 72, 39.7%(27/68) of the patients in group A achieved HBeAg seroconversion, a rate significantly higher than those in groups B (Χ=4.238, P=0.040) and C (Χ=7.681, P=0.006); the HBV DNA negative rate and ALT normalization rate in group A were 85.3%(58/68) and 86.8%(59/68), respectively, both significantly higher than those in group B (Χ=23.018, P<0.001; Χ=5.987, P=0.014) but comparable to those in group C (P>0.05). In the two subgroups in group A, the HBV DNA negative rate and HBeAg seroconversion rate were both significantly higher in ETV subgroup (Χ=9.823, P=0.002; Χ=5.450, P=0.020). In group D, all the patients remained HBeAg-positive with abnormal ALT levels and high level of HBV DNA.. For HBeAg-positive CHB patients with suboptimal response to 24-week interferon monotherapy, combined treatment with NAs (especially ETV) and extension of the treatment course can significantly improve the HBeAg seroconversion rates, HBV DNA negative rates, and ALT normalization rates.

Topics: Adenine; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferons; Organophosphonates

To compare the efficacies ofentecavir and adefovir in patients with chronic hepatitis B (CHB) and cirrhosis when administered as monotherapies using a 240-week course.. Ninety patients diagnosed with CHB and cirrhosis (compensated or decompensated) were randomly divided into two treatment groups for administration of either entecavir (0.5 mg/day, oral; n =38) or adefovir (10 mg/day, oral; n =52) for 240 weeks. All participants underwent B-ultrasound and were tested for levels of HBV-DNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, creatinine, alpha-fetoprotein (AFP) and various serological markers of the hepatitis B virus at baseline and at treatment weeks 24, 48, 96, 144, 192, and 240. Instances of drug-related complications and adverse reactions were recorded. Patients who did not achieve complete virological response by treatment week 48 or who experienced virological breakthrough at any time during the study course were recorded and started on an appropriate combination therapy regimen. Statistical analyses were carried out using the t-test, chi-square test, and Cox regression modeling.. The dropout rate in the entecavir group was 2.6% and in the adefovir group was 13.5%. At treatment week 240, significantly more patients in the entecavir group had undetectable serum HBV-DNA (91.9% vs. adefovir group: 57.8%; x2=10.362, P=0.001), a negative conversion rate of hepatitis B e antigen (HBeAg) (46.2% vs. adefovir group: 24%; x2=5.055, P=0.025), and rate of HBeAg seroconversion (23.1% vs. adefovir group: 8%, P=0.047).The entecavir group and the adefovir group showed no significant differences upon per-protocol analysis and intention-to-treat analysis, nor in the rates of hepatocellular carcinoma development (entecavir group: 8.1% vs. adefovir group: 6.7%; x2=0.000, P=1.000) or mortality (entecavir group: 8.1% vs. adefovir group: 4.4%; x2=0.051, P=0.821). The possibility of achieving undetectable serum HBV-DNA was 2.761 times higher in the entecavir group than in the adefovir group (95.0% CI: 1.630 to 4.679). The possibility of HBeAg seroconversion was 0.192 times higher for males than for females (95.0% CI: 0.046 to 0.806).. Compared to adefovir, entecavir provides high efficiency and rapid viral suppression as a monotherapy for CHB patients when administered in a 240-week course.

Topics: Adenine; Aged; Alanine Transaminase; alpha-Fetoproteins; Antiviral Agents; Aspartate Aminotransferases; Biomarkers; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Organophosphonates; Time Factors

A 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple-drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine-resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group; P = 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (-2.8 log10 IU/ml and -2.8 log10 IU/ml, respectively; P = 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P = 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01023217.).

Topics: Adenine; Adolescent; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Treatment Outcome; Viral Load; Young Adult

The aim of this study was to prospectively evaluate whether the addition of peg-IFN to a stable NA regimen leads to loss of HBsAg in HBeAg-negative patients with chronic hepatitis and HBV DNA fully suppressed by long-term NA treatment.. We analyzed HBsAg levels in 10 HBsAg-positive, HBeAg-negative patients who received peg-IFN alpha-2a in addition to a NA regimen. Treatment lasted a maximum of 96 weeks, according to changes in the HBsAg titer. Before peg-IFN therapy, HBV DNA levels had been below the limit of detection for at least three years.. HBsAg levels declined in nine patients. Among these nine, four became HBsAg-negative after 48 weeks of peg-IFN treatment; these patients received peg-IFN for only 48 weeks. NAs were stopped in these four patients, and these levels remained stable for at least 18 months (loss of HBsAg; HBV-DNA negative). HBs seroconversion was observed in two patients. The remaining five patients received 96 weeks of peg-IFN therapy. One patient became HBsAg-negative at the end of peg-IFN therapy; another became HBsAg-negative six months later. Three patients did not become HBsAg-negative. NAs were stopped in the two patients who became HBsAg-negative with no relapse during 12 months of follow up.. In HBsAg-positive, HBeAg-negative patients with HBV DNA were fully suppressed by long-term NA treatment, the addition of peg-INF for a maximum of 96 weeks based on HBsAg-titer monitoring led to a loss of HBsAg and cessation of NA therapy in six out of ten patients, with no relapse for 12-18 months of follow up. HBs seroconversion was observed in two patients.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Organophosphonates; Polyethylene Glycols; Prospective Studies; Recombinant Proteins

This longitudinal non-interventional study aims to describe the demographics data disease characteristics and clinical management of a cross-sectional CHB patient population in Poland treated in regional medical centers.. [corrected] Between March 2008 and December 2010 we observed patients with HBV related liver disease from 5 medical centers in Poland, both sexes, > 18 years old. At baseline, we used a case report form to extract data from patient charts, comprising: sociodemographic data; disease characteristics, HBeAg/ antiHBeAg status, genotype HBV; co-morbidities; viral load, liver biopsy and ALT levels in previous 12 months; treatment history in previous 12 months; current CHB treatment; changes in disease characteristics and CHB management; time from diagnosis to the therapy and resource utilization and any reasons for termination of follow-up. Written informed consent was obtained from all participants. The analysis population included 253 patients (94 treated and 159 non-treated at baseline) mostly male (69.1 vs. 56.6). Patients in treated group compared with untreated group were: significantly older (mean 42.6 vs. 37.5 years respectively, p < 0.001), observed longer since diagnosis(3.9 vs.2.9 years), with higher rate of HBeAg(+)(42.6% vs.5.1%), lower ALT activity, and higher VL HBV DNA PCR. Of the 53% of treated patients, the most frequently prescribed anti-HBV drugs were: Lamivudine (53%), Entecavir (23.7%), Pegylated IFN-alfa2a (23.7%), Adefovir (11.1%). During 24 months of follow-up in treated group 13(36.1%) patients underwent a treatment switch to another nucleosi(-ti)de analogue, in one (2.8%) patient another analogue was added, and in 25 (69.4%)patients the therapy was stopped. The proportion of all patients treated with monotherapy at the end of follow-up was 99.4%, unfortunately mostly with Lamivudine-49.3%.. 1. Despite the several methodological limitations usually associated with this type of observation, the collected data does characterize the demographics of polish patients chronically infected with HBV well, provides some insights into the determinants of treatment initiation and the clinical management of patients in real-word settings. 2. These results indicate that in clinical practice in 5 medical non-academic centers in Poland, European guidelines regarding the qualification to HBV treatment were followed, but there were discrepancies between the initial treatment decisions in real-life current clinical practice and guideline recommendations

Topics: Adenine; Adult; Antiviral Agents; Cohort Studies; Europe; Female; Guanine; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Longitudinal Studies; Male; Middle Aged; Organophosphonates; Poland; Practice Guidelines as Topic; Retrospective Studies; Socioeconomic Factors; Treatment Outcome

Clonal analysis of quasispecies of resistant HBV genomes in patients with entecavir (ETV) resistance receiving lamivudine (3TC) plus adefovir (ADV) rescue therapy has never been performed.. A sample of 10 patients with ETV resistance who were switched to 3TC+ADV treatment were analysed for changes in viral quasispecies. Serum samples at baseline, and at months 3 and 6 of 3TC+ADV treatment could be clonally analysed in 7 of 10 patients; 3-82 clones per sample (total 1,068 clones, mean 63) were sequenced.. 3TC+ADV therapy led to a modest decline in HBV DNA. Almost all clones had L180M and M204V 3TC resistance mutations before and during combination therapy. All clones had ≥1 of the S202G, T184F, T184A, T184L, T184I and M250V ETV resistance mutations. The percentages of detected clones bearing 3TC (rtL180M and rtM204V) and ETV mutations did not change with rescue 3TC+ADV therapy. In 7 of 8 patients with detectable HBV DNA (median 5.17 log(10) copies/ml) after a median 24 months of ADV therapy, HBV DNA became undetectable with 3TC plus tenofovir after 6 months of treatment.. In patients with ETV resistance tenofovir is effective. Clonal analysis data indicate no selection of specific HBV mutants during rescue 3TC+ADV.

Topics: Adenine; Adult; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genome, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Tenofovir; Treatment Outcome; Young Adult

Management of lamivudine-resistant chronic hepatitis B (CHB) remains challenging, as inappropriate choice of treatment may cause multidrug resistance. Until now, randomized trials directly comparing adding adefovir and switching to entecavir monotherapy have not been reported.. This multicentre prospective randomized study was designed to compare the efficacy of these two strategies.. Two hundred and nineteen lamivudine-resistant CHB patients were randomized to either adefovir-lamivudine combination group or entecavir monotherapy group (n = 110 vs. 109), and followed up for 24 months.. One hundred and eighty patients completed this study. At month 24, virological response rate [hepatitis B virus (HBV) DNA <60 IU/ml] was higher in the adefovir-lamivudine combination group compared with entecavir group (56.7% vs. 40%, P = 0.025), although biochemical and serological response rates were not significantly different. Genotypic resistance (9.2% vs. 24.6%, P = 0.005) and combined viral breakthrough (2.0% vs. 17.6%, P < 0.001) were more frequent in the entecavir group. However, by subgroup analysis, virological response rates were not significantly different between the two therapies in HBeAg-positive patients (44.9% vs. 35.7%, P = 0.268) or in patients with high baseline HBV DNA (≥7 log IU/ml) (40.7% vs. 31.3%, P = 0.320) at month 24.. This study showed that adefovir-lamivudine combination provides significantly higher antiviral efficacy and the lower resistance rate compared with the entecavir monotherapy in the management of lamivudine-resistant CHB. However, it had limited efficacy in HBeAg-positive patients or in patients with high baseline HBV DNA.

Topics: Adenine; Adult; Analysis of Variance; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B; Hepatitis B, Chronic; Humans; Immunoassay; Lamivudine; Male; Middle Aged; Oligonucleotides; Organophosphonates; Prospective Studies; Republic of Korea; Reverse Transcriptase Inhibitors; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Treatment Outcome

In this study, we aimed to devise a simple scoring system predicting the risk of genotypic resistance (GR) to current rescue therapies for patients with lamivudine (LAM)-resistant chronic hepatitis B.. LAM and adefovir (ADV) combination therapy should be recommended for an initial rescue therapy against LAM-resistant hepatitis B virus (HBV). However, there still are many LAM-resistant patients being treated with entecavir (ETV) or ADV monotherapy.. This retrospective cohort study included consecutive patients treated for LAM-resistant chronic hepatitis B with ETV or ADV monotherapy, or LAM/ADV combination therapy. The cumulative probabilities of GR and virological responses and breakthrough according to clinical variables were analyzed by survival analyses and derived an index for future GR.. A total of 224 patients were included (median treatment duration=117.9 wk). Using risk factors indentified on multivariable analyses, a simple index for future GR (Antiviral Resistance Prediction Index, ARPI) was developed with 3 clinical variables: the rescue therapy regimens (+0, ADV; +1, ETV; +2, LAM/ADV), HBV DNA reduction at 12 weeks (+0, <3 log10 copies/mL; +1, >3 log10 copies/mL), and the initial HBV DNA level (+0, >10 copies/mL; +1, <10 copies/mL). No patient with ARPI ≥2 exhibited GR, whereas 47% of the patients with an ARPI <2 developed GR by week 144 (P=0.005).. The results of this study suggest that the ARPI is a simple and early index that can be used to determine the risk for subsequent GR during rescue therapy for LAM-resistant chronic hepatitis B.

Topics: Adenine; Adult; Aged; Antiviral Agents; Cohort Studies; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Predictive Value of Tests; Retrospective Studies; Survival Analysis; Treatment Outcome; Young Adult

Here, we investigated the treatment response and evolution of HBV resistance during lamivudine (LAM) plus adefovir (ADV) and entecavir (ETV) monotherapy in patients with ADV-resistant mutants.. Of the 53 patients with ADV-resistant mutants, 25 received combined LAM plus ADV therapy (LAM+ADV group) and 28 received ETV monotherapy (ETV group) for at least 12 months (median 24 months and range 12-67 months).. During 24 months therapy, no significant difference was noted in HBV DNA reduction from baseline, HBV DNA<200 copies/ml, hepatitis B e antigen loss and ALT normalization between the two groups. In the LAM+ADV group, patients with single rtN236T resistant mutation had higher rates of undetectable HBV DNA than those with the double mutant rtA181T/V+rtN236T at months 3-18 of therapy. No virological breakthrough occurred except for one patient with rtN236T resistant mutation who experienced virological and biochemical breakthrough after the emergence of an additional rtA181T mutant under LAM+ADV therapy. Of the 28 patients receiving ETV monotherapy, ETV-resistant mutants developed in 8. The cumulative rates of ETV-resistant mutations and virological breakthrough at months 12, 24 and 36 were 3.6%, 25.7% and 46.8%, respectively. ADV-resistant mutations were rapidly replaced by LAM-resistant mutations (median 12 months) followed by ETV-resistant mutations.. There was no significant difference in virological response between the LAM+ADV and ETV groups in patients with ADV-resistant mutants. LAM+ADV were less effective in patients with the double mutant rtA181T/V+rtN236T than the single rtN236T mutation. The incidence of ETV-resistant mutation was high in patients with LAM/ADV-resistant mutants treated with ETV monotherapy.

Topics: Adenine; Adult; Aged; Antiviral Agents; Base Sequence; Cloning, Molecular; DNA, Viral; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates

A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudine-resistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV+ADV, n = 45) or continuation of lamivudine plus adefovir (LAM+ADV, n = 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log(10) IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV+ADV group than in the LAM+ADV group (n = 13, 29%, versus n = 2, 4%, respectively; P = 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV+ADV group than in the LAM+ADV group (-2.2 log(10) IU/ml versus -0.6 log(10) IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV+ADV group but in 15% of patients in the LAM+ADV group (P = 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.

Topics: Adenine; Adolescent; Adult; Aged; Antiviral Agents; Drug Resistance, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Young Adult

We aimed to compare the cumulative efficacy and resistance of ADV monotherapy, ADV add-on LAM (ADV + LAM), ADV and ETV (ADV + ETV) combination therapy in LAM-resistant patients.. Ninety-one adult CHB patients with LAM-resistance mutations (YMDD) were identified. Of these 91, 29 patients were treated with ADV monotherapy, 30 were treated with ADV + LAM and 32 were treated with ADV + ETV combination therapy, for at least 24 months.. The mean serum HBV-DNA decreases from baseline at 3, 6, 12, and 24 months were -3.23, -4.41, -5.32, and -5.58 log(10) IU/mL in the ADV + ETV combination therapy groups, respectively; the most significant among the three treatment groups (p<0.01). The rate of HBV-DNA PCR undetectability (<60 IU/mL) at 6 months in ADV + ETV combination therapy was 78.1%; also the most significant among the three treatment groups (p=0.024). Viral breakthrough and genotypic mutations were detected in 8 (27.6%) and 4 (13.3%) patients in the ADV monotherapy and ADV+LAM therapy groups, respectively; whereas no case of viral breakthrough and genotypic resistance was detected in the ADV+ETV combination therapy group after 24 months (p<0.05).. ADV + ETV combination therapy demonstrated faster and significantly greater suppression of HBV DNA compared with ADV add-on LAM combination therapy for patients with LAM-resistance mutations. ADV + ETV was superior to ADV + LAM in achieving initial virological response and long-term suppression activity against HBV. ADV + ETV combination therapy was the most effective to refrain from selecting HBV strains with cross-resistance to three NAs (LAM, ADV and ETV) for LAM-resistance patients.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Time Factors

A randomized, open-label comparative study of entecavir versus adefovir therapy was performed in subjects with chronic hepatitis B who had hepatic decompensation (Child-Turcotte-Pugh score ≥7). Adult subjects were randomized and treated (n = 191) with entecavir 1.0 mg or adefovir 10 mg daily for up to 96 weeks from the date of last subject randomization. Subjects were positive or negative for hepatitis B e antigen and experienced or naive for treatment with nucleos(t)ide analogues. The primary efficacy endpoint was the mean reduction in serum hepatitis B virus (HBV) DNA, as determined by polymerase chain reaction, at week 24, adjusted for baseline HBV DNA and lamivudine resistance status by linear regression analysis. Entecavir demonstrated superiority to adefovir for this endpoint (treatment difference 1.74 log(10) copies/mL [95% confidence interval -2.30, -1.18]; P < 0.0001). The entecavir group showed a greater change from baseline in HBV DNA at all time points through week 48 and a higher proportion of subjects who achieved HBV DNA < 300 copies/mL at weeks 24 (entecavir 49%; adefovir 16%; P < 0.0001) and 48 (entecavir 57%; adefovir 20%; P < 0.0001). Approximately two-thirds of subjects in both groups showed improvement/stabilization in Child-Turcotte-Pugh status. Model for End-Stage Liver Disease score change at week 48 was -2.6 for entecavir and -1.7 for adefovir. Adverse event rates were comparable between groups. Cumulative hepatocellular carcinoma rates were 12% for entecavir and 20% for adefovir. Cumulative death rates were 23% for entecavir and 33% for adefovir. Week 24 mortality rates were 12% for both groups. conclusion: Entecavir demonstrated superior virologic efficacy to adefovir in a population of patients with chronic hepatitis B who had hepatic decompensation. Biochemical and clinical benefits were also demonstrated. Entecavir was well tolerated, and early mortality rates were consistent with rates observed in similar populations treated with lamivudine.

Topics: Adenine; Antiviral Agents; DNA, Viral; Dose-Response Relationship, Drug; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Failure; Male; Middle Aged; Organophosphonates; Survival Rate; Treatment Outcome

To evaluate the safety and efficacy of the combined therapy with entecavir (ETV) and adefovir (ADV) in patients with chronic hepatitis B (CHB) who experienced failure of treatment with single or multiple nucleoside analogs, and analyze the factors that affect the patients response to the treatment.. Forty-five CHB patients who experienced treatment failure with sequential or/and combined nucleoside analogs received the combined therapy with entecavir and adefovir lasting for at least 6 months. The viroloigcal response (VR), biochemical response (BR) and combined response (CR) at 24 and 48 weeks of the treatment were evaluated. Univairante analysis was used to identify the factors that affect the response to the anti-viral therapy.. The VR, BR and CR were 67.7%, 77.8% and 57.8% at 24 weeks, as compared to 76.2%, 78.6% and 61.9% at 48 weeks, respectively. The VR differed significantly between patients with a baseline HBV DNA level [lg(copies/ml)] of 3-6 and those with a level over 6 (85.2% vs 40%, Z=-4.796, P=0.037) at 48 weeks. The presence and absence of cirrhosis at the initial treatment significantly affected the BR at 24 weeks (17.1% vs 82.9%, P=0.048) and at 48 weeks (23.8% vs 76.2%, P=0.023).. Entecavir combined with adefovir is an effective rescue therapy in CHB patients after failure of treatment with nucleoside analogs. Patients with a lower baseline HBV DNA level without cirrhosis may have better response to the combined treatment.

Topics: Adenine; Adult; Antiviral Agents; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Organophosphonates; Treatment Failure

To observe the therapeutic effect and safety of entecavir and adefovir in the treatment of lamivudine-resistant HBeAg-negative chronic hepatitis B.. Sixty-five patients with lamivudine-resistant HBeAg-negative chronic hepatitis B were randomly divided into two groups. The entecavir treatment group included 33 patients, who were administrated entecavir 1.0 mg/d. The adefovir treatment group included 32 patients, who were administrated adefovir dipivoxil 10 mg/d. Changes in serum HBV DNA, liver functions, phosphocreatine kinase, creatinine and adverse reaction were dynamically monitored.. At the end of the 12th, 24th, 48th week of treatment, the rates of serum ALT normalization of the entecavir treatment group were higher than that of the adefovir treatment group, but there wasn't statistically difference between two groups until the end of the 48 th week of treatment (P > 0.05). The rate of sera to turn negative for HBV DNA of the entecavir treatment group was significantly higher than that of the adefovir treatment group at the end of the 12th week. Moreover, the difference was statistically significant (P<0.05).. Both entecavir and adefovir dipivoxil might have a good response to lamivudine-resistant HBeAg-negative chronical hepatitis B. Entecavir could achieve better therapeutic effects.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Drug Resistance, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Treatment Outcome; Young Adult

To evaluate antiviral effects of Peg-IFNa-2a in patients with chronic hepatitis B.. 92 chronic hepatitis B patients were enrolled to receive the treatment with Peg-IFNa-2a 180 μg subcutaneous injection once weekly. The patients who did not get early response were divided into 3 groups: group 1, extend the treatment to 72 weeks; group 2, combined with nucleus(s)ide analogue (entecavir or adefovir) treatment; group 3, continue the treatment until 48 weeks. HBV DNA and quantitative HBsAg were assessed at baseline, week 12, 24, 36 and after 24 weeks follow-up.. Patients in group 1 had significantly higher SVR rate (78.3%) than patients in group 3 (38.1%, X2=7.33, P<0.05). The mean reduction of HBsAg in group 1 at 24 weeks of post-treatment follow up was higher than that in group 3 (t=2.11, P<0.05). In group 2 the mean reductions of HBV DNA at 24 weeks of post-treatment follow up were (3.9+/-1.1) log10 copy/ml and (3.7+/-1.3) log10 copy/ml respectively with combination of entecavir or adefovir, both of which were significantly higher than that in group 3(t=8.45 and 6.31, P<0.05); the SVR rates in the entecavir group and the adefovir group (83.3% and 85.7%, respectively) were significantly higher than that in group 3 (X2=8.20 and 7.78, P<0.05); the mean reductions of HBsAg in the entecavir group and the adefovir group [(0.8+/-0.5) log10 IU/ml and (0.9+/-0.3) log10 IU/ml, respectively ] were significantly greater than group 3[(0.4+/-0.3) log10 IU/ml, t=3.05 and 4.58, P<0.05]. The level of HBV DNA and C genotype were the main predictors of response.. Individualizing therapy by prolonging the duration of Peg-IFNa-2a treatment to 72 weeks or adding nucleoside analogues such as entecavir and adefovir in patients without early response may substantially increase the SVR rate and lead to the decrease of HBsAg.

Topics: Adenine; Adult; Antiviral Agents; Female; Guanine; Hepatitis B, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Organophosphonates; Treatment Outcome

To evaluate the efficacy of entecavir (ETV) 1.0 mg/d or ETV plus adefovir dipivoxil (ADV) in adults with chronic hepatitis B virus (HBV) infection who had previously resisted lamivudine (LAM) and failed with rescue treatment of LAM + ADV.. 40 patients were enrolled. 14 patients were treated with ETV 1.0 mg/d monotherapy while 26 patients were treated with ETV 1.0 mg/d + ADV 10 mg/d. The HBV DNA level, liver function, HBV serology and renal function were observed.. There was no statistically significant difference with baseline situation between group ETV 1.0 mg and group ETV + ADV. HBV DNA level in group ETV 1.0 mg was (5.768 ± 0.709) log10 copies/ml on baseline, and it declined to (4.712 ± 0.846) log10 copies/ml, (3.914 ± 0.996) log10 copies/ml, (3.702 ± 0.934) log10 copies/ml, (3.879 ± 0.913) log10 copies/ml and (3.855 ± 1.070) log10 copies/ml at 4, 8, 12, 24 and 48 weeks. HBV DNA level in group ETV + ADV was (5.703 ± 0.845) log10 copies/ml on baseline, and it declined to (4.476 ± 0.905) log10 copies/ml, (3.590 ± 0.884) log10 copies/ml, (2.987 ± 0.673) log10 copies/ml and (2.933 ± 0.535) log10 copies/ml at 4, 8, 12 and 24 weeks. At 24 weeks, there were 28.6% patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but there were 80.8% patients in group ETV + ADV achieved this level. Statistically significant difference existed between (x(2) = 8.469, P = 0.004 ). At 48 weeks, there were still 4 patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but patients in group ETV + ADV all achieved it. At 24 weeks, ALT levels of 42.9% patients in group ETV 1.0 mg were back to normal, but there were 92.3% patients' ALT levels back to normal in group ETV + ADV. There was statistically significant difference (x(2) = 9.337, P = 0.002). At 48 weeks, ALT levels of 57.1% patients in group ETV 1.0 mg were back to normal, but all patients' ALT levels were back to normal in group ETV + ADV. At 48 weeks, there was 1 patient with HBeAg seroconversion in group ETV 1.0 mg while there were 4 patients in group ETV + ADV.. As rescue treatment for patients with chronic hepatitis B who had previously resisted LAM and failed with treatment of LAM + ADV, ETV + ADV was more efficient than ETV 1.0 mg monotherapy, and it can achieve better virological and biochemical response.

Topics: Adenine; Adult; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Treatment Outcome

Entecavir is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B patients, but data on the efficacy in NA-experienced subjects are limited.. In a multi-center cohort study we investigated 161 chronic hepatitis B patients (34% NA-experienced) treated with entecavir monotherapy.. During a median follow-up of 11 (3-23)months, 82 (79%) of 104 NA-naïve patients achieved virologic response (VR), defined as HBV DNA <80IU/ml, and none of the patients (0%) developed genotypic entecavir-resistance. VR was demonstrated in 31 (54%) of 57 NA-experienced patients during a median follow-up of 12 (3-31)months. Patients with lamivudine-resistant mutations at the start of entecavir monotherapy had a reduced probability of achieving VR compared to lamivudine-naïve patients (HR 0.14; 95% CI 0.04-0.58; p=0.007). Antiviral efficacy was not decreased by prior treatment with lamivudine when lamivudine-resistance had never developed (HR 0.81; 95% CI 0.43-1.52; p=0.52). Prior adefovir therapy without development of adefovir-resistance (HR 0.84; 95% CI 0.43-1.64; p=0.61) and presence of adefovir-resistance (HR 0.86; 95% CI 0.27-2.71; p=0.80) did not influence antiviral response to entecavir. Switching to a tenofovir-containing treatment regimen resulted in viral load decline in patients with entecavir-resistance associated mutations.. Entecavir proved to be efficacious in NA-naïve patients. The antiviral efficacy of entecavir was not influenced by prior treatment with adefovir or presence of adefovir-resistance. Entecavir should not be used in patients with previous lamivudine-resistance, yet it may still be an option in lamivudine-experienced patients in case lamivudine-resistance never developed.

Topics: Adenine; Adult; Antiviral Agents; Drug Resistance, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Lamivudine; Male; Middle Aged; Organophosphonates; Proportional Hazards Models; Prospective Studies; Reverse Transcriptase Inhibitors; Virus Replication

To compare the efficacy of 48 week-Entecavir therapy with that of Adefovir therapy for chronic hepatitis B patients.. In this open-label study we randomly assigned 125 CHB patients to receive 0.5 mg of entecavir (n = 56) or 10mg of adefovir (n = 69) once daily for 48 weeks.. HBV DNA, ALT and HBeAg were quantified at baseline and at 0, 24, 48 weeks. At week 24 and 48, more patients in entecavir group than in adefovir group achieved undetectable serum HBV DNA level (68% vs 35%, 84% vs 49%, P < 0.05). The percentage of patients with normal ALT level in the two groups at week 48 was similar (100% vs 94%, P > 0.05). Among the HBeAg positive patients, more patients in entecavir group than in adefovir group had HBeAg loss at week 24 and 48 (23% vs 7%, 44% vs 15%, P < 0.05). The ratio of HBeAg seroconversion was similar in the two groups at week 24 (18% vs 7%, P > 0.05), but more patients in entecavir group than in adefovir group achieved HBeAg seroconversion at week 48 (33% vs 12%, P < 0.05). The retreated patients in the entecavir group had a higher chance to achieve undetectable serum HBV DNA level (79% vs 34%, P < 0.05), HBeAg loss (42% vs 17%, P > 0.05), and seroconversion (26% vs 17%, P > 0.05), than these in the adefovir group. The safety profiles and adverse event profiles were similar in the two groups.. Compared to adefovir, entecavir is more potent to suppress HBV replication.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Treatment Outcome; Young Adult

No study has reported on the comparative effect of adefovir (ADV) add-on lamivudine (LAM) versus switching to entecavir (ETV) in LAM-resistant patients with chronic hepatitis B. From October 2007 to September 2008, 92 consecutive LAM-resistant patients were enrolled (47 LAM+ADV and 45 ETV 1 mg). All patients were followed for at least 12 months. The parameters assessed included normalization of ALT, HBeAg seroconversion, undetectable HBV DNA, reduction of HBV DNA, and predictors of virologic response. In the LAM+ADV and ETV groups, the baseline DNA levels were 7.61 (5.19-9.49) and 7.10 (5.43-9.74)log(10)copies/ml, respectively. At month 12, a virologic response occurred in 18/47 (38.3%) and 11/45 (24.4%; P=0.182) patients; ALT normalization, in 39/41 (95.1%) and 36/40 (90.0%; P=0.432); HBeAg seroconversion, in 5.1% and 2.4% (P=0.606); and virologic breakthrough, in 2.1% and 11.1% (P=0.107), respectively. The mean reduction from the baseline HBV DNA level was greater in the LAM+ADV group at month 12 (3.80 ± 1.12 vs. 2.7 ± 1.32 log(10)copies/ml; P<0.001). In the multivariate analysis, the independent parameters related to a virologic response at month 12 were baseline ALT (OR=1.003, 95% CI=1.000-1.006, P=0.026) and baseline HBV DNA (OR=0.495, 95% CI=0.298-0.823, P=0.007). Compared with switching to ETV monotherapy, ADV add-on LAM therapy was more effective at reducing the viral load in patients with LAM resistance, and the baseline HBV DNA and ALT levels were independent predictors of the virologic response. However, ADV add-on therapy had limitations in patients with a higher baseline HBV DNA in LAM rescue therapy.

Topics: Adenine; Adult; Aged; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Treatment Outcome; Young Adult

This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside-naïve adults with chronic hepatitis B (CHB). Sixty-nine nucleoside-naïve CHB patients with baseline HBV DNA of 10(8) copies/mL or more were randomized 1:1 to open-label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (-6.23 log(10) copies/mL versus -4.42 log(10) copies/mL, respectively; mean difference -1.58 log(10) copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV-ADV difference estimate: -0.66 log(10) copies/mL; 95% CI [-0.30, -0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir-treated than adefovir-treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV-treated versus 15 (47%) ADV-treated patients had HBV DNA of 10(5) copies/mL or more. Both antivirals were well tolerated.. Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-naïve HBeAg-positive patients with CHB.

Topics: Adenine; Adolescent; Adult; Alanine Transaminase; Antiviral Agents; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Organophosphonates; Viral Load

Entecavir (ETV) is currently recommended as a rescue therapy purely for adefovir (ADV)-resistant chronic hepatitis B virus (HBV) infections. We evaluated the efficacy of ETV in patients who were resistant to lamivudine (LAM)/ADV sequential therapy and in those resistant to LAM monotherapy. Fifty LAM/ADV-resistant and 38 LAM-resistant patients who received ETV 1 mg/day for at least 48 weeks were enrolled. Mean baseline serum HBV DNA and alanine aminotransferase (ALT) levels were significantly lower in the LAM/ADV-resistant group, compared with the LAM-resistant group (6.90 versus 7.62 log(10) copies/mL and 102.6 versus 160.2 IU/L; both P < 0.05); hepatitis B e antigen (HBeAg) status and LAM-resistant mutation patterns were similar in the two groups. At week 48, mean reductions in HBV DNA and ALT levels were significantly less in the LAM/ADV-resistant group (-2.96 versus -4.86 log(10) copies/mL and -68.3 versus -128.9 IU/L; both P < 0.05). Achievement of undetectable HBV DNA was also less common in the LAM/ADV-resistant group (10.0% versus 34.2%; P = 0.006), although the rates of HBeAg loss and ALT normalization did not differ between the two groups. Resistance to both LAM and ADV was an independent risk factor for failure of HBV DNA negativity at week 48 (odds ratio, 0.138; P = 0.019). In both LAM/ADV-resistant and LAM-resistant groups, primary responders (> or =1 log decline in HBV DNA at week 12) achieved a significantly greater decrease in HBV DNA levels over the 48-week period, compared with primary nonresponders (-4.18 versus -0.97 and -5.37 versus -2.15 log(10) copies/mL, respectively; both P < 0.05).. The 48-week ETV treatment was less effective in LAM/ADV-resistant than in LAM-resistant patients. Continuing ETV monotherapy could be determined based on the virological response at 12 weeks in LAM/ADV-resistant patients.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Dose-Response Relationship, Drug; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Multivariate Analysis; Organophosphonates; Treatment Outcome

The efficacy of adefovir dipivoxil (ADV) or entecavir (ETV) rescue monotherapy has not been directly compared in hepatitis B e antigen (HBeAg)-positive patients with lamivudine (3TC)-resistant chronic hepatitis B (CHB). We compared the efficacy of ADV and ETV rescue monotherapy in HBeAg-positive patients with confirmed genotypic 3TC resistance.. A total of 160 HBeAg-positive patients with confirmed 3TC resistance underwent switch therapy (91 ADV and 59 ETV). Parameters assessed included alanine aminotransferase (ALT) normalization, HBeAg seroconversion, undetectable serum hepatitis B virus (HBV) DNA by PCR (lower detection limit <300 copies/ml), virological breakthrough and initial virological response (IVR) at 3 (IVR-3) and 6 (IVR-6) months.. Following 52 weeks of treatment in the ADV and ETV groups, serum HBV DNA became undetectable in 25 (27.5%) and 21 (35.6%; P=0.292) patients, ALT normalization occurred in 67/78 (85.9%) and 43/47 (91.5%; P=0.351), HBeAg seroconversion in 4 (4.4%) and 1 (1.7%; P=1.000), IVR-3 in 19 (20.9%) and 18 (30.5%), IVR-6 in 40 (44.0%) and 25 (42.4%) and virological breakthrough in 2 (2.2%) and 1 (1.7%; P=1.000) patients, respectively.. ADV and ETV revealed comparable efficacy after 52 weeks of treatment in HBeAg-positive patients with 3TC resistance. Undetectable HBV DNA in serum following 52 weeks of treatment was predictable with IVR-3 and IVR-6 in both groups.

Topics: Adenine; Adult; Aged; Antiviral Agents; Drug Resistance, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Salvage Therapy; Treatment Outcome; Young Adult

This study evaluated the effect of entecavir on the pharmacokinetics of adefovir and the effect of adefovir on the pharmacokinetics of entecavir using a fixed-sequence crossover design in healthy adult subjects. Subjects received 10 mg of adefovir once daily on days 1 to 4, 1 mg of entecavir on days 5 to 14, and 1 mg of entecavir plus 10 mg of adefovir on days 15 to 24. Pharmacokinetic assessments were performed on days 4 and 24 for adefovir and on days 14 and 24 for entecavir. The geometric mean ratios (90% confidence interval) for area under the plasma concentration-time curve in 1 dosing interval, peak plasma concentration, and 24-hour postdose plasma concentration of entecavir when coadministered with adefovir and of adefovir when coadministered with entecavir were within the prespecified 0.80 to 1.25 no-effect range. Entecavir and adefovir were well tolerated when administered in combination. Therefore, the pharmacokinetic data generated in this study indicate that entecavir and adefovir can be coadministered without the need for dosage adjustment.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; Area Under Curve; Cross-Over Studies; Drug Interactions; Female; Guanine; Humans; Male; Organophosphonates

To evaluate the cost effectiveness of treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with entecavir compared with lamivudine with adefovir salvage, based primarily on the results of a recent 2-year, randomised, multicentre, clinical trial (n = 709). Previous economic analyses have been limited by the lack of comparative clinical data for entecavir and lamivudine beyond 1-year duration and for salvage therapy.. We conducted a cost-utility analysis using a Markov model from a US-payer perspective over a lifetime time horizon. The hypothetical cohort was 35-year-old patients with HBeAg-positive CHB. We evaluated 2 years of treatment with entecavir 0.5mg/day versus lamivudine 100mg/day, plus addition of adefovir 10mg/day for patients who developed virologic breakthrough due to resistance to either drug. In a scenario analysis, we considered adefovir plus lamivudine combination therapy for treatment-naive patients. Clinical and economic inputs ($US, year 2006 values) were derived from publicly available data, and probabilistic sensitivity analyses were conducted to evaluate uncertainty in the results.. The estimated 10-year cumulative incidence of cirrhosis for patients initiated on entecavir was 2.3% lower than for those on lamivudine (20.5% vs 22.8%). The discounted incremental cost per QALY gained was $US7600 in the base-case analysis, and the 95% central range from probabilistic sensitivity analysis was $US2500-$US19 100. Combination therapy for treatment-naive patients led to an increase in costs without improvement in patient outcomes compared with entecavir monotherapy.. Our analysis suggests entecavir improves health outcomes in a cost-effective manner compared with lamivudine with adefovir salvage or combination therapy, and highlights the importance of using evidence-based effectiveness estimates in economic studies of CHB therapies.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Cohort Studies; Cost-Benefit Analysis; Disease Progression; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Markov Chains; Organophosphonates; Quality of Life; Salvage Therapy

Adefovir plus entecavir (ADV+ETV) rescue therapy in ETV-resistant patients with chronic hepatitis B virus (HBV) infection is suboptimal in some patients. This study aims to elucidate the evolutionary characteristics of drug-resistant HBV mutants and their association with clinical responses in such patients.. Thirty-seven ETV-resistant patients were enrolled, among whom twelve had an inadequate virological response to ADV+ETV rescue therapy. The clonal sequence (³ 20 clones/sample) of HBV reverse transcriptase gene was performed to identify the resistance mutations. Phenotypic analysis was performed to evaluate the replication capacity and drug susceptibility of the mutants.. ETV-resistant mutants were continuously detected in 10 of the 12 patients, and multidrug-resistant (MDR) mutants, including a novel strain (rtL180M+A181V+T184A+S202G+M204V), were detected in two patients. Seven of the 12 patients who subsequently received tenofovir (TDF)-based therapy for 38 (23-60) months all achieved undetectable HBV DNA after treatment, and ETV-resistant mutants converted to wild-type in the four patients' samples. In contrast, the other five patients who did not achieve an adequate virological response had remaining of ETV-resistant mutants. The novel MDR strain exhibited multiple resistances to LAM, ADV, and ETV, and 11.2-fold lower susceptibility to TDF.. This study is the first to demonstrate that MDR HBV mutations may contribute to the poor efficacy of ADV+ETV combination therapy in ETV-resistant patients. Moreover, a novel MDR HBV strain was identified. Our results indicate that a TDF-based rescue therapy would be effective for the treatment of the refractory cases.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Mutation; Organophosphonates; RNA-Directed DNA Polymerase; Tenofovir; Viral Load; Virus Replication

Multidrug-resistance hepatitis B virus (MDR HBV), defined as those with mutations resistant to both nucleoside analogs lamivudine/telbivudine/entecavir (LAM/LdT/ETV) and nucleotide analog adefovir (ADV), has potential to cause treatment difficulty. To clarify clinical prevalence and virological features of MDR HBV, we investigated serum samples from 28,236 chronic HBV-infected patients with treatment of nucleoside/nucleotide analogs. All patients underwent resistance testing in the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2019. MDR mutations were screened by direct sequencing; MDR strains (with mutations co-located on the same viral genome) were verified by clonal sequencing (≥20 clones/sample) and subjected to phenotypic analysis if necessary. MDR mutations were detected in 0.81% (229/28,236) patients. MDR strains were verified in 83.0% (190/229) of MDR mutation-positive patients. As ETV-resistance mutation (ETVr) had additional mutation(s) on LAMr conferring more resistance, MDR mutations fell into LAMr + ADVr and ETVr + ADVr subsets. Sixteen mutation patterns of MDR strains were verified, including eight with LAMr + ADVr and eight with ETVr + ADVr. Refractory to sequential therapies of LAM/LdT/ETV and ADV were closely linked with MDR HBV development. Ten representative MDR strains (five LAMr + ADVr and five ETVr + ADVr) tested all had decrease in replication capacity compared to wild-type strains and decrease extent was positively related with the number of primary resistance on viral genome. Compared to ADV + ETV, TDF/TDF + ETV showed higher inhibitory rates on MDR HBV, especially for the five ETVr + ADVr strains (74.5%-97.6% vs. 60.2%-79.5%, all P < 0.05). This study significantly extends the knowledge on MDR HBV and has clinical implications for resistance management.

Topics: Adenine; Adult; Antiviral Agents; Cohort Studies; DNA, Viral; Drug Resistance, Multiple, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Longitudinal Studies; Male; Middle Aged; Mutation; Nucleosides; Nucleotides; Organophosphonates; Phylogeny; Telbivudine; Viral Load; Virus Replication

We aim to explore the effects of nucleos(t)ide analogues (NUCs) on the changes of HBsAg in chronic hepatitis B (CHB) patients.. A total of 264 CHB patients were enrolled in our study. All of them were treated with NUCs for at least three years. Quantification of HBsAg levels were measured by Elecsys HBsAg II.. Although HBsAg levels were significantly higher in HBeAg seropositive CHB patients at baseline than in HBeAg seronegative CHB patients (3.84 ± 0.82 vs 3.21 ± 0.59 IU/mL), HBsAg levels declined more rapidly in the HBeAg seropositive group (P < 0.001). In HBeAg-positive CHB patients, HBsAg level in the telbivudine (LDT)-treated group was 3.68 ± 0.56 IU/mL after 52-week of treatment, which was significantly higher than that in lamivudine (LAM)-treated group (P = 0.009). Multivariable analyses showed that baseline HBV DNA viral load (OR = 0.75, P = 0.018), baseline ALT level (OR = 0.99, P = 0.015), and baseline HBsAg level (OR = 0.188, P < 0.001) were independent factors that affected HBsAg decline in HBeAg seropositive CHB patients. For HBeAg seronegative CHB patients, the average of serum HBsAg levels in LAM-, LdT-, adefovir (ADV)-, and entecavir (ETV)-treated groups at baseline, 52 weeks, 104 weeks, and 156 weeks were similar. Multivariable analyses showed that only baseline HBV DNA level (OR = 0.56, P = 0.020) and baseline HBsAg level (OR = 0.57, P = 0.012) were independent factors that affected HBsAg decline in HBeAg seronegative patients with CHB. Baseline HBV DNA level (OR = 0.72, P = 0.010) and baseline HBsAg level (OR = 0.19, P < 0.001) were independent factors that affected all CHB patients.. CHB Patients who had received NUCs antiviral treatment showed a slow but significant decrease in serum HBsAg level. Long-term monitoring and continuous antiviral treatment are necessary, especially for those patients with risk factors associated with HBsAg decline.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Nucleotidases; Organophosphonates; Viral Load

The study aimed to characterize the prevalence and virological features of the rtA181S + T184I + M204I mutant in a large cohort of patients with chronic HBV infection. In total, 22,009 nucleoside/nucleotide analog-treated patients who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2016 were enrolled. Serum samples were collected for HBV reverse-transcriptase gene sequencing. Phenotypic analysis of the viral replication capacity and drug susceptibility was performed. The rtA181S mutation was detected in 0.82% (180/22,009) of samples. rtA181S-positive patients had significantly higher lamivudine (LAM), adefovir (ADV), and entecavir (ETV) exposure than rtA181S-negative patients. Of 180 rtA181S-positive patients, 42 had no coexistent resistance mutations, 34 had coexisting LAM-resistance mutation (LAMr), 17 had coexisting ADV-resistance mutation (ADVr), and 86 had coexisting ETV-resistance mutation (ETVr), and one had ADVr + ETVr. rtA181S + T184I + M204I occurred in 79.1% (68/86) of patients with rtA181S + ETVr and 37.8% (68/180) of all rtA181S-positive patients. Longitudinal analysis of the clinical course of resistant mutant evolution for four representative cases showed that rtA181S + T184I + M204I developed in all patients who had received LAM/telbivudine ± ADV and was receiving ETV or ADV + ETV. Compared with wild-type, the rtA181S + T184I + M204I mutant had 53.7% lower replication capacity and >1000-, 3.9-, and 383.3-fold greater LAM, ADV, and ETV resistance, respectively, but remained sensitive to tenofovir. Artificial elimination of rtA181S from the rtA181S + T184I + M204I mutant restored viral susceptibility to ADV but decreased viral replication capacity. Our study presented the first evidence that HBV rtA181S + T184I + M204I mutation had features of multidrug-resistance that contributed to resistance to both nucleoside and nucleotide analogs.

Topics: Adenine; Adult; Antiviral Agents; Asian People; Beijing; Cohort Studies; DNA, Viral; Drug Resistance, Multiple, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Longitudinal Studies; Male; Middle Aged; Mutation; Organophosphonates; Prevalence

Topics: Adenine; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Telbivudine; Tenofovir

Renal toxicity is a concern in patients with chronic hepatitis B taking nucleotide analogues, such as adefovir (ADV) and tenofovir disoproxil fumarate (TDF). We sought to determine the long-term renal effects of nucleotide analogue treatment versus entecavir (ETV) treatment.. In this retrospective single-center study, we selected 87 patients who were treated with ADV and subsequently with TDF from June 2008 to December 2013. ETV-treated patients were matched by treatment duration. We analyzed the creatinine increase over 0.5 mg/dL, glomerular filtration rate (GFR) decrease over 25%, phosphorus decrease under 2.0 mg/dL, and dose reduction of antiviral agents.. The median follow-up period was 60.0 months for both groups. The incidence of liver cirrhosis was higher in the ADV-TDF group than in the ETV group (32.2% vs 74.7%, p<0.01). Creatinine increased in both groups during follow-up, but the difference was not significant (5.7% and 2.3%, p=0.44). In addition, GFR decreased more often in the ADV-TDF group than in the ETV group (31.0% and 14.9%, p=0.01). After multivariate Cox regression analysis, ADV-TDF treatment was significantly associated with a GFR decrease over 25% (hazard ratio, 2.10; 95% confidence interval, 1.08 to 4.10; p=0.03) after adjusting for the baseline GFR decrease.. Patients taking nucleotide analogues had a significantly higher number of renal events than did those taking ETV. Clinicians should be aware of the development of renal toxicity in this patient population. Further long-term studies are warranted.

Topics: Adenine; Adult; Aged; Antiviral Agents; Chemical and Drug Induced Liver Injury; Female; Glomerular Filtration Rate; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Incidence; Male; Middle Aged; Nucleotides; Organophosphonates; Proportional Hazards Models; Retrospective Studies; Tenofovir; Time Factors; Treatment Outcome

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antiviral Agents; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Telbivudine; Tenofovir; Young Adult

No consensus exists with respect to positive hepatitis B virus (HBV) DNA results and persistent normal or mildly elevated alanine aminotransferase (ALT). The aim of this study is to investigate the appropriate management and prognosis of these populations with chronic hepatitis B (CHB). A total of 235 subjects with positive HBV DNA results and persistent normal or mildly elevated ALT were enrolled in this study. Liver biopsy and liver stiffness measurements (LSM) were performed in all participants at baseline. Antiviral therapy was initiated in patients with significant hepatic inflammation (G ≥ 2) and/or fibrosis (S ≥ 2). The patients were divided into entecavir and adefovir groups based on HBV DNA load (>2000 IU/mL vs <2000 IU/mL). The liver biopsies were repeated at 72 weeks for the patients received antiviral therapy. We found that 112 subjects were hepatitis B e antigen (HBeAg) positive, and 123 subjects were negative. The corresponding median ALTs were 46 (39.5-52.5) and 48 (41.5-57.0) U/mL, respectively. G ≥ 2 and/or S ≥ 2 diseases were present in 48.8% (82/168) of the HBeAg-positive and 51.2% (86/168) of HBeAg-negative patients, respectively. In addition, 96 HBeAg-positive and 72 HBeAg-negative patients were divided into entecavir and adefovir groups. Meanwhile, liver biopsies had greater diagnostic accuracy for determining cirrhosis than LSM (0.711 vs 1.0, P < 0.0001). At the end of the study period, undetectable HBV DNA levels and normal ALT levels were observed in CHB-infected patients. Furthermore, the patients showed histologic improvement at 72 weeks compared with baseline measurements (G, 1.72 ± 1.00 vs 0.73 ± 0.88, P = 0.0002; S, 1.484 ± 0.90 vs 0.99 ± 1.13, P < 0.0001). Collectively, liver biopsy enhanced diagnostic accuracy for CHB-infected individuals with persistent normal or mildly elevated aminotransferase levels. Moreover, antiviral therapy can improve or regress the hepatic fibrosis and cirrhosis.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; Biopsy; Disease Management; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Male; Organophosphonates; Retrospective Studies

To compare the reduction of hepatocellular carcinoma (HCC) risk between long-term treatment of entecavir and low genetic barrier antiviral agents in hepatitis B virus (HBV)-related cirrhotic patients.. An observational study.. Department of Infectious Diseases and Hepatology, the Second Hospital of Shandong University, Jinan, China, from October 2008 to October 2016.. HBV-related cirrhotic patients with antiviral treatment for at least 12 months were consecutively included. Propensity score matching analysis was performed to improve comparability of the data from both entecavir group and the control group. Log-rank test was used to compare influence of various nucleos(t)ide analogs (NAs) for incidence of HCC. Independent risk factors were estimated by multivariable Cox proportional hazards models.. The total cohort included 207 HBV-related cirrhotic patients, of which 83 patients were treated with entecavir initially. The present study found no statistical difference for the incidence of HCC between entecavir group and the control group in the total cohort (p=0.525). However, the difference became statistically significant (p=0.014) after propensity score matching. Number needed to treat (NNT) were 8 patients, 6 patients and 3 patients at years 2, 3 and 4, respectively. Multivariable Cox regression in propensity score matching cohort revealed older age (HR: 1.066, p=0.041), NAs of low generic barrier (HR: 6.944, p=0.016), NAs resistance (HR: 3.648, p=0.041), and lower platelet counts (<80x10 ⁹/L) (HR: 6.718, p=0.009) as independent risk factors for HCC incidence.. Entecavir is more efficient in reducing the incident HCC risk for HBV-related cirrhotic patients in comparison to low genetic barrier NAs.

Topics: Adenine; Adult; Aged; Antiviral Agents; Carcinoma, Hepatocellular; China; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Incidence; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Organophosphonates; Retrospective Studies; Risk Factors; Telbivudine

Direct sequencing is the gold standard for the detection of drug-resistance mutations in hepatitis B virus (HBV); however, this procedure is time-consuming, labor-intensive, and difficult to adapt to high-throughput screening. In this study, we aimed to develop a dendron-modified DNA microarray for the detection of genotypic resistance mutations and evaluate its efficiency.. The specificity, sensitivity, and selectivity of dendron-modified slides for the detection of representative drug-resistance mutations were evaluated and compared to those of conventional slides. The diagnostic accuracy was validated using sera obtained from 13 patients who developed viral breakthrough during lamivudine, adefovir, or entecavir therapy and compared with the accuracy of restriction fragment mass polymorphism and direct sequencing data.. The dendron-modified slides significantly outperformed the conventional microarray slides and were able to detect HBV DNA at a very low level (1 copy/µL). Notably, HBV mutants could be detected in the chronic hepatitis B patient sera without virus purification. The validation of our data revealed that this technique is fully compatible with sequencing data of drug-resistant HBV.. We developed a novel diagnostic technique for the simultaneous detection of several drug-resistance mutations using a dendron-modified DNA microarray. This technique can be directly applied to sera from chronic hepatitis B patients who show resistance to several nucleos(t)ide analogues.

Topics: Adenine; Dendrimers; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Microarray Analysis; Mutation; Nucleic Acid Amplification Techniques; Organophosphonates; Reverse Transcriptase Polymerase Chain Reaction

The study aimed to characterize rtA181T/sW172stop (*) and rtA181T/sW172non-stop mutations of hepatitis B virus (HBV). Total of 22,009 patients who visited Beijing 302 Hospital from 2007 to 2016 were enrolled. These patients all received nucleos(t)ide analogues (NAs) treatment and their serum samples were collected for sequence analysis of HBV reverse-transcriptase (RT) and S regions. The rtA181T mutation was detected in 5.37% (1182/22,009) of the patients' samples. The rtA181T-causative sW172*, sW172non-stop (sW172 L/S), and mixed sW172*/non-stop mutations occupied 82.91%, 7.70%, and 9.39%, respectively. The patients with rtA181T/sW172non-stop mutants had a higher HBV DNA level compared to those with rtA181T/sW172* mutants. 44.33% (524/1182) rtA181T-positive samples were detected with signature drug-resistant mutations, including 325 with adefovir-resistant mutation rtA181V/N236T, 57 with lamivudine-resistant mutation rtM204V/I, 99 with entecavir-resistant mutation rtM204V/I plus rt184/202/250 substitution(s), and 43 with multidrug-resistant mutation rtA181V/N236T + rtM204V/I ± rt184/202/250 substitution(s). The rtA181T/sW172non-stop mutation had a higher ratio of coexistence with adefovir-resistant mutation compared to rtA181T/sW172* mutation (42.86% vs. 24.59%, P < 0.05). rtA181T/sW172S + rtN236T and rtA181T/sW172L + rtN236T mutants exhibited higher HBV DNA production and adefovir resistance fold than that of rtA181T/sW172* + rtN236T mutant (98.02% and 85.5% vs. 42.1% in HBV DNA production, and 7.38-fold and 5.49-fold vs. 3.69-fold in half maximal effective concentration of wild-type strain); rtA181T/sW172L + rtS202G + rtM204V strain exhibited higher HBV DNA production and entecavir resistance fold than that of rtA181T/sW172* + rtS202G + rtM204V strain (50.98% vs. 34.49%, 524.00-fold vs. 69.33-fold). In conclusion, rtA181T/sW172non-stop mutation may increase resistance fold of adefovir- and entecavir-resistant mutants compared to rtA181T/sW172* mutation and might influence clinical presentation of NAs-treated patients.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Mutation; Organophosphonates; RNA-Directed DNA Polymerase

Topics: Adenine; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Organophosphonates; Polyethylene Glycols; Recombinant Proteins

Post transplantation lymphoproliferative disorder (PTLD) is a rare but severe complication. Epstein-Barr virus (EBV) is considered an important pathogen for PTLD and EBV deoxyribonucleic acid (DNA) load is widely monitored to detect PTLD early. Hepatitis B virus (HBV) infection is rarely reported to be related with PTLD. We report a case of EBV negative (EBV), HBV positive (HBV) diffuse large B cell lymphoma in a patient 12 years after liver transplantation.. A 52-year-old man complained of worsening appetite, abdominal distension, and pruritus. Abdominal computed tomography (CT) detected a huge retroperitoneal mass and pathology of the fine needle biopsy established the diagnosis of diffuse large B cell lymphoma. Virology showed active hepatitis B viral duplication and EBV DNA was negative.. Treatment modalities for this patient included: reduction and subsequent cessation of immunosuppression; antiviral therapy for HBV with entecavir and adefovir; conventional chemotherapy consisting of cyclophosphamide, epirubicin, vindesine, and prednisone, followed by radiotherapy. He achieved complete remission (CR) and was kept on entecavir treatment afterwards.. He has been in remission for 2 years.. HBV infection might have played some role in this very late onset EBV PTLD patient. Therefore, HBV serology and HBV load should be monitored during the follow-up of HBV surface antigen positive (HBsAg) transplant recipients and life-long antiviral therapy is required.

Topics: Adenine; Antiviral Agents; Biopsy, Fine-Needle; Chemoradiotherapy; Guanine; Hepatitis B; Hepatitis B virus; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Organophosphonates; Tomography, X-Ray Computed; Treatment Outcome; Virus Replication

The stimulator of interferon genes (STING) plays a crucial role in the recognition of a viral infection and subsequent stimulation of an immune response. However, it is unclear whether methylation of the STING promoter affects STING transcription and response to antiviral therapy. The present study determined the methylation status of the STING promoter in patients with chronic hepatitis B (CHB).This study included 198 participants, of which 159 participants had CHB and 39 were healthy controls (HCs). Methylation-specific polymerase chain reaction was performed to detect the methylation status of the STING promoter. Reverse transcription-quantitative polymerase chain reaction was performed to determine STING mRNA level in peripheral blood mononuclear cells.The methylation frequency of the STING promoter was significantly higher and STING mRNA level was lower in the patients with CHB than in the HCs. Presence of hepatitis B virus (HBV) DNA was independently correlated with an increased risk of STING promoter methylation. Virological response frequency was higher in the patients with CHB receiving entecavir (ETV) than in those receiving adefovir (ADV). In the ETV group, the virological response frequency was evidently lower in the patients with CHB having methylated STING promoters than in those having unmethylated STING promoters. However, there was no significant difference in the virological response frequency between ADV-treated patients having methylated and unmethylated STING promoters.These results indicate that the hypermethylation of the STING promoter and thus the transcriptional repression of STING weaken the effect of STING in inhibiting HBV replication and decreases the effectiveness of antiviral therapy.

Topics: Adenine; Adult; Antiviral Agents; Biomarkers; DNA, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Leukocytes, Mononuclear; Male; Methylation; Middle Aged; Organophosphonates; Polymerase Chain Reaction; Promoter Regions, Genetic; RNA, Messenger; Sustained Virologic Response

The clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3 levels in patients with HBV and investigated its clinical significance and association with nucleos(t)ide (NUC) analogue administration.. Serum IFN-λ3 level was measured in 254 patients with HBV with varying clinical conditions using our own high sensitivity method. The resulting values were compared with various clinical variables. In addition, cell lines originating from various organs were cultured with NUCs, and the production of IFN-λ3 was evaluated.. Higher serum IFN-λ3 levels were detected in the patients treated with nucleotide analogues (adefovir or tenofovir) compared with those treated with nucleoside analogues (lamivudine or entecavir). There were no other differences in the clinical background between the two groups. A rise in the serum IFN-λ3 levels was observed during additional administration of the nucleotide analogues. In vitro experiments showed that the nucleotide analogues directly and dose-dependently induced IFN-λ3 production only in colon cancer cells. Furthermore, the supernatant from cultured adefovir-treated colon cancer cells significantly induced IFN-stimulated genes (ISGs) and inhibited hepatitis B surface antigen (HBsAg) production in hepatoma cells, as compared with the supernatant from entecavir-treated cells.. We discovered that the nucleotide analogues show an additional pharmacological effect by inducing IFN-λ3 production, which further induces ISGs and results in a reduction of HBsAg production. These findings provide novel insights for HBV treatment and suggest IFN-λ3 induction as a possible target.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antiviral Agents; Asymptomatic Infections; Carcinoma, Hepatocellular; Culture Media, Conditioned; DNA, Viral; Female; Gene Expression; Genotype; Guanine; Hep G2 Cells; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; HT29 Cells; Humans; Interferons; Interleukins; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Organophosphonates; Polymorphism, Genetic; Recombinant Proteins; Tenofovir; Up-Regulation; Young Adult

Antiviral therapy has revolutionized treatment of chronic HBV infections. First generation compounds, lamivudine and adefovir, displayed a high rate of treatment failures, and have been replaced by more potent compounds with high genetic barrier to resistance. However, the evolution of the virus towards resistance due the use of first generation compounds may still provide useful information for a better management of current antivirals. A single center sequence database including 705 HBV reverse transcriptase sequences from patients failing antiviral treatments (2002-2012) has been statistically analyzed to highlight viral evolution in relationship to the use of antiviral compounds and to their associations/sequencing in those years. The influence of viral genotypes and polymorphisms on resistance-related mutational patterns was also investigated. This study documents how, after the first years of antiviral therapy, the use of adefovir as an add-on strategy allowed a consistent reduction treatment failures. It also documents the effects of the initial misuse of entecavir in lamivudine experienced patients. In the latest years, the correct use of entecavir and the introduction of tenofovir allowed further curbing of resistance-related treatment failures, which virtually disappeared. Furthermore, the study allows a better understanding of how viral genotype (A vs D) conditions specific mutational pathways to resistance against lamivudine and entecavir, and demonstrates that the use of adefovir in lamivudine experienced patients is associated to peculiar mutational patterns, in particular A181V + F/Y221L. Despite some concern may arise for patients previously treated with lamivudine/adefovir, in sequence or combination, where the virus may have developed a lower genetic barrier against resistance to tenofovir, the outlook of antiviral treatment of HBV infection should be quite optimistic.

Topics: Adenine; Antiviral Agents; DNA Mutational Analysis; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Evolution, Molecular; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Mutation; Organophosphonates; Polymorphism, Genetic; RNA-Directed DNA Polymerase; Sequence Analysis; Tenofovir; Treatment Failure

Little clinical data are available regarding re-establishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance.. A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n = 21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n = 19), ETV (1.0 mg) monotherapy (n = 11) or ETV (0.5 mg) plus TDF combination therapy (n = 14). The efficacy and safety of four treatment regimens were compared.. There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ. TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Practice Guidelines as Topic; Retrospective Studies; Tenofovir; Treatment Outcome; Viral Load

The aim of this study is to evaluate the clinical implications of lactate concentrations in patients with hepatitis B with or without cirrhosis during treatment with nucleos(t)ide analogues.. One hundred and seven consecutive patients with chronic hepatitis B and median age 57 (24-85) years were prospectively included. Lactate concentrations were measured at baseline and at 12, 24, 36, 48, and 60 months following the baseline measurements. Eight (n=8, 7.5%) patients received lamivudine, 38 (n=38, 35.5%) patients received tenofovir, 34 (n=34, 31.8%) patients received entecavir, and 27 (n=27, 25.2%) patients received combined therapy.. None of the patients developed lactic acidosis during follow-up [median: 58 (6-155) months]. Overall, no trends of the lactic acid evolution were observed over time; however, there was a nonsignificant increasing trend in patients with cirrhosis up to 24 months of treatment. This increasing trend was significant in female patients with cirrhosis (P=0.016). The age of the patients, the presence of cirrhosis, and hepatocellular carcinoma were strongly associated with the survival of all patients. In the group of cirrhotic patients, the only independent prognostic factor that was associated with patients' survival was the Child-Pugh class.. None of the patients developed lactic acidosis. There is an indication of an increasing trend of lactic acid levels up to 24 months of therapy in female cirrhotic patients.

Topics: Acidosis, Lactic; Adenine; Adult; Aged; Aged, 80 and over; Antiviral Agents; Biomarkers; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Lactic Acid; Lamivudine; Liver Cirrhosis; Male; Middle Aged; Organophosphonates; Prospective Studies; Risk Factors; Sex Factors; Tenofovir; Time Factors; Treatment Outcome; Up-Regulation; Young Adult

The aim of this study was to evaluate the efficacy and safety of entecavir (ETV) combined treatment with adefovir (ADV) on chronic hepatitic B (CHB) patients who failed to respond to nucleotide (acid) analog (NA) treatment. On this basis, the possible factors in the combined treatment of these patients will be analyzed. The safety, biochemical index, and the possible factors that might affect the ETV and ADV combined treatment at different points in time were retrospectively analyzed. The biochemical index included the following: virological response, hepatitis B virus (HBV) DNA decline, primary nonresponse, biochemical response, and the hepatitis B virus E antigen/hepatitis B virus E antibody seroconversion rate. There were 94 CHB patients and compensated liver cirrhosis patients who received ETV plus ADV treatment for over 12 weeks after failure of treatment with NAs. The authors have also investigated 76 CHB patients (80.9%) and 18 hepatitis B cirrhosis patients (19.1%) in this study. The HBV DNA baseline was 4.4 ± 1.4 log10 IU/mL, and the positive rate of HBeAg before salvage treatment was 78.7% (74/94). The sample sizes were 94, 78, 42, 10, 6, and 1 for follow-up of 24, 48, 96, 144, 192, and 240 weeks, respectively. The virological responses (HBV DNA < 2 log10 IU/mL) and biochemical responses were 52.1%, 74.3%, and 90.4% and 63.1%, 61.6%, and 81.1%, respectively, at 24, 48, and 96 weeks, which showed significant differences (P < 0.001 and P < 0.005, respectively). The HBV DNA decline was presented as mean ± SEM, which were 1.53 ± 1.23, 1.75 ± 1.37, 2.07 ± 1.54, and 2.39 ± 1.77 log10 IU/mL at 12, 24, 48, and 96 weeks, respectively. They showed significant differences compared with the baseline (χ = 8.084, P < 0.05). The rate of primary nonresponse was 30.9% (29/94), and the primary treatment failure rates were 26.6% (25/94), 24.4% (19/78), and 4.8% (2/42) at 24, 48, and 96 weeks, respectively. They all have statistical difference (P = 0.011 < 0.05). There were 23 patients who experienced virological breakthrough after the HBV DNA levels were undetectable, whereas after follow-up for 12-24 weeks, the HBV DNA levels were back to undetectable again. ETV plus ADV treatment is an efficient and safe treatment for CHB and compensated liver cirrhosis patients who experienced NA treatment failure. The high quantity of baseline HBV DNA level is a risk factor for poor efficacy of salvage treatment.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Organophosphonates; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

Data are lacking regarding the management of chronic hepatitis B (CHB) with resistance to clevudine (CLV). This study evaluated the efficacy of different rescue therapies for CLV-resistant CHB.. Patients with CLV-resistant CHB were enrolled in the cohort, and all patients developed virologic breakthrough during CLV therapy and had confirmed-genotypic resistance to CLV (rtM204I mutation) before enrollment.. Of the 107 patients, 12 received adefovir (ADV), 21 received a CLV plus ADV combination (CLV+ADV), 34 received a lamivudine plus ADV combination (LAM+ADV), and 40 received entecavir (ETV) therapy for 48 weeks. The CLV+ADV group had the lowest hepatitis B virus (HBV) DNA level (p<0.0001) and showed the greatest reduction of HBV DNA levels from baseline compared to all other groups (p=0.004) at week 48. HBV DNA was undetectable (<70 IU/mL) in 0%, 57.1%, 21.2%, and 27.5% (p=0.003) of the patients in each group, respectively, at week 48. At the end of the study, the mean alanine transaminase (ALT) level, rate of ALT normalization, and rate of hepatitis B envelope antigen loss or seroconversion did not differ between groups.. CLV+ADV combination therapy in patients with CLV-resistant CHB more effectively suppresses HBV replication than ETV, ADV, or LAM+ADV therapy.

Topics: Adenine; Adult; Aged; Antiviral Agents; Arabinofuranosyluracil; Cohort Studies; Disease Management; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Viral Load

The study aimed to investigate the association of prevalent genotypes in China (HBV/C and HBV/B) with HBV drug-resistant mutations. A total of 13,847 nucleos(t)ide analogue (NA)-treated patients with chronic HBV infection from North China were enrolled. HBV genotypes and resistant mutations were determined by direct sequencing and confirmed by clonal sequencing if necessary. HBV/B, HBV/C, and HBV/D occupied 14.3%, 84.9%, and 0.8% across the study population, respectively. NA usage had no significant difference between HBV/B- and HBV/C-infected patients. Lamivudine-resistant mutations were more frequently detected in HBV/C-infected patients, compared with HBV/B-infected patients (31.67% vs. 25.26%, p < 0.01). Adefovir- and entecavir-resistant mutation detection rates were similar, but the mutational pattern was different between the two genotypes. For adefovir-resistant mutations, HBV/C-infected patients had a higher detection rate of rtA181 V (HBV/C 5.29% vs. HBV/B 1.36%, p < 0.01) and a lower detection rate of rtN236T (2.70% vs. 6.54%, p < 0.01). For entecavir-resistant mutations, HBV/C-infected patients had a higher detection rate of rtM204 V/I+T184 substitution or S202G/C (3.66% vs. 2.16%, p < 0.01) and a lower detection rate of rtM204 V/I+M250 V/I/L substitution (0.67% vs. 1.46%, p < 0.01). Multidrug-resistant mutations (defined as coexistence of mutation to nucleoside and nucleotide analogues) were detected in 104 patients. HBV/C-infected patients had a higher detection rate of multidrug-resistant mutation than HBV/B-infected patients (0.83% vs. 0.35%, p < 0.05). The study for the first time clarified that HBV/C-infected patients had a higher risk to develop multidrug-resistant mutations, compared with HBV/B-infected patients; and HBV/C- and HBV/B-infected patients had different inclinations in the ETV-resistant mutational pattern.

Topics: Adenine; Adult; Antiviral Agents; China; Cohort Studies; Drug Resistance, Multiple, Viral; Female; Gene Expression; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Microbial Sensitivity Tests; Middle Aged; Mutation Rate; Organophosphonates; Phylogeny; Viral Proteins

Inhibition of viral replication is the most important goal in patients with Hepatitis B virus chronic infection (CHB). Currently, five oral nucleo(t)side analogs (NAs), including Lamivudine, Adefovir, Telbivudine, Entecavir, and Tenofovir, have been approved for treatment. The widespread use of NAs has also been linked with a progressive growth of unlikely anomaly attributable to mitochondrial dysfunctions, not previously recognized. Here, we explore the hypothesis that NAs may cause persistent epigenetic changes during prolonged NAs therapy in CHB patients. We obtained peripheral blood mononuclear cells (PBMC) from whole blood samples of consecutive patients with chronic HBV infection, 18 receiving NAs and 20 untreated patients. All patients were Caucasian and Italians. Epigenetic analysis was performed by Bisulphite sequencing PCR to search the existence of methylated cytosine residues in the Light (L)-strands of mitochondrial DNA control region (D-loop). Gene expression analysis of DNA methyltransferases 1 was performed by a quantitative relative Real-Time Polymerase Chain Reaction (PCR). DNMT1 expression was significantly (P < 000001) higher in NA treated patients (4.09, IQR 3.52-5.15) when compared with HBV naives (0.61, IQR 0.34-0.82). Besides, DNMT1 expression was significantly correlated with NA therapy duration (Spearman Rho = 0.67; P < 0.05). Furthermore, NA therapy duration was the only significant predictor of DNMT1 expression at multivariate analysis (Beta = 0.95, P < 0.0000001). Bisulphite PCR sequencing showed that methylation of cytosine residues occurred in a higher percentage in patients treated with NAs in comparison with untreated patients and healthy controls. Our data showed a DNMT1 overexpression significantly correlated to NA therapy duration and an higher regional mtDNA hypermethylation. This might suggest an epigenetic alteration that could be involved in one of the possible mechanisms of mitochondrial gene regulation during NAs therapy.

Topics: Adenine; Aged; Antiviral Agents; Cross-Sectional Studies; Cytosine; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; DNA, Mitochondrial; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Leukocytes, Mononuclear; Male; Middle Aged; Nucleosides; Organophosphonates; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine

Topics: Adenine; Aged; Antiviral Agents; Fanconi Syndrome; Female; Guanine; Hepatitis B, Chronic; Humans; Organophosphonates

This study compared virologic response to entecavir monotherapy and de novo lamivudine plus adefovir (LAM + ADV) combination therapy in patients with chronic hepatitis B (CHB) with high viral load (HVL). Hepatitis B e antigen (HBeAg)-positive patients [hepatitis B virus (HBV) DNA levels >1 × 10(7) copies/ml] were assigned to LAM + ADV or entecavir treatment. The primary efficacy endpoint measure of the multicenter prospective cohort study was proportion of patients with CHB with virologic response, defined as HBV DNA <300 copies/ml at week 48. During treatment, 39.1 % (18/46) of patients in the LAM + ADV group and 48.1 % (25/52) of those in the entecavir group achieved virologic response in week 48 (P = 0.37). A baseline alanine aminotransferase (ALT) level ≥5 × ULN (upper limit of normal) or baseline serum HBV DNA level <8 log10 IU/ml could predict virologic response at week 48 (P = 0.025). The mean reduction in HBV DNA was comparable (P = 0.45); no significant difference was found in the proportion of ALT normalization (P = 0.46) or HBeAg seroconversion (P = 0.88). Two cases of genotypic resistance were found (rtM204 V + rtL180 M and rtA181T/V) in the LAM + ADV group, with a resistance rate of 4.3 %; there was no genotypic resistance in the entecavir group (P = 0.13). De novo LAM + ADV combination therapy is as effective as entecavir monotherapy in HBeAg-positive patients with CHB with HVL. Moreover, genotypic resistance was only found in the LAM + ADV group at week 48. Baseline ALT levels ≥5 ULN or baseline serum HBV DNA levels <8 log10 IU/ml were favorable predictors of virologic response in CHB with HVL.

Topics: Adenine; Adolescent; Adult; Alanine Transaminase; Antiviral Agents; Blood; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Prospective Studies; Treatment Outcome; Viral Load; Young Adult

Little is known about the prognosis and complications of chronic hepatitis B in countries with low disease prevalence including Germany.. This retrospective/prospective study analyzes the course of 608 HBsAg-positive patients between 2002 and 2012 in Germany. The follow-up duration was 5.2±2.9 years (mean±SD) and the age of the patients was 40.4±13.8 years. Of the total cohort, 59.9% were men; 34.9% had been born in Germany, 30.4% in Turkey, and 34.7% in other countries.. In 78.3% of women, diagnosis was made during pregnancy screening, which is the only reinforced screening procedure in Germany. During follow-up, 21 patients died, five had a LTX, and 20 developed a hepatocellular carcinoma. Of the total cohort, 15% developed at least one severe liver-associated complication. By multivariate analysis, prognosis was associated with high age and cirrhosis, but not with sex, HBV-DNA, alanine aminotransferase, and ethnic origin. Of the 608 patients, 211 (34.7%) had at least one antiviral therapy. Of the 178 patients who were treated with nucleot(s)ides at the last visit 88.8% had an HBV-DNA less than 20 IU/ml.. Today, in Germany, hepatitis B is a disease of migrants. The present data show that mandatory screening is effective and needs to include more high-risk groups. Mortality and complications including hepatocellular carcinoma are associated primarily with cirrhosis and age, but not with HBeAg status or viral load probably because modern therapies considerably reduce viral replication in almost all patients. The prognosis is exclusively determined by the risk for hepatocellular carcinoma.

Topics: Adenine; Adult; Age Factors; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Germany; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Mass Screening; Middle Aged; Organophosphonates; Prognosis; Prospective Studies; Retrospective Studies; Telbivudine; Tenofovir; Thymidine; Time Factors; Turkey

Lamivudine, telbivudine, and entecavir are the first-line drugs covered by the Taiwan National Health Insurance as 3-year treatments for patients with chronic hepatitis B virus (HBV), but the optimal treatment duration of each remains unclear. We aimed to detect HBV treatment-cessation durability, and compare the predictors in patients with and without clinical relapse. In this retrospective cohort study, 210 patients with chronic HBV who tested hepatitis B e-antigen positive or hepatitis B e-antigen negative were treated for 3 years with a nucleos(t)ide analogue. Of these, 102 patients continued therapy after 3 years, while 88 patients stopped treatment and were followed for 1 year due to financial difficulties. Efficacy was assessed in terms of alanine aminotransferase (ALT) level normalization, HBV DNA clearance, virus breakthrough, clinical relapse, and liver decompensation. The durability predictors were evaluated by host factors, HBV DNA, and drug differences. Eighty patients (14 on lamivudine, 19 on telbivudine, and 47 on entecavir) were recruited. There was no difference in clinical-relapse rate among lamivudine, telbivudine, and entecavir (35.7% vs. 36.8% vs. 31.9%, respectively; p = 0.916), and liver decompensated hepatitis was absent. In baseline clinical characteristics, there were no differences between the clinical-relapse and nonrelapse groups in age, sex, cirrhosis, prior treatment, HBV DNA, pretreatment ALT, or hepatitis B e-antigen (HBeAg). The mean 3(rd) year serum ALT level differed significantly between clinical-relapse and nonrelapse patients (37.5 U/L vs. 27.7 U/L, respectively; p = 0.044). The 3-year nucleos(t)ide analogue off-treatment in patients with chronic HBV delivered according to the Taiwan National Health Insurance guidelines had an overall 33.8% 1-year clinical-relapse rate without any decompensated hepatitis flare-ups.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

To investigate drug-resistant mutations in and genotypes of hepatitis B virus (HBV) in chronic HBV carriers using PCR sequencing technology.. Chronic HBV carriers were recruited from Tianjin Second People's Hospital between June 2013 and May 2014 and 317 were enrolled in the study according to receipt of nucleos(t)ide analogues (NAs) for at least three months prior. Drug-resistant mutations were detected by PCR followed by sequencing. SPSS21.0 was used for statistical analysis.. Drug-resistant mutations were detected in 119 of the 317 patients, including 20 of 46 patients who received lamivudine (LAM), 16 of 34 patients who received adefovir (ADV), 13 of 80 patients who received entecavir (ETV), 5 of 23 patients who received telbivudine (LdT), and 65 of 124 patients who received various sequential/combined NA therapies. Each of the NAs had dominant drug-resistant mutational profiles, with rtM204I+rtL180M±rtL80I (30.9%) for LAM, rtA181T/N (21.3%), rtS213T/N (21.3%) and rtV214A (21.3%) for ADV, rtl180M (48%) for ETV, rtM204I for LdT, and rtA194T for tenofovir disoproxil fumarate (TDF). A total of 308 HBV genotypes were detected, including type B in 27 cases (8.8%), type C in 279 cases (90.6%), and type D in 2 cases (0.6%). The different HBV genotypes had no statistically significant difference in drug-resistance mutations, though (χ(2) = 1.11, P > 0.05). Two TDF drug-resistant mutations rtA194T were detected.. The results provide new information on NA drug-resistant mutations and HBV genotype profiles in chronic HBV carriers and may have important clinical implication for HBV drug resistance management. In addition, the data confirmed the preexisting TDF mutation rtA194T.

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Mutation; Organophosphonates; Polymerase Chain Reaction; Telbivudine; Tenofovir; Thymidine

We investigated the efficacy of entecavir (ETV) monotherapy in 54 naïve patients and 27 lamivudine (LMV) and/or adefovir (ADV) experienced patients.. Eighty-one chronic hepatitis B patients with a viral load above 4 log 10 copies/ml and high levels of serum alanine aminotransferase were treated with ETV 0.5mg daily. The viruses of patients were sequenced before ETV therapy and after every three months of ETV therapy.. Eight LAM-experienced and ADV-experienced patients emerged mutations in the ETV treatment. In one of these experienced patients, the ETV-resistant mutations were detected during ETV treatment, with the virological and the biochemical breakthrough. Two LAM-experienced and ADV-naïve patients were detected mutation during 1-2 years ETV therapy. All three LAM-naïve and ADV-experienced patients were detected mutations in the ETV treatment. Five in fifty for LAM-naïve and ADV-naïve patients showed mutations in the ETV monotherapy.. ETV has a high genetic barrier to resistance and the efficacy in LAM-experienced and/or ADV-experienced patients were much lower than in naïve patients.

Topics: Adenine; Adolescent; Adult; Alanine Transaminase; Antiviral Agents; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Viral Load; Young Adult

Ground glass hepatocytes (GGHs) have been shown to predict the development of hepatocellular carcinoma (HCC). Type I GGH and type II GGH harbor hepatitis B virus (HBV) pre-S1 and pre-S2 deletion mutants, respectively. Whether anti-HBV therapy can inhibit the expression of GGHs and potentially reduce HCC development is explored in this study. Two sets of liver specimens were included: the first contained 31 paired biopsy specimens obtained from chronic HBV patients receiving oral nucleos(t)ide analogue (NA) treatment; the second contained 186 resected liver tissues obtained from HBV-related HCC patients receiving surgery: 82 received NA before surgery and 104 did not. Compared with the baseline biopsy specimens, type I (P=0.527) and type II GGH (P=0.077) were not significantly decreased after 48 weeks of NA treatment in the first set of patients. In the second set, despite suppression of viral load (P<0.001) and periportal necrosis (P=0.006) in treated patients, GGH (P=0.594), cccDNA (P=0.172) and serum pre-S mutants (p=0.401) were not significantly suppressed. A significant decrease of type I (P=0.049) and type II GGH (P=0.029) could only be observed in patients after long duration of treatment (median duration: 4.3 years). In the treated patients, the persisted type II GGH remained an independent variable associated with decreased local recurrence-free survival of HCC (P=0.019) as in non-treated patients (P=0.001). In conclusion, the persistence of GGHs could explain the residual risk of HCC development under anti-HBV treatment. Therefore, intrahepatic GGHs and pre-S mutant are potential additional targets for HCC prevention in patients already receiving anti-HBV treatment.

Topics: Adenine; Administration, Oral; Adolescent; Adult; Amino Acid Sequence; Antiviral Agents; Biopsy; Carcinoma, Hepatocellular; DNA, Circular; Drug Resistance, Viral; Fatty Liver; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Humans; Lamivudine; Liver; Liver Neoplasms; Male; Middle Aged; Necrosis; Organophosphonates; Protein Precursors; Sequence Deletion; Viral Load; Young Adult

Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatment is ill-defined.. To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the efficacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine, was explored.. In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45-70) were enrolled.. The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy (29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobulinemias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1-14), rheumatoid factor was 200U/L (range 20-5850), C4 was 12mg/dl (range 2-31), ALT 71U/L (range 36-114). All patients were HBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight), Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no disease progression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regression of purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidney failure and two of liver cirrhosis.. NUC therapy appeared to be safe and effective in CV-related HBV.

Topics: Adenine; Aged; Antiviral Agents; Cryoglobulinemia; Female; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Italy; Lamivudine; Male; Middle Aged; Organophosphonates; Treatment Outcome; Vasculitis

Tenofovir disoproxil fumarate (TDF) is newly available for treatment of chronic hepatitis B patients in China. To date, no study has been conducted to examine the cost-effectiveness of this treatment. The aim of this study was to estimate the cost-effectiveness of TDF versus four oral nucleos(t)ide analogs [lamivudine (LAM), adefovir (ADV), telbivudine (LdT), and entecavir (ETV)] and from a pharmacoeconomic perspective to assess current drug pricing for TDF.. Based on Chinese healthcare perspectives, a Markov model was applied to simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for five different monotherapy strategies. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: directly using ETV + ADV) were separately considered for treatment of patients refractory to monotherapy. Model parameters (including disease transition, cost, and utility) were obtained from previous Chinese population studies. Both branded and generic drugs were separately analyzed. Study model uncertainties were assessed by one-way and probabilistic sensitivity analyses. Two-way sensitivity analysis was used to explore uncertainties between efficacy and price of TDF.. In the base-case analysis, the lowest lifetime cost and the best cost-effectiveness ratio were obtained by ETV, which was considered the reference treatment. LAM, ADV, and LdT treatments had significantly greater costs and lower efficacies. Compared to ETV, TDF was more effective but also more expensive. The incremental cost-effectiveness ratios of TDF versus ETV were much higher than the willing-to-pay threshold of $20,466 US dollars (USD) per QALY gained (3 × gross domestic product per capita of China, 2014). TDF would be the most cost-effective strategy if the annual cost did not exceed $2260 USD and $1600 USD for branded and generic drugs, respectively.. For Chinese chronic hepatitis B patients, ETV is still the most cost-effective strategy over TDF and other nucleos(t)ide analogs, with a threshold of $20,466 USD/QALY gained.

Topics: Adenine; Antiviral Agents; Cost-Benefit Analysis; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Markov Chains; Organophosphonates; Quality-Adjusted Life Years; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Before tenofovir (TDF) become available in South Korea, combination therapy with entecavir (ETV) and adefovir (ADV) was the most potent regimen for chronic hepatitis B (CHB) patients who fail to respond to rescue therapy for drug resistance. We analyzed the efficacy of ETV-ADV combination therapy and investigated the clinical and clonal results of TDF-based rescue therapy in CHB patients refractory to this combination.. We retrospectively reviewed the medical records of CHB patients treated for up to 3 years with ETV-ADV combination therapy as a rescue therapy for drug resistance. In cases refractory to this combination, clinical and clonal analyses were performed for TDF-based rescue therapy.. The analysis was performed on 48 patients. Twelve patients achieved a virological response (VR) within 3 years. A VR was subsequently achieved in nine of the ten patients without a VR who switched to TDF monotherapy. A VR was also achieved in six of the seven patients who switched to lamivudine-TDF combination therapy, and in two of the two patients who switched to ETV-TDF combination therapy. In an in vitro susceptibility test, viral replication was detected with TDF monotherapy but not with ETV-TDF combination therapy.. The efficacy of ETV-ADV combination therapy was insufficient in CHB patients who were refractory to rescue therapy. A more potent regimen such as ETV-TDF combination therapy may be considered in such refractory cases.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Polymerase Chain Reaction; Republic of Korea; Retrospective Studies; Tenofovir; Treatment Outcome

Entecavir (ETV) is a potent viral replication inhibitor for chronic hepatitis B (CHB) patients. To investigate the efficacy of ETV in Chinese nucleos(t)ide(NA)-experienced CHB patients. Among 89 CHB patients with ETV monotherapy for ≥6 months, 33/89 (37%) or 56/89 (73%) were NA-naïve or NA-experienced. During a median follow-up of 5.75 years, all NA-naïve CHB patients achieved VR without genotypic ETV-resistance. However, VR was observed in 50/56 (~90%) of NA-experienced CHB patients during a median follow-up of 4.75 years. Antiviral efficacy was not reduced in patients with previous lamivudine (LAM) with/without LAM-resistance (HR 0.465; 95% CI 0.196-1.100; p > 0.05) (HR 0.472; 95% CI 0.205-1.091; p > 0.05). Patients with a primary treatment failure to adefovir (ADV) had a reduced probability of achieving VR compared to NA-naïve (HR 0.496; 95% CI 0.287-0.857; p < 0.01). Previous ADV-experienced patients with a partial VR (HR 1.253; 95% CI 0.429-3.665; p > 0.05) did not influence antiviral response to ETV. The antiviral efficacy of ETV is not influenced by previous treatment LAM with/without LAM-resistance. ETV may still be an option in ADV-experienced patients with a partial VR, but not advised in patients with a primary treatment failure to ADV.

Topics: Adenine; Adult; Antiviral Agents; Asian People; China; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Time Factors; Treatment Outcome; Viral Load

Nucleos(t)ide analogs (NAs) have made a hepatitis B immunoglobulin (HBIG)-sparing protocol an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, this approach is considered controversial in patients transplanted for HBV and hepatitis D (HDV) co-infection.. All patients transplanted for HBV/HDV cirrhosis were evaluated. After LT, each patient received HBIG + NAs and then continued with NAs prophylaxis. All patients were followed up with HBV serum markers and HBV DNA, while anti-HDV/HDV RNA was performed in those with HBV recurrence.. A total of 34 recipients were included (22 men, age: 46.7 ± 16 years). After HBIG discontinuation, NAs were received as monoprophylaxis (lamivudine [LAM]: 2, adefovir [AFV]: 1, entecavir: 9, tenofovir [TDF]: 12) or dual prophylaxis (LAM + AFV [or TDF]: 10 patients). Two (5.8%) of the 34 patients had HBV/HDV recurrence after HBIG withdrawal (median follow-up: 28 [range, 12-58] months). These 2 patients had undetectable HBV DNA at LT. Statistical analysis revealed that those with recurrence had received HBIG for shorter period, compared to those without recurrence (median: 9 vs. 28 months, P = 0.008).. We showed for the first time, to our knowledge, that maintenance therapy with NAs prophylaxis after HBIG discontinuation was effective against HBV/HDV recurrence, but it seems that a longer period of HBIG administration might be needed before it is withdrawn after LT.

Topics: Adenine; Adult; Antiviral Agents; Coinfection; DNA, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis D, Chronic; Humans; Immunoglobulins; Lamivudine; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Organophosphonates; Secondary Prevention; Tenofovir; Treatment Outcome; Withholding Treatment; Young Adult

To investigate HBsAg clearance rate in previously untreated patients with HBeAg-positive chronic hepatitis B (CHB) treated with nucleos(t)ides and interferons and its influencing factors based on the clinical diagnosis and treatment dat.. A retrospective cohort study was conducted in 1 767 previously untreated HBeAg-positive CHB patients who visited Beijing You'an Hospital from February 14, 2008 to December 31, 2012. HBsAg clearance rates were calculated for patients with different characteristics, and the Cox regression model was used to investigate the influencing factors for HBsAg clearance.. The overall annual HBsAg clearance rate was 0.46% in 1767 patients, and in the patients treated with adefovir, entecavir, telbivudine, and common interferon, the annual HBsAg clearance rate was 0.52%, 0.47%, 0.45%, and 1.18%, respectively. No patients in the lamivudine and pegylated interferon-α groups experienced HBsAg clearance, which might be due to the small sample size. The univariate analysis showed that HBsAg clearance rate was associated with the patient's age when he/she visited the hospital and baseline HBsAg titer level. After adjustment for other factors, the patients treated with common interferon had a significantly higher possibility of HBsAg clearance than those treated with entecavir (HR = 8.33, 95% CI: 1.19-58.50, P = 0.0329), but the possibility of HBsAg clearance showed no significant difference between patients treated with other nucleos(t)ides and entecavir. The patients aged≥50 years had a probability of HBsAg clearance 4.92 times that of those aged < 50 years (HR = 4.92, 95% CI: 1.38-17.50, P = 0.0139) and the patients with baseline HBsAg titer level < 3 log10 IU/ml had a probability of HBsAg clearance 22.77 times higher than that of those with baseline HBsAg titer level≥3 log10 IU/ml (HR = 23.77, 95% CI: 6.17-91.51, P < 0.0001).. The previously untreated CHB patients achieve a low annual HBsAg clearance rate under current antiviral therapeutic regimens, especially nucleos(t)ides. Baseline HBsAg titer level is closely associated with HBsAg clearance.

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Organophosphonates; Retrospective Studies; Telbivudine; Thymidine; Treatment Outcome

To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naïve chronic hepatitis B patients receiving entecavir (ETV) monotherapy.. This study enrolled 73 antiviral-naïve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010.. During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naïve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (. The long-term clinical outcomes of antiviral-naïve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression.

Topics: Adenine; Adult; Alanine Transaminase; Antibodies, Viral; Antiviral Agents; Disease Progression; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Treatment Outcome

This study aimed to clarify the clinical significance of drug-resistant HBV in nucleoside/nucleotide analogue (NA)-naive Chinese patients with chronic HBV infection in real clinical practice.. A total of 845 NA-naive patients who were admitted to Beijing 302 Hospital between July 2007 and March 2012 were included in the study. HBV drug-resistant mutations were examined by direct sequencing of the viral reverse transcriptase gene and verified by clonal sequencing. Phenotypic analysis of viral replication capacity and drug susceptibility were performed by measuring viral replicative intermediate level in 1.1-mer mutant or wild-type HBV amplicon-transfected HepG2 cells in absence or presence of serially diluted drugs.. Drug-resistant mutations were detected in 2.01% (17/845) of the patients by direct sequencing, including 15 with lamivudine-resistant mutations (rtM204V, rtM204I), one with adefovir-resistant mutation (rtA181V), and one with both lamivudine- and adefovir-resistant mutations (rtA181V, rtM204I). Clonal sequencing identified 13 drug-resistant HBV strains: rtL80I+M204I, rtL80I+M204V, rtL180M+M204I, rtL180M+M204V, rtM204I, rtM204V, rtL80I+L180M+M204I, rtL80I+L180M+M204V, rtA181V, rtA181V+M204I, rtA181T+N236T, rtA181V+N236T and rtN236T. Phenotypic analysis showed that two pre-existing lamivudine-resistant strains (rtL80I+M204I, rtL180M+M204V) had >1,000-fold resistance to lamivudine, and one pre-existing adefovir-resistant strain (rtA181V+N236T) had 15.4-fold resistance to adefovir compared with the wild-type strain. A follow-up study showed that the presence of pre-existing rtM204I strain in one patient increased from 20% at baseline to 85% after 13 months of entecavir treatment with corresponding recession of wild-type strain in the viral pool.. The incidence of drug-resistant HBV mutations was low in NA-naive Chinese HBV-infected patients. Pre-existing mutants had similar resistance characteristics to those from NA refractory patients.

Topics: Adenine; Adult; Antiviral Agents; China; Clone Cells; Drug Resistance, Viral; Female; Gene Expression; Genotype; Guanine; Hep G2 Cells; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Organophosphonates; Phenotype; RNA-Directed DNA Polymerase; Sequence Analysis, DNA; Viral Proteins

Nucleoside/nucleotide analogue (NA) treatment causes selection pressure for HBV strains carrying mutations conferring NA resistance. Drug-resistance mutations occur in the reverse transcriptase (RT) region of the HBV polymerase gene and spontaneously arise during viral replication. These mutations can also alter the hepatitis B surface (HBs) protein and in some cases reduce binding to HBs antibodies. The spread of NA-resistant HBV may impact the efficacy of antiviral treatment and hepatitis B immunization programmes. In this study, we used direct sequencing to assess the occurrence of HBV carrying known mutations that confer NA resistance in the largest cohort of treatment-naive patients with chronic hepatitis B (CHB) to date.. HBV DNA samples isolated from 702 patients were sequenced and the RT region subjected to mutational analysis.. There was high genetic variability among the HBV samples analysed: A1 (63.7%), D3 (14.5%), A2 (3.3%), A3 (0.1%), B1 (0.1%), B2 (0.1%), C2 (0.9%), D1 (0.9%), D2 (4.6%), D4 (5.1%), D unclassified subgenotype (0.7%), E (0.6%), F2a (4.6%), F4 (0.4%) and G (0.4%). HBV strains harbouring mutations conferring NA resistance alone or combined with compensatory mutations were identified in 1.6% (11/702) of the patients.. HBV strains harbouring resistance mutations can comprise the major population of HBV quasispecies in treatment-naive patients. In Brazil, there is a very low frequency of untreated patients who are infected with these strains. These findings suggest that the spread and natural selection of drug-resistant HBV is an uncommon event and/or most of these strains remain unstable in the absence of NA selective pressure.

Topics: Adenine; Antibodies, Viral; Antiviral Agents; Brazil; DNA, Viral; Drug Resistance, Viral; Gene Products, pol; Genotype; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Microbial Sensitivity Tests; Mutation; Organophosphonates; Retrospective Studies; Sequence Analysis, DNA; Tenofovir; Virus Replication

Low-dose hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogs (lamivudine/adefovir) used for the prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) are associated with some risk of HBV recurrence and antiviral resistance.. The study cohort included 176 patients (at least >12 months follow-up) with HBV cirrhosis/hepatocellular carcinoma who received secondary prophylaxis with indefinite entecavir/tenofovir after living-donor LT (LDLT). All patients received 10,000 IU intravenous HBIG in anhepatic phase followed by 600-1000 IU intramuscularly daily for 7 days, weekly for 3 weeks, and then monthly, to keep antiHBs levels >100 mIU/mL for 1 year. Hepatitis B surface antigen (HBsAg) and HBV DNA were tested every 6 months.. The study cohort is composed of 157 men and 19 women, mean age 47.9 ± 10.1 years, all HBsAg positive, 35 (19.8%) had HBV DNA >2000 IU/mL before LT. After LT, patients received entecavir (n = 126, 71.5%), tenofovir (n = 20, 11.3%), or a combination of entecavir and tenofovir (n = 30, 17% for 3 months), followed by entecavir alone. During follow-up of 43 (12-117) months, 2 patients (including 1 with non-compliance) had HBV recurrence.. In a large cohort of LDLT recipients for HBV-related liver disease, use of low-dose short-term HBIG with high genetic barrier drugs results in a substantially lower incidence of HBV recurrence, even in high-risk patients.

Topics: Adenine; Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cohort Studies; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunoglobulins; Lamivudine; Liver Transplantation; Male; Middle Aged; Organophosphonates; Prospective Studies; Recurrence; Tenofovir

Entecavir (ETV) plus adefovir (ADV) combination therapy is one of the useful treatment option for the patients with chronic hepatitis B (CHB) who had failed on prior nucleos(t) ide analogue (NA) treatments. This study compared the efficacies of the combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients who had failed on prior multiple NA treatments. This retrospective analysis included 148 consecutive patients with CHB infection in Korea (n = 37 with ETV 0.5 mg plus ADV and n = 111 with ETV 1.0 mg plus ADV). The virological and biochemical responses were compared between the two groups. The cumulative probability of viral suppression of ETV 0.5 mg plus ADV was not inferior to that of ETV 1.0 mg plus ADV (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.38-1.08; P = 0.094). The changes in serum HBV DNA level in the ETV 0.5 mg plus ADV group were not different between the two groups over 12 months. Moreover, no significant difference was observed in acquiring ETV-resistant variants between the two groups during the treatment (HR, 0.95; P = 0.953). This study suggests the proof-of-concept that the lower dose of NA in combination with other NA might be the theoretical option for rescue combination therapy in patients with CHB who had failed on prior multiple NA treatments in order to reduce systemic exposure and possible side effects of NA.

Topics: Adenine; Adult; Aged; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Republic of Korea; Retrospective Studies; Time Factors; Treatment Failure; Treatment Outcome; Viral Load; Young Adult

Acute hepatitis B, caused by hepatitis B virus (HBV) strains with drug resistant mutations or pre-core/basal core promoter (PC/BCP) mutations, is a public health concern, because this infection is often associated with poor disease outcome or difficulty in therapeutic choice. The HBV genotype, the prevalence of drug resistant mutations, and PC/BCP mutations in Korean patients with acute hepatitis B were studied. From 2006 to 2008, 36 patients with acute hepatitis B were enrolled prospectively in four general hospitals. Among them, 20 showed detectable HBV DNA (median value was 4.8 log copies/mL). HBV genotyping and analysis of HBV mutations that conferred resistance against lamivudine, adefovir, or entecavir and of PC/BCP mutations were performed using highly sensitive restriction fragment mass polymorphism (RFMP) analysis. All 20 patients were infected with HBV genotype C, which causes almost all cases of chronic hepatitis B in Korea. No patient showed mutations that conferred resistance against lamivudine (L180M, M204V/I), adefovir (A181T, N236S), or entecavir (I169M, A184T/V, S202I/G, M250V/I/L). However, four patients had BCP mutations, and two had PC mutations. Platelet counts were significantly lower in the four patients with PC/BCP mutations compared to those with wild type. In this study, all acute hepatitis B patients had genotype C HBV strains with no drug resistant mutations. However, 20% showed PC/BCP mutations. This highlights the need for further study on the significance of PC/BCP mutations.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Genotype; Guanine; Hepatitis B; Hepatitis B Core Antigens; Hepatitis B virus; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Promoter Regions, Genetic; Prospective Studies; Republic of Korea; Viral Core Proteins; Virus Replication

In clinical practice, establishing a subsequent optimum treatment for chronic hepatitis B patients with a history of multiple NAs treatment failures, including a suboptimal response to a final therapy with combined ETV and ADV, is a complicated but crucial challenge. This study investigated the efficacy and safety of a tenofovir rescue regimen in these patients. A total of six eligible patients were enrolled and were switched to a tenofovir rescue regimen. At baseline, the genotypes and genotypic mutations of the reverse transcriptase and surface gene were determined by ultra-deep pyrosequencing, and further clonal analyses of the reverse transcriptase domain were performed to identify multidrug-resistant HBV strains. In addition, HBV DNA levels, serology, and biochemistry parameters were monitored at baseline and every 3 months, and abdominal ultrasonography was performed at baseline and every 6 months. All patients were confirmed to harbor LAM-related resistant HBV strains. After switching to the tenofovir rescue treatment, all patients had an undetectable level of HBV DNA within 6 months and achieved normalization of the ALT level within 9 months. These virological and biochemical responses persisted until the end of the observation period. None of the patients developed clinical deterioration or any adverse events related to the tenofovir therapy during the median 16.5-month follow-up. In conclusion, the tenofovir rescue regimen can be employed confidently as a highly effective and safe treatment choice following a suboptimal response to ETV plus ADV therapy for a subset of chronic hepatitis B patients with a history of multiple unsuccessful antiviral treatments.

Topics: Adenine; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; High-Throughput Nucleotide Sequencing; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; ROC Curve; Tenofovir; Treatment Failure; Treatment Outcome

Little is known about the optimal management of patients with chronic hepatitis B (CHB) who develop drug resistance. The aim of this study was to investigate the effectiveness of different drug regimens in chronically HBV-infected patients. HBV viral load was determined using a bDNA assay and the substitutions in HBV-DNA were studied by polymerase sequencing test. The study involved 38 patients who experienced a therapeutic failure to lamivudine (LAM). The sequential treatments used were: LAM + adefovir (ADV), LAM + tenofovir (TDF), entecavir (ETV) monotherapy, ADV monotherapy and TDF monotherapy. Similar activity against HBV replication was observed with all drug regimens. Of the patients treated with LAM, 44% developed resistance mutations. The rt M204I mutation was observed more frequently. Sequential ADV add-on LAM and TDF therapy induced the appearance of resistance in 3/18 (16.6%) and in 1/8 (5.5%) treated patients, respectively. Genotype D was the most prevalent (78.9%), followed by genotype A (13%), genotype E (5.2%) and genotype C (2.6%). Our study showed that baseline serum HBV DNA is an important predictor of virologic response and that virologic breakthrough is significantly associated with the insurgence of genotypic resistance.

Topics: Adenine; Adult; Aged; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Tenofovir; Treatment Outcome; Viral Load; Viral Matrix Proteins; Young Adult

Analysing the mutation pattern of multidrug resistance (MDR) is important in the treatment of chronic hepatitis B (CHB). In this study, the evolutionary pattern of MDR mutations was investigated in patients receiving entecavir (ETV) rescue therapy.. Eight CHB patients with lamivudine (LAM)- and adefovir (ADV)-resistant mutations showing suboptimal response to ETV and to subsequent ETV-plus-ADV therapy were enrolled. The clonal evolution of the mutation pattern was investigated through direct sequencing, multiplex restriction fragment mass polymorphism (RFMP), and clonal analysis and the utility of these methods was compared.. Among 160 clones at baseline, wild-type hepatitis B virus (HBV) was present in 62 (38.8%), LAM-resistant mutations in 92 (57.6%) and ADV-resistant mutations in 55 (34.4%). LAM-resistant mutations increased to 70.6% at the end of ETV therapy and increased to 74.4% at the 12th month of ETV-plus-ADV therapy. During the same time periods, ETV-resistant mutations were present in 46.3% and 38.8%, and ADV-resistant mutations were present in 3.1% and 9.4% respectively. When 256 nucleotides from 32 samples were examined for mutations, clonal analysis detected 93 mutations (36.3%), direct sequencing detected 36 mutations (14.1%) and RFMP detected 73 mutations (28.5%). The sensitivity (73.1%, 95% CI; 64.1-82.1%) and specificity (96.9%, 95% CI; 94.4-99.4%) of RFMP were high, showing a concordance rate of 88.3% with the results from clonal analysis. All mutations exceeding 40% of the total clones detected by clonal analysis were also detected by RFMP.. The clonal evolution of the mutation pattern in MDR HBV showed the selection of LAM-resistant (±ETV-resistant) HBV during ETV rescue therapy, which may be the primary reason for patients' suboptimal response. Multiplex RFMP is a useful method for detecting MDR mutations in clinical practice.

Topics: Adenine; Adult; Antiviral Agents; Clonal Evolution; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Viral Load

Monotherapy with telbivudine or adefovir can affect estimated the glomerular filtration rate (eGFR). However, only a few studies have assessed changes in eGFR in patients who have chronic hepatitis B (CHB) and are receiving nucleos(t)ide analogue (NA) combination therapy. In our study, we aimed to evaluate the effects of long-term NA combination therapy on eGFR in Chinese CHB patients. This retrospective study included 195 CHB patients. Patient subgroups included those treated with lamivudine plus adefovir (n = 73), telbivudine plus adefovir (n = 51), and entecavir plus adefovir (n = 35); untreated patients (n = 36) served as a control group. After an average follow-up duration of 24 months with combination therapy, analysis of changes in eGFR from baseline values, calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) formulas, showed decrease by 11.08 and 18.34 mL/min (P < .001), respectively, in the lamivudine plus adefovir group; decrease by 3.73 and 10.04 mL/min (P = .012), respectively, in the entecavir plus adefovir group; and increase by 0.91 and 2.12 mL/min (P = .46), respectively, in the telbivudine plus adefovir group. The eGFR in the telbivudine plus adefovir group was similar to that for the untreated group. The eGFR decreases due to adefovir therapy could be rescued by adding telbivudine, and the eGFR increase due to telbivudine could be compromised by adding adefovir. Adefovir in combination with lamivudine or entecavir therapy was significantly associated with decreased eGFR, but telbivudine could rescue the eGFR decrease that results from adefovir treatment.

Topics: Adenine; Adult; Aged; Antiviral Agents; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Nucleosides; Nucleotides; Organophosphonates; Retrospective Studies; Telbivudine; Thymidine

Hepatitis B immune globulin (HBIg) in combination with a nucleos(t)ide analog is the mainstay of prophylactic regimen to prevent recurrence of hepatitis B following orthotopic liver transplantation (OLT). HBIg therapy is costly and inconvenient for the patients. There is a growing experience converting HBIg/nucleos(t)ide to combination nucleotide/nucleoside analogs from.. Twenty-six patients that underwent OLT between March 2001 and July 2011 who had received at least 12 months of HBIg and single nucleos(t)ide were enrolled. HBsAg and HBV DNA were undetectable, and anti-HBs were detectable at the time of switch. HBV DNA and HBsAg were measured every 3 months following discontinuation of HBIg and addition of nucleos(t)ide.. Patients included 23 Asians/3 Caucasian, 21 males/5 females. Mean time of conversion from HBIg/nucleos(t)ide to nucleoside/nucleotide combination was 77.5 (range 11-132) months after OLT. Mean duration of follow-up after conversion was 31.9 (range 14-70) months. All patients had undetectable HBV DNA, and 24 patients remained HBsAg negative during follow-up. Two patients recurred 7 and 9 months later, respectively, with detectable HBsAg. Both patients continued to have undetectable HBV DNA and normal ALT. HBsAg was neutralized by reinfusion of HBIg.. Nucleoside/nucleotide combination is an effective alternative to HBIg/nucleos(t)ide to prevent recurrence of hepatitis B after OLT.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunoglobulins; Lamivudine; Liver Transplantation; Male; Middle Aged; Organophosphonates; Prospective Studies; Recurrence; Tenofovir

In the past decade, many chronic hepatitis B (CHB) patients have undergone sequential treatment with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) to manage antiviral resistance or insufficient suppression of HBV-DNA. Very limited data are available on the efficacy of tenofovir (TDF) rescue regimens in patients with multidrug resistance (MDR).. We investigated the antiviral efficacy of TDF/LAM combination therapy versus TDF/ETV combination therapy in 52 patients who failed three previous antiviral therapies.. The study subjects were treated with TDF/LAM combination therapy (n = 25) or TDF/ETV combination therapy (n = 27) for more than six months. Virologic response (VR) occurred in 39 (75%) patients (19 patients belonged to the TDF/LAM group and 20 patients belonged to the TDF/ETV group). The VR rates were not different between the TDF/LAM and TDF/ETV groups (56.0% vs 51.9% at month 12, and 72.0% vs 78.8% at month 18; log rank P = 0.515). In addition, treatment efficacy of TDF/LAM combination or TDF/ETV combination was not statistically different according to types of MDR. In multivariate analysis, absolute HBV-DNA level at the start of TDF rescue treatment (P < 0.001; OR, 0.452; 95% CI, 0.306-0.666) was only significantly associated with VR.. TDF/ETV combination therapy was not associated with higher rate of VR compared with TDF/LAM combination therapy in MDR CHB patients. These results raise the suspicion about the superiority of the combination therapy over TDF monotherapy. The lower HBV-DNA levels at the start of TDF-based rescue therapy were associated with higher VR.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Multiple; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Multivariate Analysis; Organophosphonates; Tenofovir; Treatment Failure

The presence of therapy-associated hepatitis B virus (HBV) variants is the main drawback of antiviral therapy for HBV infection. Moreover, drug-resistant variants are more insensitive to a second agent and more therapy-associated mutations will be present. To apply better nucleos(t)ide analogues (NA) and reduce the occurrence of resistance, the prevalence and types of drug-resistant mutations in acute hepatitis B patients were investigated in this study. One hundred three HBV DNA-positive patients with symptomatic acute hepatitis B that were observed from 2011 to 2013 were enrolled. Direct polymerase chain reaction sequencing was used firstly to screen HBV reverse-transcriptase domain to detect HBV mutants. Five lamivudine-resistant variants were identified. Clonal sequencing was performed for 5 resistance-positive samples and 10 other random samples. Interestingly, all detected samples harbored drug-resistant mutations, although with different percentage. Thirteen harbored lamivudine-related alone (five) or together with other NA related mutations (five with adefovir, one with entecavir, and one with telbivudine), and two of them harbored adefovir-related mutations. Also, mutations associated with four currently used NA were all detected, and the frequency is in accordance with the popularity of NA used in clinical practice. These data suggest that drug-resistant variants are present in patients with acute hepatitis B and NA should be applied more carefully for chronic hepatitis B patients developed from acute hepatitis B.

Topics: Adenine; Adult; Antiviral Agents; China; DNA, Viral; Drug Resistance, Viral; Female; Genetic Variation; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation, Missense; Organophosphonates; Prevalence; RNA-Directed DNA Polymerase; Telbivudine; Thymidine; Time Factors; Young Adult

Exomethylene acycloguanine nucleosides 4, 6 and its monophosphate derivatives 5, 7, and 8 have been synthesized. Mitsunobu-type coupling of 2-N-acetyl-6-O-diphenylcarbamoylguanine (11) with primary alcohols proceeded regioselectively to furnish the desired N(9)-substituted products in moderate yield. Evaluation of 4-8 for anti-HBV activity in HepG2 cells revealed that the phosphonate derivative 8 was found to exhibit moderated activity (EC50 value of 0.29 μM), but cytotoxicity (CC50 value of 39 μM) against the host cells was also observed.

Topics: Adenine; Antiviral Agents; Drug Design; Guanine; Hep G2 Cells; Hepatitis B virus; Humans; In Vitro Techniques; Organophosphonates

The emergence of compensatory mutations in the polymerase gene of drug resistant hepatitis B virus (HBV) is associated with treatment failure. We previously identified a multi-drug resistant HBV mutant, which displayed resistance towards lamivudine (LMV), clevudine (CLV), and entecavir (ETV), along with a strong replication capacity. The aim of this study was to identify the previously unknown compensatory mutations, and to determine the clinical relevance of this mutation during antiviral therapy. In vitro mutagenesis, drug susceptibility assay, and molecular modeling studies were performed. The rtL269I substitution conferred 2- to 7-fold higher replication capacity in the wild-type (WT) or YMDD mutation backbone, regardless of drug treatment. The rtL269I substitution alone did not confer resistance to LMV, ETV, adefovir (ADV), or tenofovir (TDF). However, upon combination with YMDD mutation, the replication capacity under LMV or ETV treatment was enhanced by several folds. Molecular modeling studies suggested that the rtL269I substitution affects template binding, which may eventually lead to the enhanced activity of rtI269-HBV polymerase in both WT virus and YMDD mutant. The clinical relevance of the rtL269I substitution was validated by its emergence in association with YMDD mutation in chronic hepatitis B (CHB) patients with sub-optimal response or treatment failure to LMV or CLV. Our study suggests that substitution at rt269 in HBV polymerase is associated with multi-drug resistance, which may serve as a novel compensatory mutation for replication-defective multi-drug resistant HBV.

Topics: Adenine; Amino Acid Substitution; Antiviral Agents; Arabinofuranosyluracil; Cell Line, Tumor; Drug Resistance, Multiple, Viral; Gene Products, pol; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Microbial Sensitivity Tests; Models, Molecular; Organophosphonates; Tenofovir; Virus Replication

Regardless of significant improvement in the area of anti-HBV therapy, resistance and cross-resistance against available therapeutic agents are the major consideration in drug discovery of new agents. The present study is to obtain the insight of the molecular basis of drug resistance conferred by the B and C domain mutations of HBV-polymerase on the binding affinity of four anti-HBV agents [Adefovir (ADV), Tenofovir (TNF), Entecavir (ETV) & 2'-Fluoro-6'-methylene-carbocyclic adenosine (FMCA)]. In this regard, homology modeled structure of HBV polymerase was used for minimization, conformational search and Glide XP docking followed by binding energy calculation on wild-type as well as on mutant HBV-polymerases (N236T, L180M+M204V+S202G & A194T). Our studies suggest a significant correlation between the fold resistances and the binding affinity of anti-HBV nucleosides. The domain B residue, L180 is indirectly associated with other active-site hydrophobic residues such as A87, F88 and M204, whereas the domain C residue, M204 is closely associated with sugar/pseudosugar ring positioning in the active site. These hydrophobic residues can directly influence the interaction of the incoming nucleoside triphosphates and change the binding efficacy. The carbohydrate ring part of natural substrate dATP, dGTP, FMCA and ETV, are occupied in similar passion in the grooves of HBV polymerase active site. The exocyclic double bond of Entecavir and FMCA occupies in the backside hydrophobic pocket (made by residues A87, F88, L180and M204), which enhances the overall binding affinity. Additional hydrogen bonding interaction of 2'-fluorine of FMCA with R41 residue of polymerase promotes a positive binding in wild-type as well as in ADVr, ETVr and TNFr with respect to that of entecavir.

Topics: Adenine; Adenosine; Amino Acid Sequence; Antiviral Agents; Binding Sites; Catalytic Domain; Databases, Protein; Drug Resistance, Viral; Gene Products, pol; Guanine; Hepatitis B; Hepatitis B virus; HIV Reverse Transcriptase; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Molecular Sequence Data; Mutation; Organophosphonates; Sequence Alignment; Tenofovir

To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients.. Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by real-time PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a log-rank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively.. Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.. If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Viral Load; Young Adult

We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy.. We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months.. The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period.. In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Odds Ratio; Organophosphonates; Real-Time Polymerase Chain Reaction; Retrospective Studies; Tenofovir; Viral Load

Hepatitis B virus (HBV) infection is a critical global health issue and moderately epidemic in Western China, but HBV molecular epidemiology characteristics are still limited. We conducted this study to investigate HBV genotypes and antiviral resistant mutations in this multi-ethnic area. A total of 1316 HBV patients were recruited from four ethnic groups from 2011 to 2013. Genotypes and resistant mutations were determined by Sanger sequencing. Four genotypes (B, C, D and C/D) were identified. Genotype B and C were common in Han population, while genotype D was predominant in Uygurs. Genotype C was the major genotype in both Tibetans and Yis, and recombinant C/D was found in Tibetans only. Lamivudine resistance was common in all populations, especially in Hans with prevalence of 42.8%. Entecavir resistance was barely observed regardless of ethnicity. Genotype C isolates had higher rates of rtA181T/V than genotype B (13.5% vs. 5.1%, P < 0.001), in accordance with higher prevalence of resistance to adefovir (20.0% vs. 9.5%, P < 0.001). While incidence of resistant mutations to other drugs and clinical factors showed no difference among different genotypes. HBV genotypes and resistance-conferring mutations had different geographic and demographic distributions in Western China, which provided molecular epidemiology data for clinical management.

Topics: Adenine; Adult; Antiviral Agents; China; DNA, Viral; Drug Resistance, Viral; Ethnicity; Female; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Molecular Epidemiology; Mutation; Organophosphonates; Prevalence

There is increasing concern about the potential for nephrotoxicity in patients with chronic hepatitis B (CHB) treated long-term with nucleotide analogs.. We examined renal dysfunction and its associated risk factors in patients with CHB treated with antiviral regimens containing either nucleosides or nucleotide analogs. We undertook a retrospective cohort study from 2006 to 2014 at the Hospital for Tropical Diseases, Bangkok, Thailand, and analyzed the data of 102 patients with a median follow-up time of 44.5 months (range 4-101 months).. Seventy-three patients were treated with an antiviral regime containing a nucleoside analog, and 29 with a regime containing a nucleotide analog. Abnormally elevated serum creatinine concentration was observed in 12 patients (11.8 %) after 8 years of treatment. Thirty one percent of patients treated with nucleotide analogs had elevated serum creatinine levels and three of these patients (10.3 %) developed nephrotoxicity. In contrast, serum creatinine concentrations were elevated in three of the 73 patients treated with a nucleoside analog (4.1 %), and none developed nephrotoxicity. The incidence of renal dysfunction by the nucleotide analog regimen was cumulative, with 11.1, 21.0, 26.5 and 47.6 % of patients affected after 2, 4, 6 and 8 years, respectively. Univariate and multivariate analysis indicated that a nucleotide analog-based regimen significantly predicted renal dysfunction (odds ratio 10.5, 95 % confidence intervals 2.6-42.4, P <0.001).. The long-term use of nucleotide analogs increased the risk of nephrotoxicity in patients with CHB. Thus, the regular assessment of renal function is recommended for all patients with CHB, particularly those treated with a nucleotide analog.

Topics: Adenine; Adult; Antiviral Agents; Creatinine; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Hospitals; Humans; Incidence; Kidney Diseases; Lamivudine; Male; Middle Aged; Nephrons; Organophosphonates; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Telbivudine; Tenofovir; Thailand; Thymidine; Tropical Medicine

We investigated the long-term efficacy of entecavir (ETV) + adefovir (ADV) combination therapy versus ETV monotherapy in lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients who failed to respond to ADV rescue therapy.. A total of 91 ADV refractory patients with prior LAM resistance received ETV (1.0 mg/day) + ADV (10 mg/day) combination therapy (group A, n = 45) or ETV (1.0 mg/day) monotherapy (group B, n = 46) for more than 48 weeks.. The rates of undetectable serum hepatitis B virus DNA levels (≤20 IU/ml) at weeks 48 and 96 were not significantly different between group A and group B (31.1 vs. 23.9% at week 48, p = 0.442, and 44.7 vs. 34.5% at week 96, p = 0.457). However, the incidence of virological breakthrough in group A was significantly lower than that in group B (0 vs. 17.4% at week 48, p = 0.006, and 2.6 vs. 44.8% at week 96, p < 0.001). ETV monotherapy was the only independent factor significantly associated with virologic breakthrough (p = 0.015).. ETV + ADV combination therapy is a better therapeutic option than ETV monotherapy for ADV refractory CHB patients with prior LAM resistance.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Treatment Outcome

Entecavir (ETV) plus adefovir (ADV) combination therapy may be a promising option for chronic hepatitis B (CHB) patients who have failed on prior nucleos(t)ide analog (NA) treatment. However, the long-term efficacy and safety of this combination are not well-defined. In a single-center, retrospective study, 104 patients (mean age 31.7 years; 88.5% male) with HBV DNA >10(3)IU/mL who had received one or multiple prior NAs for ⩾ 6 months (median 44.5 months) were treated for ⩾ 24 months with ETV (0.5mg/day) plus ADV (10mg/day). Among patients with available samples, 44/90 (48.9%) had drug-resistant mutations. At 2 years, HBV DNA levels were undetectable (<12 IU/mL) in 52/104 (50.0%) patients. The mean HBV DNA level was 2.0 ± 1.2 log 10 IU/mL, and it was decreased by 3.2 ± 2.0 log 10 IU/mL from the pre-combination treatment (V0) value. The 2-year HBeAg loss rate was 14.4% (13/90), HBeAg seroconversion rate was 10.0% (9/90), and ALT normalization rate was 75%. In multivariate analyses, the prior NA treatment duration, the V0 HBV DNA level, and the HBV DNA reduction at 1 year after ETV+ADV therapy were associated with the virological response after 2 years. No patients developed renal impairment, clinical decompensation or new HCC, and no relapses of HCC or deaths occurred. Thus, 2-year rescue therapy with ETV+ADV was effective and well-tolerated in CHB patients who had previously failed on multiple NA treatments. The HBV DNA level just before ETV+ADV combination therapy and the decrease of HBV DNA at 1 year could predict the efficacy of 2 years of ETV+ADV treatment.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; Cohort Studies; DNA, Viral; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Organophosphonates; Retrospective Studies; Salvage Therapy; Treatment Outcome

Hepatitis B virus (HBV) DNA levels are crucial for managing chronic hepatitis B (CHB). It was unclear whether Daan real-time polymerase chain reaction test (Daan test) or COBAS TaqMan HBV DNA Test (Cobas TaqMan) was superior in measuring different HBV DNA levels in clinical specimens.. We enrolled 67 treatment-naïve, HBV surface antigen-positive CHB patients (high baseline viral levels) who received either lamivudine/adefovir or entecavir. Serum samples were tested at baseline and treatment week 24 using the Daan test and Cobas TaqMan.. In the 67-baseline samples, the HBV DNA levels with the Cobas TaqMan (7.90 ± 0.73 log10 IU/mL) were significantly greater than those of the Daan test (7.11 ± 0.44 log10 IU/mL; P < 0.001). Of the 67 24-week samples (low viral levels), the Cobas TaqMan detected 59 (88.1%; 8 undetected); the Daan test detected 33 (49.3%; 34 undetected; P < 0.001). The Cobas TaqMan detected HBV DNA in 26 of 34 samples undetectable by the Daan test (range, 1.4-3.7 log10 IU/mL) or 38% of samples (26/67). The reductions in viral load after 24 weeks of oral antiviral treatment in the 33 samples that were positive for both the Daan test and the Cobas TaqMan test were significantly different (3.59 ± 1.11 log10 IU/mL versus 4.87 ± 1.58 log10 IU/mL, respectively; P = 0.001). Spearman correlation analysis showed positive correlation between results from two tests (rp = 0.602,P<0.001). The HBV genotypes and the anti-viral treatment did not affect the measurements of the HBV DNA by the Daan assay and the Cobas Taqman assay.. The Cobas Taqman was more sensitive at low viral loads than the Daan test and the change from complete to partial virological response could affect clinical decisions. The Cobas Taqman may be more appropriate for detection of HBV DNA levels.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Polymerase Chain Reaction; Prospective Studies; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Sensitivity and Specificity; Viral Load; Young Adult

Emergence of lamivudine (LAM) resistance causes treatment failure in patients with chronic hepatitis B and compromise the efficacy of subsequent salvage therapies with other nucleot(s)ide analogs (NAs). Establishment of cell-based assays supporting LAM-resistant hepatitis B virus (HBV) replication will not only provide tools for investigating the replication property, but also screening for antiviral agents efficiently inhibiting the replication of LAM-resistant HBV variants. Accordingly, a human hepatoma (HepG2)-derived cell line was established by stable transfection of a plasmid containing a 1.2 unit length of HBV genome harboring rtL180M and rtM204V mutations that confer LAM resistance. In addition to support efficient viral genome replication, the cell line also produces high levels of HBV virions and subviral particles. As expected, HBV DNA replication in this cell line is completely resistant to lamivudine, but sensitive to adefovir (ADV), entecavir (ETV) and tenofovir (TDF). The cell line is suitable for screening for antiviral agents that inhibit LAM-resistant HBV replication and inhibitors of HBsAg biosynthesis and secretion, which may reduce HBsAg antigenemia and ultimately help to restore host antiviral immune response against HBV and cure chronic HBV infection.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hep G2 Cells; Hepatitis B virus; Hepatocytes; Humans; Lamivudine; Organophosphonates; Tenofovir; Virus Replication

The optimal duration of antiviral therapy for kidney transplant recipients (KTR) with chronic hepatitis B virus (HBV) infection remains unclear. We reported the long-term outcomes after withdrawal of antiviral agent in KTR with chronic HBV infection.. We retrospectively investigated the hepatitis B surface antigen (HBsAg)-positive KTR with antiviral agents between January 2002 and January 2012. Antiviral treatments were withdrawn in patients who met all of the following 7 criteria: (i) no clinical and histologic evidence of cirrhosis, (ii) normal liver biochemistry, (iii) negative for both HBV DNA and hepatitis B envelope antigen (HBeAg), (iv) no resistance to antiviral agent, (v) antiviral therapy > 9 months, (vi) maintenance dosage of immunosuppressant for > 3 months, and (vii) no history of acute rejection during recent 6 months. All patients were followed regularly at approximately 3-6 months for liver enzyme, viral markers, and HBV DNA level after antiviral withdrawal.. Among a total of 445 KTR, 14 HBsAg-positive patients were included in this study. Antiviral agents were used, with lamivudine in 11 patients, and with adefovir, entecavir, and telbivudine in 3 patients, respectively. Discontinuation of antiviral agent was attempted in 6 (42.9%) of 14 patients who satisfied the criteria. The median duration of antiviral therapy before withdrawal was 14.3 months (range, 9-24 months). Four (66.7%) of 6 patients were successfully withdrawn and remained negative for HBV DNA for a median 60.5 months (range, 47-82 months). The baseline HBV DNA level was not related to maintenance of remission after withdrawal. Two reactivated patients resumed antiviral treatment immediately, with subsequent normalization of HBV DNA. During the follow-up, 1 patient developed hepatocellular carcinoma; however, no patient death or graft failure was reported for all HBsAg-positive KTR.. Antiviral therapy can be discontinued successfully and safely in selected KTR with chronic HBV infection, after complete suppression of HBV and sufficient duration of antiviral therapy.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Telbivudine; Thymidine; Time Factors; Virus Activation; Withholding Treatment

Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2014, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection.. A hepatitis B- és D-vírus-fertőzés időben történő felfedezése és kezelése a beteg szempontjából a munkaképesség megőrzését, az életminőség javulását, rákmegelőzést, valamint a betegségmentes várható élettartam meghosszabbodását, a beteg környezete és a társadalom szempontjából a továbbfertőzés veszélyének megállítását és a kezelés révén a későbbi súlyos májbetegségekből adódó jelentős egészségügyi ráfordításigény-csökkenést jelent. Az irányelv célja a 2014. évre érvényes, a kezelőorvosok konszenzusán alapuló kezelési rend rögzítése. A magyar lakosság 0,5–0,7%-át sújtó hepatitis B-vírus-fertőzés kezelésének indikációja a vírusdiagnosztikán (benne vírusnukleinsav kimutatása), a májbetegség aktivitásának és stádiumának értékelésén (beleértve biokémiai, patológiai és/vagy nem invazív vizsgálómódszereket), valamint az ellenjavallatok kizárásán alapul. Az ajánlás hangsúlyozza a kivizsgálás során a gyors és részletes virológiai vizsgálatok jelentőségét, a biopszia mellett a tranziens elasztográfia, illetve egyéb, validált, noninvazív tesztek alkalmazhatóságát csakúgy, mint a terápia vezetésében a vírusnukleinsav-titer követésének nélkülözhetetlenségét mind a mellékhatások elkerülése, mind a költséghatékonyság szempontjából. Az idült hepatitis B kezelésében egyaránt első választás lehet a határozott – egyéves – időtartamú pegilált interferon vagy a folyamatos entecavir- vagy tenofovirkezelés, amelyet a hepatitis B felszíni antigén szerokonverziója után még legalább 12 hónapig kell folytatni. Az adefovir leginkább kombinációban javasolható. Nem megfelelő első választás a lamivudin, az ezt már szedő betegeket hatástalanság esetén másik szerre kell átállítani. Fontos az immunszuppresszív kezelésben és/vagy biológiai terápiában részesülő betegek megfelelő antivirális kezelése. Egyidejű hepatitis D esetén pegilált interferon kezelés szükséges. Orv. Hetil., 2014, 155(Szuppl. 2), 25–35.

Topics: Adenine; Antiviral Agents; Consensus; Drug Administration Schedule; Drug Therapy, Combination; Evidence-Based Medicine; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans; Hungary; Interferon-alpha; Lamivudine; Liver Neoplasms; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir

The aim of the present study was to assess the long-term impact of entecavir (ETV) on T, B and natural killer (NK) cell immunity in patients with suboptimal responses to adefovir (SRA) chronic hepatitis B (CHB). Thirty SRA CHB patients and 20 age- and gender-matched healthy controls (HC) completed at least 6 months of ETV treatment. Hepatitis B virus (HBV) DNA loads, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the frequency of different subsets of T, B and NK cells in individual subjects were measured. There were smaller numbers of CD3(-) CD56(+) and CD244(+) NK cells, CD3(+) CD8(+) T cells and cytokine-secreting CD4(+) T cells, but greater numbers of CD3(+) CD4(+) , CD4(+) CD25(+) Foxp3(+) , CD4(+) CD25(+) CD127(low) T cells and CD19(+) CD27(+) B cells, detected in SRA patients. After switching to ETV monotherapy, the levels of HBV DNA and hepatitis B s antigen, as well as hepatitis B e antigen seropositivity, decreased gradually, accompanied by decreases in ALT and AST levels. Furthermore, the number of NK, CD8(+) and cytokine-secreting CD4(+) T cells increased, whereas the number of CD4(+) , CD4(+) CD25(+) Foxp3(+) , CD4(+) CD25(+) CD127(low) T cells and CD19(+) CD27(+) B cells decreased, in SRA CHB patients. The frequency of CD4(+) interferon-γ-positive T cells was negatively associated with serum HBV DNA levels. Thus, treatment with ETV inhibits HBV replication, modulates T and NK cell immunity and improves liver function in SRA CHB patients.

Topics: Adenine; Antiviral Agents; B-Lymphocytes; Case-Control Studies; CD4-Positive T-Lymphocytes; DNA, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Organophosphonates; Tumor Necrosis Factor Receptor Superfamily, Member 7; Viral Load

Some reports have documented the coexistence of Hepatitis B surfage Antigen (HBsAg) and anti-HBsAg antibodies (HBsAb) in patients with chronic hepatitis B (CHB), often in the absence of amino acid substitutions in the HBsAg sequences of the Hepatitis B Virus (HBV) genome able to explain an immunological escape variant.HBV genome has a very compact coding organization, with four partially overlapping open reading frames (ORFs). Because the reverse transcriptase region (rt) of HBV polymerase overlaps the HBsAg ORF, it is possible that some mutations in the HBsAg region correspond to mutations in the rt ORF, conferring resistance to current antiviral therapies. This unique case explores the response to antiviral therapies of a CHB with concurrent HBsAg and HBsAb positivity, and analyse the clinical implications of possible mutations in rt and HBsAg ORFs.. Here we describe the case of a 59 year-old Italian man suffering from Hepatitis B envelope Antigen (HBeAg) positive CHB with concurrent HBsAb positivity. By ultra-deep pyro-sequencing (UDPS) technique, mutations conferring immunological escape or resistance to antiviral therapies were found neither in HBsAg nor in HBV rt ORFs, respectively. The patient was unsuccessfully treated with interferon, adefovir monotherapy and adefovir plus entecavir combination. Surprisingly, during entecavir plus tenofovir combination, anti-HBe seroconversion and HBsAg loss were observed, while the titer of HBsAb persisted.. Concurrent HBsAg/HBsAb positivity in active CHB is a clinical and virological dilemma. In this setting, there are not consistent data about the response to conventional therapies and the immunological balance between host and virus remains so far unexplained. This is, to our knowledge, the first case described of a CHB with HBsAg/HBsAb positivity, wild type for clinically relevant mutations in HBsAg and rt ORFs, successfully treated with a combination of nucleot(s)ide analogues (NAs).

Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B Antibodies; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Organophosphonates; Recombinant Proteins; Tenofovir; Treatment Failure; Treatment Outcome; Viral Load

This study was designed to prospectively evaluate the antiviral responses and evolution of resistance mutations during adefovir (ADV) plus lamivudine (LMV) therapy in patients with entecavir (ETV)-resistant hepatitis B virus (HBV) infection.. Twenty chronic hepatitis B (CHB) patients who had been receiving ETV for more than 6 months and developed virologic breakthrough due to ETV resistance were consecutively enrolled.. Patients received ADV plus LMV therapy for 12 months. The baseline mean serum HBV DNA level was 5.59 ± 1.28 log10 IU/ml. The rtT184L/I/A/F (50%), rtS202G (25%) and mixed ETV-resistant mutations (25%) were detected at enrollment. The mean reduction in serum HBV DNA levels from baseline to 12 months was -2.3 ± 1.06 log10 IU/ml (p < 0.001). Seventeen patients were followed up for the full 12 months, and complete virologic response (HBV DNA <20 IU/ml) was observed in 4 patients (23.5%). Among the remaining 13 patients who still had detectable HBV DNA, 7 patients showed disappearance of ETV-resistant mutations or reduction of the proportion of ETV-resistant mutants. An ADV- and LMV-resistant mutant (rtA181T) emerged in 2 patients (11.7%).. ADV plus LMV combination therapy suppresses ETV-resistant mutants in the viral population and significantly reduces serum HBV DNA levels in ETV-resistant CHB patients.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Prospective Studies; Serum; Treatment Outcome; Viral Load

Since the licensing of lamivudine in 1999, the treatment of chronic hepatitis B has been revolutionized by the introduction of oral nucleoside and nucleotide analogues (NAs), which act as inhibitors of the HBV polymerase. The effectiveness of the first of these substances was limited by incomplete response and resistance development in many patients, but today, highly potent substances are available that make a reliable and durable suppression of HBV replication, a reduction of necroinflammatory activity in the liver, and even a reversion of liver fibrosis achievable for almost all patients. Beyond that, NA treatment can prevent the development of hepatocellular carcinoma in many patients. HBeAg seroconversion appears in approximately 50% of all HBeAg-positive patients during NA treatment. However, the ideal treatment endpoint, the serologic loss of HBsAg, remains a rare event almost exclusively achievable for HBeAg-positive patients. After cessation of the treatment, HBV replication tends to relapse in most patients, which is why the duration of NA treatment is indefinite. Future treatment strategies should aim at tailoring individual NA treatment regimens to increase HBs loss rates and optimize treatment duration.

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Carcinoma, Hepatocellular; Gene Products, pol; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver; Liver Cirrhosis; Liver Neoplasms; Organophosphonates; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Telbivudine; Tenofovir; Thymidine; Treatment Outcome; Virus Replication

Hepatitis B virus (HBV) resistance to nucleos(t)ide analogue (NA) therapy is essentially structure specific, with each NA falling within three main structural groups. Resistance to each of these is characterized by specific mutations in the reverse transcriptase domains of the HBV polymerase, and may be associated with compensatory mutations which can increase replication. HBV polymerase is considered to have a traditional 'right-handed' structural conformation, and each of the resistance mutations is predicted to cause a specific structural change of the polymerase, thereby preventing incorporation of NA into replicating DNA. The selection of resistance occurs at different rates for each NA, and is affected by the high mutational rate of HBV and the ability of the drug to suppress viral replication. Some mutations or combinations of mutations may be associated with multidrug resistance, limiting treatment options. In contrast to most other viruses, resistance in HBV is confounded by the overlapping surface gene, the major NA-resistant mutations also altering the surface proteins in most cases, potentially altering virus secretion and neutralization, which may pose a public health threat in the future.

Topics: Adenine; Amino Acid Substitution; Antiviral Agents; Deoxycytidine; Drug Resistance, Multiple, Viral; Emtricitabine; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Telbivudine; Tenofovir; Thymidine; Virus Replication

Drug resistance testing, genotype analysis, and the determination of immune and vaccine escape variants support personalized antiviral treatment for hepatitis B patients. As phenotypic drug resistance testing for hepatitis B virus (HBV) is especially labor-intensive, due to the lack of simple cell culture systems, genotypic methods play a very pronounced role. The genetic structure of HBV allows the simultaneous analysis of two different genes by examination of a single region in the genome of HBV. Nevertheless, the overlapping open reading frames of the hepatitis B surface antigen (HBsAg) and the reverse transcriptase (RT) have to be interpreted separately. In diagnostic procedures, standard Sanger type sequencing (mostly performed as a dye-dideoxynucleotide terminator system) is still the most commonly used method. This allows using established techniques for interpreting those types of genetic information. Besides reviewing the foundation of drug resistance interpretation for HBV, different interpretation systems, either commercially available (TRUGENE, Abbott, ViroScore) or free to use (geno2pheno[HBV], HIV-GRADE HBV tool), are compared in this article.

Topics: Adenine; Antiviral Agents; Base Sequence; Drug Resistance, Multiple, Viral; Genotype; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immune Evasion; Lamivudine; Microbial Sensitivity Tests; Organophosphonates; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Sequence Analysis, DNA; Telbivudine; Tenofovir; Thymidine

The treatment of HBeAg-negative chronic hepatitis B (CHB) is considered to be open-ended, with no guidelines for treatment cessation.. To evaluate biochemical and virological relapse requiring retreatment in noncirrhotic HBeAg-negative CHB in patients who stopped treatment following a period of prolonged viral suppression with nucleotides/nucleosides.. We performed a single-centre retrospective chart review of patients with HBeAg-negative CHB who maintained viral suppression for 4-5 years on anti-viral treatment, and thus subsequently stopped treatment. The primary end point of composite relapse was defined by an increase in HBV DNA >2000 IU/mL, ALT elevation above 1.25 × normal or doubling of ALT from cessation, and re-initiation of anti-viral therapy.. We identified 33 patients with HBeAg-negative CHB who stopped treatment following viral suppression. Mean treatment duration was 5.28 ± 2.73 years. Patients were treated with lamivudine (3), adefovir (14), entecavir (4), and tenofovir (12). Eleven (33%) patients met the primary end point of composite relapse. For individual end points, 21 (63%) patients had a viral relapse, 16 (48%) had a biochemical relapse, and 16 (48%) restarted treatment, leaving 17 (52%) patients who remained treatment-free over a median 36 months of follow-up. Lower pre-treatment ALT and detectable HBV DNA within the first month after treatment discontinuation were associated with increased rates of composite relapse (HR 1.01; P = 0.022 for ALT and HR 1.01; P = 0.038 for HBV DNA).. Patients with noncirrhotic HBeAg-negative CHB can stop treatment after greater than 4-5 years of suppressive therapy with nucleosides/nucleotides with more than 50% remaining treatment-free.

Topics: Adenine; Adult; Antiviral Agents; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Nucleosides; Nucleotides; Organophosphonates; Recurrence; Tenofovir; Withholding Treatment; Young Adult

To investigate the efficacy of anti-hepatitis B virus (HBV) drugs for preventing vertical transmission of HBV and the safety of these drugs when given as treatment during pregnancy (to women) or insemination (to men).. Cases of women and men who had taken anti-HBV drug therapy during pregnancy or insemination, respectively, were retrospectively selected for study from among 18 hospitals and 33 specialists in the Guangdong Province. Demographic, HBV infection and treatment data was collected for puerperal men or women and their newborns from the medical records.. A total of 122 cases with detailed follow-up data were included in the study and including 74 women who were administered lamivudine (LAM) more than telbivudine (LdT) more than adefovir (ADV)more than entecavir (ETV) (hierarchy ranking by number of cases) and 48 men who were administered LAM more than ADV more than LdT more than ETV.None of the 122 newborns related to these cases showed HBV infection at 7 months of follow-up.None of the 74 puerperal women showed complications related to reproduction.There was one ease of a newborn being underweight at birth (2.1 kg), for which the mother had taken LdT during pregnancy. There was also one case of a newborn with a harelip and one case of a newborn with an inguinal hernia, for which both of the fathers had taken ADV during the time of insemination.. This retrospective investigation carried out in Guangdong Province indicated that not only are anti-HBV drugs efficacious for blocking vertical transmission of HBV but also are safe for both mothers and infants when taken by fathers or mothers during the reproduction phases of insemination and pregnancy.

Topics: Adenine; Antiviral Agents; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Male; Mothers; Organophosphonates; Pregnancy; Retrospective Studies; Telbivudine; Thymidine; Time Factors

North American data are lacking on the effect of nucleos(t)ide analogues (NA) in preventing chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC).. To determine the incidence of HCC in NA-treated patients and compare this risk with that predicted without treatment based on the REACH-B model.. In this retrospective study, the incidence of HCC was determined in CHB patients initiated on NA from 1999 to 2012. Pre-treatment data utilised in the REACH-B model were used to predict the annual HCC risk. The standardised incidence ratio (SIR) for HCC was calculated by comparing the observed to expected number of cases, and HCC risk factors determined by Cox proportional hazards regression.. Five hundred and forty nine initiated NA (14% lamivudine, 5% adefovir, 1.5% telbivudine, 39% entecavir, 41% tenofovir). Over a median follow-up of 3.2 years (IQR 1.9-4.6), 11 (3.2%) were diagnosed with HCC. Among 322 with data to calculate the REACH-B model, the median age at treatment initiation was 46 years (IQR 38-55), 65% were male, 32% HBeAg positive and 20% had cirrhosis. The median pre-treatment ALT was 71 U/L (IQR 41-127) and HBV DNA was 6.48 log10 copies/mL (4.95-8.04). The observed annual HCC incidence (0.9%; 95% CI 0.5-1.7) was significantly lower than predicted without treatment by the REACH-B model (SIR 0.46; 95% CI 0.23-0.82); this risk was reduced after 4 years of therapy (SIR 0.49; 95% CI 0.2-1.00).. In this Canadian study of nucleos(t)ide analogues-treated patients with chronic hepatitis B, the incidence of HCC was lower than expected, suggesting that NA reduce the risk of chronic hepatitis B-related HCC.

Topics: Adenine; Adult; Antiviral Agents; Canada; Carcinoma, Hepatocellular; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Nucleosides; Organophosphonates; Retrospective Studies; Risk Factors; Telbivudine; Tenofovir; Thymidine

Adefovir (ADV) and lamivudine (LAM) combination therapy (ADV+LAM) has been a useful option for patients with LAM-resistant (LAM-r) chronic hepatitis B (CHB). However, the long-term outcomes of LAM+ADV and 1-mg entecavir (ETV) rescue therapies have still been limited. The aim of this study was to determine the long-term outcomes of these two rescue therapies.. Sixty patients with LAM-r CHB underwent rescue therapy with LAM+ADV (n=36) or 1-mg ETV (n=24). We determined the duration of rescue therapy, timing and type of mutation, undetectable serum hepatitis B virus (HBV) DNA by PCR (lower limitation of detection, < 140 copies/mL), biochemical response (alanine aminotransferase < 40 IU/mL), and the incidence of hepatitis B virus e antigen (HBeAg) seroconversion and virologic breakthrough.. Baseline characteristics did not differ between the two therapy groups. The duration of rescue therapy was 56 months (range, 14-100 months) in the ADV+LAM group and 42 months (range, 12-73 months) in the ETV group (P=0.036). The cumulative rates of HBV DNA undetectability and HBeAg seroconversion up to 6 years were 88.6% and 43.0%, respectively, in the ADV+LAM group, and 45.8% and 31.8% in the ETV group. The rate of virologic breakthrough and resistance was 14.4% in the ADV+LAM group and 71.9% in the ETV group (P=0.001).. Combination of LAM and ADV therapy for up to 6 years achieved modest rates of virological suppression and resistance. ETV is not an optimal therapy because the risk of viral breakthrough to ETV increases over time.

Topics: Adenine; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Treatment Outcome

To evaluate the efficacy of tenofovir (TDF) 300 mg/d, comparing with entecavir (ETV), in adults with chronic HBV infection who had previously virologic failure with lamivudine(LAM) and failed with rescue treatment of LAM combined adefovir(ADV).. Fifty-seven patients of chronic hepatitis B on rescue treatment with TDF were analyzed retrospectively. The serum HBV DNA levels, HBeAg, ALT and serum creatinine (Cr) were detected after treatment for 12, 24 and 48 weeks respectively. In addition, data of 40 cases treated with ETV 1 mg per day as a control group were also collected.. The baseline characteristics including HBV viral loads, median age, serum levels of ALT and Cr were compatible between TDF group and ETV group. At the time point of 24 weeks, there was only one patient (2.5%) in ETV group with HBV DNA<100 IU/ml, which means negative viral replication, while 49 patients in TDF group reached HBV negativity (86.0% vs 2.5%, χ(2) = 22.26, P < 0.001). At the time point of 48 weeks, the proportion of patients with HBV DNA<100 IU/ml in TDF group was significantly higher than that in ETV group (87.7% vs 12.5%,χ(2) = 24.17, P < 0.001). The ratios of ALT normalization (84.2% vs 77.5%, P = 0.431) and HBeAg seroconversion were similar in both groups. Elevated Cr was not found in both cohorts at the end of treatment.. Tenofovir (300 mg/d) is an effective and safe rescue therapy in chronic hepatitis B patients who failed initial treatment with LAM and secondary treatment of LAM plus ADV.

Topics: Adenine; Adult; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Retrospective Studies; Tenofovir; Treatment Failure; Treatment Outcome

The evolution of hepatitis-B virus (HBV) drug resistance is characterized by the emergence of resistance conferring mutations and compensatory mutations. Therefore HBV drug-resistant isolates often harbor multiple mutations in the reverse transcriptase (RT) and corresponding mutations in the hepatitis B surface antigen (HBsAg). In this study mutational patterns of 60 HBV isolates harboring drug resistance mutations rtM204V or rtM204I were retrospectively analyzed. Both mutations, especially mutation rtM204V, were most often accompanied by compensatory mutations rtV173L and rtL180M but also by mutations conferring entecavir (n = 5) or adefovir resistance (n = 4). In addition, 22 (36.7%) drug resistant HBV isolates carried mutations related to immune escape in the HBsAg. In seven cases premature stop codons in HBsAg were detected resulting in the expression of truncated HBsAg. Clonal analysis of these seven quasispecies even disclosed the presence of HBV isolates carrying further stop codons and in one case the occurrence of resistance mutation rtA181T without the stop codon mutation sW172*. Interestingly, only one HBV clone carried the resistance mutations rtM204V and rtA181T. HBV drug resistant isolates frequently harbored HBsAg mutations associated with immune escape or disease progression pointing to a complex interaction of both proteins. HBV genotypic resistance tests based on population sequencing methods seemed to be inappropriate for determining the clinical relevance of stop codons in the HBsAg.

Topics: Adenine; Antiviral Agents; Codon, Nonsense; Drug Resistance, Viral; Genotype; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Lamivudine; Mutation, Missense; Organophosphonates; RNA-Directed DNA Polymerase

Topics: Adenine; Adult; Aged; Antiviral Agents; Biomarkers; Deoxycytidine; DNA, Viral; Drug Substitution; Emtricitabine; Guanine; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Core Antigens; Hepatitis B Vaccines; Hepatitis B virus; Humans; Liver Transplantation; Middle Aged; Organophosphonates; Tenofovir; Time Factors; Tissue Donors; Treatment Outcome

Lamivudine (LAM) has been shown to prevent de novo hepatitis B virus (HBV) infection in recipients of hepatitis B core antibody (HBcAb)-positive liver transplants (LT) but primarily in small studies with limited follow-up.. We conducted a retrospective cohort study of HBcAb+ graft recipients at our institution from October 1999 to August 2008.. One hundred nineteen recipients without prior HBV were identified (median age, 54 years; 70% male), of which 62 received LAM. The median follow-up was 2.6 years overall and 5.3 years in the LAM group. Among LAM recipients, 44% were HBV naïve (HBsAb-/HBcAb-) at LT, of which 6% developed HBsAb+ and 3% developed HBcAb+ after LT. Eight percent developed de novo HBV: two recipients became hepatitis B surface antigen positive at 70 and 23 months and three experienced breakthrough with HBV DNA more than 2000 IU at 1 to 9 months after LT. Sixty percent (3 of 5) were HBV naïve. Four (6%) other recipients also had transiently detectable HBV less than 2000 IU, which did not require any changes to their prophylaxis regimen. When compared with recipients who received other nucleos(t)ide analogues, there was no difference in de novo rates: LAM 8% (5 of 62), adefovir 15% (5 of 33), tenofovir 0% (0 of 3), entecavir 0% (0 of 1), and 5% (1 of 20) for those not given prophylaxis (P=0.59).. LAM monoprophylaxis was effective in preventing de novo HBV in the vast majority of recipients over long-term follow-up. Adefovir had a higher rate of de novo infections numerically, whereas tenofovir and entecavir had no cases and may be more effective, but this was limited by a small sample size.

Topics: Adenine; Adult; Aged; Analysis of Variance; Antiviral Agents; Biomarkers; Chi-Square Distribution; DNA, Viral; Donor Selection; Female; Guanine; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunosuppressive Agents; Lamivudine; Liver Transplantation; Logistic Models; Male; Middle Aged; Organophosphonates; Retrospective Studies; Risk Factors; Tenofovir; Time Factors; Tissue Donors; Treatment Outcome; Viral Load

While the selection of complex HBV drug-resistance patterns on therapeutic failure can compromise the efficacy of anti-HBV therapies, recent data show that patients failing treatment without drug-resistance have a rate of virological success close to drug-naive patients. The goal of this study is defining, in clinical practice, the burden of drug-resistance mutations in a cohort of patients treated with anti-HBV drugs. Prevalence and patterns of drug-resistance were analyzed by RT-sequencing in 204 patients infected chronically: 148 experiencing virological rebound (defined as an increase in serum HBV-DNA > 20 IU/ml after achieving virological success [HBV-DNA < 20 IU/ml]), and 56 null/partial responders (always detectable serum HBV-DNA [>20 IU/ml] within 48 weeks of therapy). The highest rate of drug-resistance was observed in patients experiencing virological rebound (prevalence, 79.1%). Conversely, almost half (46.4%) null/partial responders have no evidence of drug-resistance. The rate of drug-resistance was higher in patients treated with lamivudine (76.8% [109/142]) and telbivudine (83.3% [5/6]), followed by adefovir (62.5% [15/24]), and entecavir (52.2% [12/23]). Complex mutational patterns characterized by the co-presence of rtM204V/I-rtA181T/V (impairing the efficacy of all anti-HBV drugs) were detected in four patients (2.7%) with virological rebound. Drug-resistance is the main cause of failure to therapy in patients experiencing virological rebound, supporting the need of rapid switch to anti-HBV drugs with higher genetic barrier and potency (entecavir/tenofovir). Conversely, nearly half of null/partial responders shows no evidence of drug-resistance mutations, maintaining high chance of achieving therapeutic success with the same class of drug. In this setting, genotypic resistance may help in selecting patients still carrying wild-type viruses, that may take major benefits from antiviral treatment.

Topics: Adenine; Adult; Antiviral Agents; Cohort Studies; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Recurrence; Telbivudine; Thymidine; Treatment Outcome

The long-term outcomes of oral antiviral therapy without hepatitis B immune globulin (HBIG) in prevention of reinfection with hepatitis B after liver transplantation are not known. We aimed to determine the long-term outcomes from a large population of chronic hepatitis B (CHB) liver transplant recipients using oral antiviral therapy alone.. A total of 362 consecutive CHB patients transplanted from January 2003 to May 2011 were included. None of the patients received HBIG. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up.. Of the 362 patients, 176 (49%), 142 (39%), and 44 (12%) were on lamivudine (LAM), entecavir (ETV), and combination therapy (predominantly LAM+adefovir), respectively, at the time of transplant. The median follow-up length was 53 months. The rate of hepatitis B surface antigen seronegativity and hepatitis B virus (HBV) DNA suppression to undetectable levels at 8 years was 88 and 98%, respectively. The virological relapse rates (>1 log increase IU/ml) at 1, 3, 5, and 8 years was 5, 10, 13 and 16%, respectively. The virological relapse rate at 3 years for LAM, ETV, and combination group was 17, 0, and 7%, respectively (P<0.001). Forty-two patients had virological relapse, of which 36 had YMDD mutation (31 in the LAM group and 5 in the combination group). The overall 8-year survival was 83%, with no difference between the three treatment groups (P=0.94). No mortality from HBV recurrence occurred in the 362 patients.. Oral nucleoside/nucleotide analogs without HBIG are effective in preventing graft loss secondary to hepatitis B recurrence after liver transplantation. However, new agents with a high barrier to resistance should be used to minimize drug resistance and to prevent virological rebound.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Lamivudine; Liver Transplantation; Male; Middle Aged; Organophosphonates; Postoperative Care; Proportional Hazards Models; Secondary Prevention; Survival Rate; Viral Load; Young Adult

Either combination treatment or monotherapy using agents with a high genetic barrier are recommended for the retreatment of chronic hepatitis B (CHB) patients. In search of reasonable treatment, we compared the efficacy and safety of lamivudine (LAM) plus adefovir (ADV) and entecavir (ETV) alone for retreatment of patients with viral relapse after cessation of ADV.. This is a prospective controlled study, and CHB patients with HBV DNA levels more than 4 log copies/mL were enrolled. All patients were treated with either LAM plus ADV (n=30) or ETV (n=25) for 48 weeks.. After 12-months treatment, the biochemical response (BR) rates were 96.7% and 84.0%, the virological response (VR) rates were 96.7% and 68% in the LAM plus ADV and ETV groups respectively. Between two groups, the difference in BR was not significant, but in VR was statistically significant (p = 0.097 for BR, and p = 0.003 for VR). Eleven patients receiving LAM plus ADV had HBeAg seroconversion, as compared with 1 in patients receiving ETV alone (36.7% versus 4%, p = 0.003). During 12-months retreatment, 1 patients receiving ETV alone had virological breakthrough and detected ETV-resistance strains, while no LAM- or ADV-associated resistance strains were detected in patients receiving LAM plus ADV. All patients receiving LAM plus ADV were well tolerated, and no serious side effects were reported.. LAM plus ADV combination therapy is effective in retreatment of CHB patients with viral relapse after cessation of ADV, but further studies are needed to obtain long term results.  

Topics: Adenine; Adult; Antiviral Agents; Case-Control Studies; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Function Tests; Male; Organophosphonates; Prospective Studies; Recurrence; Treatment Outcome

To evaluate the efficacy and safety of Entecavir (ETV) plus adefovir (ADV) for chronic hepatitis B (CHB) patients after multiple nucleos(t)ide analogue (NAs) failure treatment.. Hepatitis B e antigen (HBeAg)-positive patients who had a suboptimal response or developed resistance to two or more previous NAs treatments were included, and all subjects were treated with ETV in combination with ADV for ≥ 24 months. Complete virologic response (CVR) was defined as an undetectability of serum hepatitis B virus (HBV) DNA level during treatment. Safety assessment was based on the increasing of serum creatinine and creatine kinase levels.. A total of 45 eligible patients were included. Twenty-five patients had been treated with lamivudine (LAM) or telbivudine (LdT) and developed genotypic resistance. Resistance to ADV was present in 18 patients and 4 patients had a suboptimal response to ETV. Two patients had a resistance to both LAM and ADV. The cumulative probabilities of CVR at 12 and 24 months of ETV + ADV treatment were 88.9% (40/45) and 97.8% (44/45), respectively. Although one patient failed to achieve CVR, its serum HBV DNA level decreased by 3.3 log copies/mL after 24 months of combination therapy. The cumulative probability of HBeAg seroconversion was 15.6% (7/45) and 26.7% (12/45) at 12 and 24 months of treatment, respectively. History of prior exposure to specific NAs did not make a difference to ETV + ADV treatment outcome. There were no significant adverse events related to ETV + ADV therapy observed in the study subjects.. ETV + ADV can be used as an effective and safe rescue therapy in patients after multiple NA therapy failures, especially in the areas where tenofovir is not yet available.

Topics: Adenine; Adult; Antiviral Agents; Creatine Kinase; Creatinine; DNA, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Salvage Therapy; Treatment Outcome; Viral Load

Improvements in the outcomes of patients transplanted for hepatitis B virus (HBV) have been substantial in the past two decades. With current therapies, the vast majority of transplant recipients are protected against recurrent and/or progressive liver disease. Effective prophylactic therapies include hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues (NAs) and NA therapy alone (without HBIG). Definitions of recurrence in the setting of prophylaxis are evolving--persistence or reappearance of hepatitis B surface antigen in serum remains a marker of reinfection, but is not necessarily a marker of progressive hepatitis. The level of HBV DNA at the time of transplant remains the most consistent factor predicting risk of recurrent HBV. An individualized, rather than a "one size fits all", approach to prophylaxis that is based on risk of reinfection and/or risk of progressive disease, if reinfected, is the optimal means of insuring optimal graft survival for HBV-infected patients.

Topics: Adenine; Antiviral Agents; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Transplantation; Male; Organophosphonates

Hepatitis B immune globulin (HBIG) is routinely used in liver transplantation for hepatitis B virus (HBV)-related liver disease. With potent oral antivirals, HBIG may not be required. We conducted a prospective trial to evaluate living related liver transplantation (LRLT) without HBIG. Eighty-nine patients with HBV-related liver disease underwent LRLT between January 2005 and January 2012. All donors were vaccinated with the HBV vaccine. All patients were given oral antivirals for HBV before transplantation. Patients with HBV DNA levels ≤ 2000 IU/mL were not given HBIG, and patients with HBV DNA levels > 2000 IU/mL were given HBIG. Recurrence was defined as HBV DNA positivity 6 months after transplantation. Seventy-five of the 89 patients who underwent LRLT for HBV-related liver disease were not given HBIG. Nineteen patients received a combination of lamivudine and adefovir, 42 received entecavir, 12 received tenofovir, and 2 received a combination of entecavir and tenofovir. At the last follow-up (median = 21 months, range = 1-83 months), all patients were HBV DNA-negative. Sixty-six patients cleared hepatitis B surface antigen (HBsAg), and 19 patients formed antibody to hepatitis B surface antigen (anti-HBs). The cumulative probabilities of clearing HBsAg were 90% and 92% at 1 and 2 years after transplantation, respectively. Nine patients were HBsAg-positive with undetectable DNA at the last follow-up. The recurrence rate in our series was 8% (6/75). Five of these 6 patients had stopped taking oral antivirals, and 1 had entecavir resistance. All recurrences were salvaged with changes in the oral antivirals. The actuarial probability of survival in this cohort was 73.7% at 83 months. There was no mortality due to HBV recurrence. In conclusion, HBV prophylaxis with oral antivirals and without HBIG is safe and effective in LRLT. A majority of the patients will clear HBsAg, and some will develop anti-HBs antibodies.

Topics: Adenine; Adolescent; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunoglobulins; Immunosuppression Therapy; Immunosuppressive Agents; Lamivudine; Liver Transplantation; Living Donors; Male; Middle Aged; Organophosphonates; Prospective Studies; Recurrence; Tenofovir; Treatment Outcome

Primary mutations conferring hepatitis B virus (HBV) antiviral resistance and associated secondary/compensatory mutations were investigated in this study by DNA sequencing (SEQ) and two commercial Line Probe Assays (LiPAs) (Inno-Lipa HBV DRv2 and Inno-Lipa HBV DRv3, Innogenetics, Belgium). A total of 71 subjects under follow-up for chronic hepatitis B and receiving lamivudine (LVD) therapy for one year or longer at the Hacettepe University Faculty of Medicine, Department of Internal Medicine, Gastroenterology Unit were included in the study with informed consent. Male to female ratio and mean age was noted as 47/24 and 43 ± 15.8 (age range: 13-71) years, respectively. Twenty samples with low HBV DNA levels (mean: 204.6 IU/ml) could not be interpreted by SEQ due to insufficient amplification. All samples with a positive consensus PCR were further analysed via LiPAs, as directed by the manufacturer. Thus a total of 51 and 56 samples could be evaluated via SEQ and LiPA assays, respectively. In 13 of the 51 (25.5%) samples by SEQ and in 9 of 56 (16%) samples by LiPAs, primary and compensatory mutations associated with resistance were identified. Multiple mutations that comprise L180M + M204I in four and L180M + M204V in one sample and single mutations (M204I) in three samples were identified by SEQ. In one sample which had multiple mutations associated with LVD resistance single mutations (S202G, N236T) associated with entecavir resistance and in two other such samples mutations associated with adefovir resistance were detected by SEQ. Also, in three samples amino acid substitution at position rt215 (QÆS) as alone and in one sample with multiple mutations were observed via SEQ. In five of nine samples primary and compensatory multiple mutations (L180M + M204I in one sample, L80I + L180M + M204I in two samples, L80I/V + M204I in one sample) and primary single mutations associated with LVD resistance (M204I/V) in four samples were detected by Inno-Lipa HBV DRv2. Two different mutations (G202, ILFM184) were observed in two samples with multiple mutations associated LVD resistance via Inno-Lipa HBV DRv3. However, mutation at position rt184 was evaluated as a weak positive. Any mutation associated with adefovir resistance was not detected by LiPA. As a result, SEQ and LiPAs displayed comparable performances for the detection of HBV drug resistance mutations. We suggested that for the evaluation of discordant results, it should be better to test consecutive serum s

Topics: Adenine; Adolescent; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Polymerase Chain Reaction; Young Adult

The aim of this study was to compare the effect of combination lamivudine (LAM) and adefovir dipivoxil (ADV) versus entecavir (ETV) monotherapy for naïve HBeAg-positive chronic hepatitis B (CHB) patients.. Fifty enrolled patients with CHB were evenly divided into 2 groups: a group treated with of lamivudine (LAM) (100 mg/day) plus adefovir (ADV) (10 mg/day) combination, and a group treated with entecavir (ETV) (0.5 mg/day). Serum levels of ALT, AST, creatinine, bilirubin, HBsAg, HBeAg and HBV viral load, and genotypic resistance were analyzed at 0, 12, 24, 52, and 104 weeks. HBV DNA levels were determined by real-time PCR and HBsAg and HBeAg by chemiluminescence. Serum levels of ALT, AST, creatinine, and bilirubin were measured by an automatic biochemical analyzer. Data analysis was performed with SPSS 12.0 software.. There were no significant differences in the virological response (VR) rates between LAM+ADV and ETV cohorts at 24, 52, and 104 weeks (P>0.05). The HBeAg seroconversion rates were 28% and 20%, and the biochemical response (BR) rates were 88% and 84% at week 104 in the LAM+ADV and ETV groups, respectively. The rates of undetectable HBV DNA, HBeAg seroconversion, and ALT normalization rates were similar in both cohorts. No virological breakthrough or serious adverse effects were noted for any patient during the study period.. Both LAM+ADV combination therapy and ETV monotherapy were effective and safe in the treatment of -naïve HBeAg-positive CHB patients. However, further studies are needed to obtain long-term results.

Topics: Adenine; Adult; Alanine Transaminase; Analysis of Variance; Aspartate Aminotransferases; Bilirubin; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Organophosphonates; Pilot Projects

Treatment strategies for entecavir (ETV)-resistant chronic hepatitis B (CHB) patients are not yet well established. The aim of this study was to evaluate overall antiviral efficacy and to compare the efficacy of combination therapy with adefovir (ADV) plus nucleoside analogues (lamivudine [LAM], telbivudine [LdT], or ETV) in patients infected with LAM- and ETV-resistant hepatitis B virus (HBV) variants. Virologic, biochemical, and serologic responses during combination therapy with ADV plus nucleoside analogues were assessed. Propensity score analysis was used to select a matched group of patients for the comparison of rescue therapy regimens. A total of 67 consecutive patients were analyzed. Complete virologic suppression was achieved in 27 patients. The overall cumulative incidence of complete virologic suppression at month 24 was 47.4%: 44.3% in the LAM or LdT plus ADV group and 51.4% in the group given ETV and ADV. There was no significant difference between these two groups (P = 0.234). The cumulative incidences of complete virologic suppression were still comparable between the two groups selected and matched using the propensity score model (P = 0.419). Virologic breakthrough was observed in 9 patients, and rtA181V substitution was newly detected in one patient. Hepatitis B e antigen (HBeAg) negativity and lower baseline HBV DNA level were associated with complete virologic suppression in univariate analysis. In multivariate analysis, lower baseline HBV DNA level remained an independent predictor. In conclusion, combination therapy with ADV plus nucleoside analogues fails to show sufficient antiviral efficacy in CHB patients with resistance to both LAM and ETV. Further study is warranted to evaluate the efficacy of a more potent tenofovir-based regimen in such patients.

Topics: Adenine; Adult; Aged; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome

To evaluate the cost-effectiveness of different drug therapies for chronic hepatitis B in adult patients.. Using a Markov model, a hypothetical cohort of 40 years for HBeAg-positive or HBeAg-negative patients was constructed. Adefovir, entecavir, tenofovir and lamivudine (with rescue therapy in cases of viral resistance) were compared for treating adult patients with chronic hepatitis B undergoing treatment for the first time, with high levels of alanine aminotransferase, no evidence of cirrhosis and without HIV co-infection. Values for cost and effect were obtained from the literature, and expressed in effect on life years (LY). A discount rate of 5% was applied. Univariate sensitivity analysis was conducted to assess model uncertainties.. Initial treatment with entecavir or tenofovir showed better clinical outcomes. The lowest cost-effectiveness ratio was for entecavir in HBeAg-positive patients (R$ 4,010.84/LY) and lamivudine for HBeAg-negative patients (R$ 6,205.08/LY). For HBeAg-negative patients, the incremental cost-effectiveness ratio of entecavir (R$ 14,101.05/LY) is below the threshold recommended by the World Health Organization. Sensitivity analysis showed that variation in the cost of drugs may make tenofovir a cost-effective alternative for both HBeAg-positive and HBeAg-negative patients.. Entecavir is the recommended alternative to start treating patients with chronic hepatitis B in Brazil. However, if there is a reduction in the cost of tenofovir, it can become a cost-effective alternative.

Topics: Adenine; Adult; Analysis of Variance; Antiviral Agents; Brazil; Cost-Benefit Analysis; Disease Progression; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Markov Chains; Organophosphonates; Tenofovir; Treatment Outcome

Lamivudine, adefovir, telbivudine, and entecavir are nucleoside analogues that can inhibit hepatitis B virus replication and are licensed in China by the Food and Drug Administration. This study presents the cases of 2 patients who were chronically infected with HBV and suffered hepatic failure resulting from withdrawal of telbivudine and adefovir, respectively.

Topics: Adenine; Adult; Antiviral Agents; Guanine; Hepatitis B, Chronic; Histocytochemistry; Humans; Lamivudine; Liver Failure, Acute; Liver Transplantation; Male; Medication Adherence; Necrosis; Organophosphonates; Telbivudine; Thymidine

Reported HBV drug resistance mutations among previously untreated patients with chronic hepatitis B are variable. Whether resistant HBV strains are transmitted in the acute setting is uncertain. We sought to document the presence of antiviral resistance (AVR) mutations in patients with acute HBV (AHB) infection.. AHB infection was defined by HBsAg/IgM anti-HBc positivity, ALT>10X ULN and compatible clinical history. The TRUGENE HBV kit was used to perform genotyping and direct sequencing of the viral polymerase. INNO-LiPA HBV DRv2 and DRv3 were used to detect AVR mutations. Clonal sequencing was conducted on selected specimens.. Twenty-three patients were evaluated (mean age, 43 years; 54% male; 39% African American, 39% Caucasian, 13% Hispanic and 4% Asian). The mean peak ALT was 1554.2IU/L and mean peak total serum bilirubin was 12 mg/dl. The HBV DNA median viral load (N = 15) was 5.14 log(10)IU/ml. Nineteen patients were genotype A, and 1 each were genotype C, D, E and G. HBV drug resistance mutations were not detected by direct sequencing or INNO-LiPA. Clonal sequencing was conducted on 192 clones isolated from three patients and showed rtA181T, rtM250V and rtS202G mutations at an overall frequency of 1.54%, 1.39%, and 1.67% respectively.. We detected adefovir/lamivudine and entecavir relevant mutations in a minor population (<2%) of viral clones by clonal sequencing only. The clinical significance of these mutations is uncertain and may represent small populations of quasi-species vs. transmission of drug resistant strains.

Topics: Acute Disease; Adenine; Adult; Antiviral Agents; Cohort Studies; Cross-Sectional Studies; Drug Resistance, Viral; Female; Genotype; Guanine; Hepatitis B; Humans; Lamivudine; Male; Mutation; Organophosphonates; Retrospective Studies; Sequence Analysis, DNA; United States

Whether multidrug-resistant (MDR) hepatitis B virus (HBV) harbors mutations co-located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. Sera were obtained from six patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV-resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in five patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V ± rtN236T mutations, which were detected in the absence of rtM204 and ETV-resistant mutations in 37 clones (94.9%). Only two clones (5.1%) harbored both rtA181T/V and ETV-resistant mutations. The rtA181T/V mutation emerged after reversion from ETV-resistant mutants to wild-type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. In conclusion, the majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co-localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for patients infected with MDR HBV.

Topics: Adenine; Adult; Antiviral Agents; Clonal Evolution; DNA, Viral; Drug Resistance, Multiple, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation, Missense; Organophosphonates; RNA-Directed DNA Polymerase

The efficacy of adefovir (ADV) plus entecavir (ETV) combination in patients with chronic hepatitis B (CHB) who developed multidrug refractoriness had not been fully evaluated. We aimed to evaluate the efficacy of ADV plus ETV as compared to that of lamivudine (LAM) plus ADV in the patients with antiviral refractoriness to sequential LAM monotherapy and then ADV monotherapy.. Twenty-seven patients were treated with a combination of ADV plus ETV and 63 patients were treated with a combination of LAM plus ADV. The virological and biochemical parameters were compared between the two groups, retrospectively.. Treatment with a combination of ADV plus ETV produced significantly superior virological response than that of a combination of LAM plus ADV. At 12 months, the HBV DNA declined more in the ADV plus ETV group than in the LAM plus ADV (-4.52 ± 1.956 vs. -2.65 ± 1.723 log 10 IU/mL; p = 0.001). The rate of a complete response at 12 months was greater in the ADV plus ETV group than that in the LAM plus ADV group (63.16 vs. 14.81 %, p < 0.001).. In the patients with CHB refractory to both LAM and ADV, the response to ADV plus ETV was significantly superior compared to that of the LAM plus ADV in suppressing HBV DNA. The result indicates that ADV plus ETV can be used as a bridging therapy in the patients with refractoriness to both LAM and ADV, especially in the areas where tenofovir is not yet available.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Treatment Failure

Sequential antiviral therapy for chronic hepatitis B may lead to the selection of multidrug-resistant mutation. This study was carried out to assess the efficacy of entecavir in patients that have experienced adefovir monotherapy failure after the development of lamivudine resistance.. Fifty-three patients with confirmed genotypic lamivudine-resistant chronic hepatitis B were treated with entecavir. Thirty patients were switched to entecavir directly (LAM-ETV group), whereas the remaining 23 were adefovir-refractory patients who were switched to entecavir (LAM-ADV-ETV group). These 23 patients included 9 patients with inadequate response (ADV-I subgroup) and 14 that exhibited adefovir resistance (ADV-R subgroup).. Significantly greater reductions in HBV DNA levels were observed after 24, 48 and 72 weeks of entecavir therapy in the LAM-ETV group than in the LAM-ADV-ETV group, respectively. However, between these two groups at 48 and 72 weeks, no significant differences were observed in cumulative proportions of virological response or breakthrough, respectively. Furthermore, efficacy of entecavir was not significantly different in the ADV-I and ADV-R subgroups. Four patients in the LAM-ETV group and six patients in the LAM-ADV-ETV group developed genotypic resistance to entecavir.. Entecavir therapy is less effective in adefovir-refractory patients with prior lamivudine resistance than in lamivudine-resistant patients.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Function Tests; Male; Middle Aged; Organophosphonates; Retrospective Studies; Treatment Outcome

Information regarding long-term HBsAg kinetics during treatment with nucleoside/nucleotide analogues is limited. The aim of the present study was to assess whether finite nucleoside/nucleotide analogue treatment duration could be envisaged during the patient's lifetime.. Patients with chronic hepatitis B receiving different schedules of nucleoside/nucleotide analogues were followed for a median duration of 102 months, i.e., 8.5 years (interquartile range: 88-119 months). Long-term HBV DNA and HBsAg level kinetics were modeled in order to estimate time to clear HBsAg during therapy in patients with undetectable HBV DNA.. Antiviral therapy was associated with a slow but consistent reduction in the level of HBsAg in most of the patients. Three patterns of HBsAg level declines were identified: decline during both the detectable and undetectable HBV DNA phases; decline during the HBV DNA detectable period only; decline during the HBV DNA undetectable period only. The mean HBsAg titer at the time when HBV DNA became undetectable was 3.29 ± 0.49 Log₁₀ international units (IU)/ml, and the mean slope was -0.007 ± 0.007 Log₁₀ IU/month, i.e., an average decline of 0.084 Log₁₀ IU/year. The corresponding calculated median number of years needed to clear HBsAg was 52.2 years (interquartile range: 30.8-142.7).. This study, based on the very long-term follow-up of patients with chronic hepatitis B treated with potent nucleoside/nucleotide analogues, shows that HBsAg clearance is unlikely to occur during the patient's lifetime, even if HBV replication is well controlled. Thus, lifetime therapy is required in the vast majority of HBV-infected patients.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kinetics; Lamivudine; Longitudinal Studies; Male; Middle Aged; Nucleosides; Nucleotides; Organophosphonates; Tenofovir

To correlate early HBV-DNA suppression by antiviral treatment with posthepatectomy long-term survivals in patients with HBV-related hepatocellular carcinoma (HCC).. A retrospective study was conducted on patients with a baseline HBV-DNA load of >2,000 IU/ml. The cumulative rates of HBV-DNA undetectability at weeks 24 and 48, as well as long-term tumor recurrence and overall survivals were determined.. Of 1,040 patients with a high baseline HBV-DNA load, 865 patients received antiviral treatment. At a median follow-up of 42 months, 616 patients (59.2 %) had developed HCC recurrence and 482 patients (46.3 %) had died. The median time to recurrence was 25 months. In patients who received antiviral treatment, the cumulative rates of HBV-DNA undetectability (<200 IU/ml) were 54.3 and 88.1 % at weeks 24 and 48, respectively. There was no significant difference between the two groups of patients who received antiviral treatment or not for disease-free survival. On multivariate analyses, tumor size >5 cm, blood transfusion, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak inflammation score were significant risk factors of HCC recurrence. Also, tumor size >5 cm, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak fibrosis score were significant factors associated with poor postoperative overall survival. On the other hand, an undetectable HBV-DNA level before week 24 was a significant protective factor of disease-free survival and overall survival.. Early HBV-DNA suppression with antiviral treatment improved prognosis of patients with HBV-related HCC.

Topics: Adenine; Adult; Antiviral Agents; Carcinoma, Hepatocellular; Disease-Free Survival; DNA, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kaplan-Meier Estimate; Lamivudine; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Organophosphonates; Portal Vein; Proportional Hazards Models; Retrospective Studies; Risk Factors; Viral Load

In 18 of 547 patients who had received nucleoside analogue preparations for 1 year or more, multi-drug resistance was detected, after a median follow-up of 53 months. No patient showed liver failure related to multi-drug resistance acquisition. Multi-drug resistance was associated with entecavir (ETV) therapy in 7 lamivudine (LAM) -resistant patients, combination therapy with adefovir dipivoxil (ADV) in 8 LAM-resistant patients, LAM switching to ETV in 2 patients, and initial ETV administration in 1. For treatment, combination therapy with LAM and ADV was performed. In non-responders, combination therapy with ADV and ETV was employed. In all LAM- and ADV-resistant patients, and the HBV DNA level decreased to 3.0LC/ml or less. However, a similar decrease was noted in 7 (58.3%) of 12 LAM- and ETV-resistant patients. Of the 18 patients, 1 did not respond to combination therapy with ADV and ETV. Therapy with tenofovir disoproxil fumarate (TDF) was required.

Topics: Adenine; Aged; Aged, 80 and over; Antiviral Agents; Drug Resistance, Multiple, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Organophosphonates

In patients affected by chronic hepatitis because of HBV infection, long-term suppressive therapy with nucleos(t)ides analogues in the HBeAg- patients has shown low effects on HBsAg titre (qHBsAg) decrease, and HBsAg loss is difficult to achieve. Thus, in this type of patients the main goals of antiviral therapy is the suppression of HBV-DNA and ALT normalization.. We retrospectively evaluated different qHBsAg kinetics in 134 treatment-naïve patients having the same characteristics: HBeAg-, infection sustained by HBV genotype D and persistently undetectable HBV-DNA. Patients were treated with NAs therapy (lamivudine, adefovir, telbivudine, entecavir and tenofovir) for at least 2 years. qHBsAg was performed every 6 months.. Our results showed a significantly greater qHBsAg decline after 2 years in patients treated with tenofovir (0.45 logIU/ml) than in patients treated with telbivudine (0.12 logIU/ml; P < 0.001). The calculated expected time to HBsAg loss was shorter in the tenofovir group than in the telbivudine group (nearly 17 vs 63 years, P < 0.001).. HBeAg negative patients infected by HBV genotype D should be treated with more potent NAs such as entecavir or tenofovir to obtain a significant qHBsAg decrease, but the achievement of HBsAg loss seems to require almost two decades of therapy.

Topics: Adenine; Aged; Antiviral Agents; Biomarkers; Chi-Square Distribution; DNA, Viral; Female; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kinetics; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Currently, no treatment guidelines are available for posttransplant hepatitis B virus (HBV) recurrence. We retrospectively evaluated the rate of clearance of hepatitis B surface antigen (HBsAg) from serum according to various treatment regimens in two large Korean liver transplantation centers.. Between 1996 and 2008, HBV recurred in 59 patients among 933 HBV liver recipients (6.3 %). Patients with HBV recurrence were divided into four groups according to their treatment: group L (lamivudine-based therapy n = 21) and group N [new nucleos(t)ide analogue (NA)-based therapy, n = 38]. Intravenous hepatitis B immunoglobulin (ivHBIG) had been simultaneously administered to 10 patients in group L and 26 patients in group N. The mean posttransplant follow-up duration and time to HBV recurrence were 69 (14-152) months and 37 (3-120) months.. Overall, 22 patients (37.3 %) showed seronegative conversion of HBsAg for a median 8 months after treatment (range 1-15 months). The seroclearance rate was significantly higher in group N (n = 20, 52.6 %) than in group L (n = 2, 9.5 %) (p < 0.000). The time to seroconversion did not differ between group L (7 months, range 5-16) and group N (7 months, range 1-15) (p = 0.428). Subgroup analysis showed that the HBsAg seroconversion rate was much higher for patients given combined ivHBIG and new NAs (15/26 patients, 58.0 %) than the others (p = 0.006).. Seroclearance of HBsAg could be achieved using new NAs in half of the patients after posttransplant HBV recurrence. Combined ivHBIG may add a synergistic effect to new NAs for clearing HBsAg.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Biomarkers; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Lamivudine; Liver Transplantation; Male; Middle Aged; Organophosphonates; Recurrence; Retrospective Studies; Treatment Outcome; Young Adult

To conduct a cost-effectiveness analysis of drug alternatives with rescue therapy in case of relapse due to viral resistance for the treatment of patients with chronic hepatitis B (CHB).. Hypothetical cohort of patients with CHB, HBeAg-negative, without clinical or histological evidence of cirrhosis, detectable HBV DNA, histological diagnosis of the disease, positive serum HBsAg for longer than six months, high levels of alanine aminotransferase (ALT) (twice as high as the upper limit of normality) and mean age of 40 years. A Markov model was developed for chronic hepatitis B (HBeAg- negative) with a 40-year time horizon. Costs and benefits were discounted at 5%. Annual rates of disease progression, costs due to complications and the efficacy of medicines were obtained from the literature. One-way and probabilistic sensitivity analysis evaluated uncertainties.. Initiation of treatments with entecavir resulted in an increase of 0.35 discounted life-years gained compared to lamivudine. The incremental cost-effectiveness ratio was R$16,416.08 per life-years gained. In the sensitivity analysis, the incremental cost-effectiveness ratio was more sensitive to variation in the probability of transition from chronic hepatitis B to compensated cirrhosis, discount rate and medicine prices (± 10%). In the probabilistic sensitivity analysis, the acceptability curve showed that beginning treatment with entecavir was the most cost-effective alternative in comparison with the use of lamivudine.. The availability of entecavir is economically attractive as part of early treatment for patients with chronic hepatitis B without HIV co-infection.

Topics: Adenine; Antiviral Agents; Cost-Benefit Analysis; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Markov Chains; Models, Theoretical; Organophosphonates; Quality-Adjusted Life Years; Tenofovir

This study evaluated the efficacy of adefovir (ADV) plus lamivudine (LAM) or ADV add-on therapy for patients with entecavir (ETV)-refractory hepatitis B infection. Twenty-nine ETV-resistant and 8 patients with suboptimal response to ETV were enrolled. Twenty-seven patients received ADV + LAM therapy and 10 patients received ADV + ETV therapy for >24 weeks. In 29 patients who were ETV-resistant, the mean reduction in HBV DNA levels at 24 weeks was not different between the ADV + LAM and ADV + ETV groups (-1.98 log(10)  IU/ml vs. -2.16 log(10)  IU/ml; P = 0.792). Primary non-response was observed in 52.2% (12/23) of ADV + LAM group and 33.3% (2/6) of ADV + ETV group (P = 0.651). Initial virologic response (IVR) was observed in 17.4% (4/23) of ADV + LAM group and 33.3% (2/6) of ETV + ADV group (P = 0.362). In eight patients with suboptimal response to ETV, the ADV + ETV group had a greater reduction in HBV DNA at 24 and 48 weeks than the ADV + LAM group (-2.29 log(10)  IU/ml vs. -0.09 log(10)  IU/ml and -2.04 log(10)  IU/ml vs. -0.72 log(10)  IU/ml; P = 0.020 and P = 0.012, respectively). Primary non-response and IVR did not significantly differ between the two groups [100% (4/4) vs. 50% (2/4) and 0% (0/4) vs. 50% (2/4); P = 0.429 and P = 0.429, respectively]. The antiviral efficacies of ADV-based therapy with ETV or LAM for patients with ETV-resistant hepatitis B were limited and did not differ between the two groups. However, adding ADV to ETV may be more effective than ADV + LAM therapy in patients with suboptimal virologic response to ETV.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Treatment Outcome; Viral Load

Hepatitis B surface antigen (HBsAg) clearance is the closest cure outcome in hepatitis B. The goal of this study was to investigate clinical features in chronic hepatitis B patients achieving seroconversion of HBsAg after treatment with α-interferon (IFN-α) and a nucleos(t)ide analog.. This retrospective study enrolled 38 chronic hepatitis B patients treated with IFN-α plus a nucleos(t)ide analog who achieved HBsAg seroconversion during the period from June 2001 to May 2009. Clinical and laboratory data of the patients were collected before and after treatment every 3 months. All patients with HBsAg seroconversion in this study were followed up for at least 12 months post-treatment.. A total of 38 out of 142 patients achieved HBsAg seroconversion after treatment with IFN-α and a nucleos(t)tide analog for a prolonged period of time (medium 31 months). The median time to hepatitis B e antigen seroconversion and to HBsAg seroconversion was 19.5 months (range 3-60 months) and 25.5 months (range 9-63 months), respectively. Thirty-six patients (95%) sustained HBsAg seroconversion during the post-treatment follow up. Three different HBsAg response patterns were observed with classical model accounting for 57.9% (22/38 cases), simultaneous transition mode accounting for 23.7% (9/38 cases), and HBsAg prior transition model accounting for 18.4% (7/38 cases).. Extended treatment with IFN-α in combination with a nucleos(t)ide analog in patients with hepatitis-B-e-antigen-positive appears to be a promising approach for achieving a high rate of HBsAg clearance-the closest outcome to cure.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Male; Middle Aged; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Time Factors; Young Adult

The optimal treatment of patients with chronic hepatitis B (CHB) who develop resistance to both lamivudine (LMV) and entecavir (ETV) after sequential monotherapy of LMV and ETV remains little known.. We evaluated the efficacy of entecavir (ETV) plus adefovir dipivoxil (ADV) combination therapy for patients with resistance to LMV and ETV. We reviewed the medical records of 12 patients, and treated all 12 patients with ETV plus ADV combination therapy for at least 18 months. Quantitative hepatitis B virus (HBV) DNA levels, serologic markers, and hepatic panel values were monitored at baseline and 3-month intervals thereafter for 18 months.. The baseline mean serum HBV DNA level was 7.26 ± 1.11 log(10) copies/ml. The mean reductions in serum HBV DNA levels from baseline to 3, 6, 9, 12, 15, and 18 months were -1.98 ± 1.03, -2.87 ± 1.02, -3.32 ± 1.10, -3.92 ± 1.30, -4.36 ± 1.22, and -4.57 ± 1.18 log(10) copies/ml, respectively. Complete virological response (HBV DNA of <2 log(10) copies/ml) at 6, 12, and 18 months was observed in 1 (8.3%), 4 (33.3%), and 6 (50.0%) patients, respectively. The 2 patients with baseline HBV DNA of <6 log(10) copies/ml achieved complete virological response at 18 months, while 4 of 10 patients with baseline HBV DNA of ≥6 log(10) copies/ml achieved complete virological response at 18 months. None of the 12 patients experienced virological breakthrough during follow-up.. ETV plus ADV combination therapy effectively reduced serum HBV DNA levels in patients with CHB who developed resistance to both LMV and ETV. Additional long-term studies are needed to assess the effect of long-term treatment with these drugs.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Monitoring; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Function Tests; Male; Middle Aged; Organophosphonates; Treatment Outcome; Viral Load; Virus Replication

There is little clinical information on the management of hepatitis B virus (HBV) that is resistant to multiple drugs including entecavir (ETV). The present retrospective cohort study assessed the antiviral efficacy of ETV/adefovir dipivoxil (ADV) combination therapy for ETV-resistant HBV with prior lamivudine (LAM) resistance, and either with or without previous ADV resistance. The cumulative probability of achieving a virological response (undetectable serum HBV DNA) was compared by Kaplan-Meier analysis and the Breslow method. Seventeen patients with ETV-resistant HBV who were treated with ETV/ADV combination therapy for at least 6 months at a tertiary care center, were included; seven had dual resistance to ETV and LAM [ADV-r(-) group] and 10 had triple resistance to ETV, LAM, and ADV [ADV-r(+) group]. The median follow-up period was 9 months (range, 6-23). A virological response was noted in seven patients after a median of 3 months (range, 3-12) of treatment; five in the ADV-r(-) group and two in the ADV-r(+) group. The cumulative probability of a virological response was significantly higher in the ADV-r(-) group than in the ADV-r(+) group (6 months cumulative probability, 57.1% vs. 11.1%). In conclusion, ETV/ADV combination therapy led to virological responses in five of seven patients with resistance to ETV and LAM, but a significantly poorer response in patients with prior ADV resistance than in those without prior ADV resistance. Therefore, ETV/ADV combination therapy could be a useful therapeutic option for ETV- and LAM-resistant HBV without prior ADV resistance.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Treatment Outcome; Viral Load

The combination of entecavir, a nucleoside analogue, and adefovir, a nucleotide analogue, would be a promising salvage treatment for chronic hepatitis B (CHB) patients who fail nucleoside/nucleotide analogue (NA) regimens.. A total of 89 CHB patients who had failed NA regimens and were treated with entecavir plus adefovir combination for at least 12 months were included.. Mean baseline HBV DNA of patients was 6.16 ±1.44 log(10) IU/ml. Patients were classed by the number of previously failed NAs; 1 NA (lamivudine; n=15; Group 1), 2 NAs (lamivudine and either adefovir or entecavir; n=39; Group 2) and 3 NAs (lamivudine, adefovir and entecavir; n=35; Group 3). After 12 months of treatment, the mean reduction in HBV DNA was greater in Group 1 than in Group 2 or 3 (-5.81 ±1.71, -3.20 ±1.36 and -2.93 ±1.56 log(10) IU/ml, respectively; P<0.01). The rates of virological response (HBV DNA<2,000 IU/ml) were 100%, 79.5% and 34.3% (P<0.01), and the rates of complete virological response (HBV DNA<60 IU/ml) were 53.3%, 25.6% and 14.3% in Group 1, 2 and 3, respectively (P<0.01) at 12 months. Higher baseline HBV DNA (odds ratio =0.59; P=0.02) and increasing number of previously failed NAs (P<0.01) were independently associated with a lower rate of complete virological response at 12 months.. Entecavir plus adefovir combination treatment was effective in achieving virological response in CHB patients after failure of NAs. However, its effect progressively decreased as the number of previously failed NAs increased.

Topics: Adenine; Adult; Antiviral Agents; Cohort Studies; DNA, Viral; Drug Combinations; Drug Resistance, Viral; Female; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Treatment Failure; Viral Load

Antiviral therapy by nucleoside/nucleotide analogues (NAs) effectively reduces HBV replication in chronic hepatitis B (CHB) patients. Because long-term NA treatments will eventually select for drug-resistant mutants, early detection of mutants and frequent monitoring of viral loads is crucial for successful NA therapy. Because no efficient test for one-tube quantification and qualification of various HBV-resistant mutants exists, we propose to use high-resolution melting (HRM) analysis in combination with real-time PCR to achieve this unmet need.. We developed a single amplicon for detecting HBV mutants resistant to lamivudine (LMV), adefovir (ADV) and entecavir (ETV), which are commonly used for CHB treatment. Our design consists of two steps: real-time PCR for viral quantification, and hybridization probe HRM analysis for detection of specific drug-resistant mutants.. Assay quantification was accurate (R=0.98) for viral loads from 10(3) to 10(9) copies/ml. HRM analysis produced distinct melting temperatures that clearly distinguished the mutants, rtM204V/I (LMV), rtA181V and rtN236T (ADV), and rtT184G and rtM250V (ETV), from their respective wild types. The assay detected mutants at only 10-25% of the HBV population. The clinical applicability of this assay was tested in a pilot study with serial samples from patients receiving LMV treatment.. Flexibility, speed and cost-efficiency are additional benefits unique to our assay. The clinical sample results further support the feasibility of applying our design to frequent and long-term monitoring of CHB patients receiving NA treatments in the clinical setting.

Topics: Adenine; Antiviral Agents; DNA, Complementary; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Molecular Diagnostic Techniques; Nucleic Acid Denaturation; Organophosphonates; Pilot Projects; Polymerase Chain Reaction; Viral Load

More than 1% of the Hungarian population is infected with hepatitis B, C, or D viruses. Since 2006 the diagnostics and therapy of these infections are carried out in treatment centers according to national guidelines - since 2010 according to financial protocols. The consensus-based guidelines for 2012 are published in this paper. The guidelines stress the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection is pegylated interferon for 48 weeks or continuous entecavir therapy. The later must be continued for at least 6 months after hepatitis B surface antigen (HBsAg) seroconversion. Tenofovir disoproxil fumarat is not yet reimbursed by the National Health Insurance Fund. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Treatment naive chronic hepatitis C patients should initially receive pegylated interferon and ribavirin dual combination therapy. In genotype 1 infection if response is insufficient at 4 or 12 weeks one of the two new direct acting antivirals (boceprevir or telaprevir) should be added. The length of treatment is usually 48 weeks; in cases of extended early viral response shorter courses are recommended. Previous treatment failure patients with genotype 1 infection should receive a protease inhibitor backed triple combination therapy, mostly for 48 weeks. However, relapsers without cirrhosis and with extended rapid viral response, shorter telaprevir based combination therapy is sufficient. Drug-drug interactions as well as emergence of viral resistance are of particular importance. For genotype 2 or 3 HCV infections 24 weeks, for genotype 4 infections 24, 48 or 72 weeks of pegylated interferon plus ribavirin therapy is recommended in general. The guidelines published here become protocols when published as official publications of the Hungarian Health Authority.

Topics: Adenine; Antiviral Agents; Comorbidity; Consensus; Drug Administration Schedule; Drug Therapy, Combination; Genotype; Guanine; Hepacivirus; Hepatitis B; Hepatitis C; Hepatitis D; Humans; Hungary; Interferon-alpha; Interferons; Lamivudine; Oligopeptides; Organophosphonates; Polyethylene Glycols; Proline; Recombinant Proteins; Ribavirin; RNA, Viral; Tenofovir; Time Factors; Treatment Outcome

Few studies have adequately examined the efficacy of lamivudine plus adefovir (LAM+ADV) combination therapy vs. entecavir (ETV) monotherapy in HBeAg-positive hepatitis B patients who fail to respond to sequential treatment with LAM and ADV. We compared directly the efficacy of LAM+ADV vs. ETV in such patients and assessed prognostic factors associated with a virologic response at month 12.. In total, 72 HBeAg-positive patients who showed resistance (n = 33) or a suboptimal virologic response (n = 39) to ADV monotherapy with resistance to LAM therapy underwent rescue therapy (31 LAM+ADV and 41 ETV). All patients were followed for at least 12 months.. Following 12 months of treatment, in the LAM+ADV and ETV groups, a virologic response was observed in 7/31 (22.6%) and 8/41 (19.5%; P = 0.777) patients; ALT normalization occurred in 11/13 (84.6%) and 16/18 (88.9%; P = 0.566); HBeAg seroconversion in 1/31 (2.3%) and 4/41 (9.8%; P = 0.341) and a virologic breakthrough in 3/31 (9.0%) and 5/41 (12.1%; P = 0.452) respectively. Independent prognostic factors associated with a virologic response were the baseline HBV-DNA level (OR = 0.37; 95% CI 0.17-0.80; P = 0.011) and the duration of prior ADV monotherapy (OR = 0.89; 95% CI 0.83-0.95; P = 0.044).. Neither LAM+ADV nor ETV was adequately effective in patients with sequential LAM and ADV treatment failure. Thus, when chronic hepatitis B patients show resistance or suboptimal response to ADV monotherapy, early modification of treatment should be considered.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Prognosis; Retrospective Studies; Treatment Failure

Newly developed and potent antiviral agents suffer from the problem of drug resistance. Multidrug resistance is a major impediment in the treatment of patients with chronic hepatitis B (CHB). In line with American Association for the Study of Liver Diseases guidelines, adefovir dipivoxil (ADV) add-on therapy is recommended in the case of lamivudine resistance, while tenofovir disoproxil fumarate (TDF) is recommended for ADV or entecavir (ETV) resistance. TDF is currently not available in Korea. ADV+ETV combination therapy may be a viable alternative to TDF in patients with either ADV or ETV resistance. However, the efficacy of ADV+ETV combination therapy in patients with CHB and multidrug resistance is unclear. This study investigated the efficacy of ADV+ETV combination therapy in patients with multidrug resistance.. Twenty-five patients were enrolled and were administered ADV+ETV combination therapy for at least 6 months. Blood was drawn at baseline and at 3, 6, 9, and 12 months after commencing treatment, and the following blood parameters were analyzed: alanine transaminase, hepatitis B e-antigen (HBeAg), anti-hepatitis B e-antigen, and hepatitis B virus (HBV) DNA levels. The initial virological response (IVR) was defined as an HBV DNA level of <4 log(10) copies/mL after 6 months of combination therapy.. The IVR rate was 76%. The proportion of patients with a high viral load (≥5.0 log) dropped from 76% at baseline to only 5% after 6 months of treatment. The biochemical response rate during the first 6 months was 71%. HBeAg was lost in 2 patients (10%).. ADV+ETV combination therapy induced a good IVR in CHB patients who were refractory to more than 2 antiviral agents. This regimen may be a good alternative to TDF in Korea, where that drug is not available.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B Antibodies; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Organophosphonates

Newer nucleos(t)ide analogues (NUCs) have better resistance profiles making hepatitis B immunoglobulin (HBIG)-sparing protocol an attractive prophylactic approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). We evaluated the risk of HBV recurrence after withdrawal of HBIG in patients who had been under HBIG plus NUCs after LT. Stable patients without HBV recurrence after LT while receiving combination of HBIG plus NUCs for at least 12 months were eligible for HBIG discontinuation. The patients were at low risk for HBV recurrence (only 4.5% had detectable HBV DNA at the time of LT, and 32% had HBV/hepatitis D virus co-infection). All patients were followed up with HBV serum markers, HBV-DNA, and evaluation of renal function, including glomerular filtration rate. Forty-seven recipients discontinued HBIG and were maintained on newer NUCs. Median follow-up post-HBIG withdrawal was 24 months (range: 6-40 months). Twenty-eight (60%) patients continued on lamivudine in combination with adefovir dipivoxil (n = 23, 82%) or tenofovir (n = 5, 18%); 10 (21%) and 9 (19%) of the 47 patients continued on tenofovir and entecavir monoprophylaxis, respectively. Although 3 (6.3%) patients developed detectable hepatitis B surface antigen, all of them had undetectable HBV DNA and no clinical manifestations of HBV recurrence. Renal function was similar between the different groups of patients. In conclusion, maintenance therapy with newer NUCs after discontinuation of HBIG prophylaxis was effective, but further studies in larger cohorts with longer follow-up are needed.

Topics: Adenine; Adult; Aged; Antiviral Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Immunoglobulins; Lamivudine; Liver Transplantation; Male; Middle Aged; Nucleotides; Organophosphonates; Secondary Prevention; Tenofovir; Treatment Outcome; Young Adult

In 2008, the Netherlands Association of Gastroenterologists and Hepatologists (Nederlands Vereniging van Maag-Darm-Leverartsen) published the Dutch national guidelines for the treatment of chronic hepatitis B virus infection. New insights into the treatment of chronic hepatitis B with relevance for clinical practice have been adopted in these concise, revised guidelines. The most important changes include the choice of initial antiviral therapy, licensing of tenofovir for the treatment of chronic hepatitis B and the management of antiviral resistance.

Topics: Adenine; Antiviral Agents; Drug Approval; Drug Resistance, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Infectious Disease Transmission, Vertical; Lamivudine; Milk, Human; Netherlands; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Infectious; Renal Insufficiency; Telbivudine; Tenofovir; Thymidine

Chronic hepatitis B infection is a common cause of secondary membranous nephropathy (MN) in endemic areas. Lamivudine treatment improves renal outcome in patients with hepatitis B virus-associated MN (HBV-MN), but prolonged use leads to the emergence of lamivudine-resistant variants. We describe our experience treating lamivudine-resistant and other strains of HBV-MN with new antiviral drugs.. Of the 89 patients biopsied and diagnosed with MN from 1996 to 2011, 10 positive for hepatitis B surface antigen were recruited for this study. We investigated the clinical courses, therapeutic responses, and prognoses of patients with HBV-MN.. The incidence of HBV-MN among the original 89 patients was 11.2%. Of these patients, four were treated with supportive care and six with antiviral drugs. One of the four patients treated with supportive care had a spontaneous remission. Four of the six patients treated with antiviral drugs were given lamivudine, and the other two were given entecavir. Two of the four patients treated with lamivudine achieved complete remission with seroconversion (i.e., development of anti-hepatitis B e antigen antibodies), whereas the other two had lamivudine-resistant strains, which were detected at 22 and 23 months after lamivudine treatment, respectively. We added adefovir to the treatment regimen for one of these patients, and for the other patient we substituted clevudine for lamivudine. Both of these patients experienced complete remission, as did the two patients initially treated with entecavir, neither of whom showed resistance to the drug.. New nucleoside analogues, such as entecavir, adefovir, and clevudine, can be effective for treatment of HBV-MN, including lamivudine-resistant strains.

Topics: Adenine; Adult; Antiviral Agents; Arabinofuranosyluracil; Drug Resistance, Viral; Female; Glomerulonephritis, Membranous; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Young Adult

The hepatitis B virus (HBV) replicates via an error-prone reverse transcriptase generating potential drug-resistant quasispecies. The degree of HBV variability in liver vs peripheral blood mononuclear cells (PBMC) in patients on long-term suppressive antivirals is unclear. We characterized HBV replication, drug resistance and molecular diversity in patients with plasma HBV DNA undetectable by clinical assays. Explant liver (n=9), PBMC (n=6) and plasma (n=7) from nine such patients undergoing liver transplantation were evaluated for HBV genomes by sensitive PCR/nucleic acid hybridization assay. Cases with HBV DNA in liver and PBMC were tested for covalently closed circular DNA (HBV cccDNA). HBV polymerase (P) amplicons were cloned, sequenced and both P and overlapping surface (S) gene sequences were analysed. HBV DNA was detected in 43% (3/7) of plasma, 100% (9/9) of liver and 83% (5/6) of PBMC samples. HBV cccDNA was detected in all liver and one PBMC sample. Four patients had a clinical diagnosis of resistance. HBV P gene sequencing revealed 100% wild type (wt) in plasma (2/2), 83% wt in PBMC (5/6) but livers of 3/9 (33%) contained wt and 6/9 (66%) carried resistance to lamivudine and/or adefovir. The translated S gene revealed no changes affecting HBV antigenicity. Sequences from livers with antiviral resistant mutants revealed greater interpatient quasispecies diversity. Despite apparent HBV suppression, the liver continues to support HBV replication and extrahepatic HBV can be detected. PBMC may be a sanctuary for wt virus during antiviral therapy, while the liver harbours more drug-resistant viruses. Drug resistance correlates with intrahepatic viral diversity.

Topics: Adenine; Adult; Aged; Antiviral Agents; Asian People; DNA, Circular; DNA, Viral; Drug Resistance; Female; Gene Products, pol; Genetic Variation; Genome, Viral; Guanine; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Liver; Liver Transplantation; Male; Middle Aged; Organophosphonates; Phylogeny; Tenofovir; Trans-Activators; Viral Envelope Proteins; Viral Regulatory and Accessory Proteins; Virus Replication

Long-term treatment with nucleos(t)ide analogues (NUCs) is associated with increasing rates of antiviral drug resistance. Medication adherence is important in preventing drug resistance. This study aimed to determine, first, the persistence rates and the adherence rates to NUCs in patients with chronic hepatitis B (CHB), and second, the factors associated with adherence.. Pharmacy claims of three cohorts of patients with CHB who were receiving lamivudine, adefovir, or entecavir in January 2007, January 2008, and January 2009, and data of patients receiving tenofovir in January 2009, were analyzed. Persistence was defined as continuing acquisition of pharmacy claims during a 12-month period and adherence as the percent of days in which patients had medication during the period in which the medication was prescribed.. A total of 11,100 patients were included, 4.7% were patients newly started on a NUC and 95.3% were existing patients already on a NUC at the start of each year. The mean ± SD persistence rate was 81 ± 3.8%, and was higher among existing patients than among new patients, 81.4% vs. 73.4% (p < 0.001). The mean ± SD adherence rate was 87.8 ± 19.1% and was higher among existing patients than among new patients, 88% vs. 84.6% (p = 0.001). Multivariate analysis showed that new patients (OR = 0.68, 95% CI 0.53-0.86), those receiving lamivudine (OR = 0.66, 95% CI 0.58-0.76), and young adult patients (OR=0.82, 95% CI 0.74-0.91) were less likely to have adherence rate > 90%.. Persistence and adherence to NUCs were high among CHB patients. Counseling of young and/or new patients on medication adherence may decrease the rate of antiviral drug resistance.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; Cohort Studies; Drug Resistance, Viral; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Medication Adherence; Middle Aged; Organophosphonates; Retrospective Studies; Tenofovir; Young Adult

Current agents used in the treatment of chronic hepatitis B (CHB) can be classified into interferons-α (IFN-α: standard or pegylated) and nucleos(t)ide analogues (NUCs). NUCs are now used in most CHB patients for several reasons. They can be given to all CHB patients, even those with contraindications to IFN-α. NUCs are more convenient to use (one oral tablet daily) than IFN-α (subcutaneous injections) and are well tolerated with a good safety profile, while IFN-α has frequent and potentially severe side effects and worsens the patient's quality of life. All NUCs are potent anti-hepatitis B virus agents (all but adefovir are more potent than IFN-α) with entecavir(ETV) and tenofovir offering the highest potency and most importantly minimal to negligible risk of resistance during long-term monotherapy [corrected]. Prolongation of entecavir or tenofovir monotherapy maintains and slightly increases the initially high virological remission rates (67-76% of HBeAg-positive and 90-93% of HBeAg-negative patients) and this is expected to result in improved long-term outcomes. The need for long-term, perhaps indefinite, treatment is the main limitation of NUCs and the finite duration (48 weeks) the main advantage of IFN-α. However, only a minority of IFN-α-treated patients achieve durable sustained off-treatment responses (HBeAg-positive: 30-35%, HBeAg-negative: 20-25%), while NUCs may be safely discontinued in HBeAg-positive patients with stable HBeAg seroconversion. Because there will always be concerns for safety and family planning issues with long-term therapy, NUCs should be used judiciously and should not be prescribed in young CHB patients with mild liver disease.

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Time Factors; Treatment Outcome

Lamivudine (LAM) has been extensively used to treat hepatitis B, but high incidence of drug resistance has required rescue studies. We validated the optimum treatment strategy for LAM-resistant patients by means of a comparative study of add-on adefovir (ADV) and a switch to entecavir (ETV).. We assessed the virologic response in consecutive LAM-resistant patients who received add-on ADV or a switch to ETV.. The mean reduction of serum hepatitis B virus (HBV) DNA levels was significantly less in the ETV group than in the add-on ADV group (-3.45 vs. -4.17; P = 0.047 at week 24 and -3.81 vs. -4.68 log(10) IU/mL; P = 0.044 at week 48). Achievement of undetectable HBV DNA was significantly lower in the ETV group than in the add-on ADV group (P = 0.043). Multivariate analysis showed that add-on ADV, baseline HBV DNA levels, and initial virologic response were significant predictors of HBV DNA negativity (adjusted OR, 2.582; P = 0.008, 0.304; P = 0.001, and 5.928; P = 0.001). Virologic breakthrough was observed for 12 patients, in the ETV group only.. Add-on ADV was more effective and durable than ETV as rescue therapy. Therefore, add-on ADV might be the preferred strategy for LAM-resistant patients who need long-term antiviral treatment.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates

The study investigated the hepatitis B virus (HBV) genotypic resistance profile in 1803 nucleos(t)ide analogue (NA)-experienced Chinese patients with chronic HBV infection. Serum HBV DNA was extracted, and the reverse transcriptase region was analysed by a high-sensitive direct PCR sequencing and verified by clonal sequencing if necessary. Drug-resistant mutations were detected in 560 of the 1803 patients, including 214 of 490 patients who received lamivudine (LAM), 35 of 428 patients who received adefovir (ADV), five of 18 patients who received telbivudine and 306 of 794 patients who received various sequential/combined NA therapies. ADV-resistant mutations were detected in 36 of 381 patients who received LAM and then switched-to ADV in contrast to one of 82 patients who received ADV add-on LAM. Entecavir (ETV)-resistant mutations were detected not only in LAM- and ETV-treated patients but also in LAM-treated ETV-naïve patients. Double mutations rtM204I and rtL180M were detected more frequently in genotype C than in genotype B virus, and patients infected with this mutant had higher alanine transaminase levels than those infected with mutant containing the rtM204I substitution alone. Multidrug-resistant HBV strains were identified in eight patients, including two novel strains with mutational patterns rtL180M + A181V + S202G + M204V + N236T and rtL180M + S202G + M204V + N236T. The results provide new information on HBV genotypic resistance profiles in a large cohort of Chinese patients with chronic HBV infection and may have important clinical implication for HBV drug resistance management in China.

Topics: Adenine; Adult; Amino Acid Substitution; Antiviral Agents; China; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Nucleosides; Organophosphonates; Pyrimidinones; RNA-Directed DNA Polymerase; Sequence Analysis, DNA; Telbivudine; Thymidine; Viral Proteins

Serum alanine aminotransferase (ALT) increase is a well-known phenomenon during interferon treatment for chronic hepatitis B. However, little is known about these increases during nucleoside/nucleotide treatment and the effects on long-term clinical outcomes.. A total of 170 treatment-naive hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogue for at least 2 years and followed up for 1 more year post-treatment. Clinical characteristics were detected and analysed at baseline and at every 3-month interval.. Two patterns of ALT increase, virus- and host-induced, were detected. Virus-induced increases were characterized by a rapid increase in serum ALT and HBV DNA typically after 2 years of treatment, and were more common than host-induced ALT increases (15.9% versus 6.5%; P<0.05) with a median ALT increase of 5.7-fold the upper limit of normal (ULN). Host-induced ALT increases were characterized by moderately increased ALT (median 2.5-fold ULN) with a slow decrease in HBV DNA that occurred mainly in the first year of treatment (63.6%). Most importantly, host-induced increases were associated with favourable long-term treatment outcomes in HBV DNA undetectable rate (82% versus 0%), HBeAg seroconversion (82% versus 7%) and histological improvement. Moreover, interferon-γ-expressing T-helper cells were increased in patients with host-induced ALT increases.. Two patterns of ALT increases may occur during nucleoside/nucleotide analogue treatment. Host induced ALT increases, accompanied by decreased HBV DNA, lead to better long-term clinical outcomes.

Topics: Adenine; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Female; Guanine; Hepacivirus; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-gamma; Lamivudine; Male; Middle Aged; Nucleosides; Organophosphonates; Predictive Value of Tests; Pyrimidinones; T-Lymphocytes; Telbivudine; Thymidine; Treatment Outcome; Up-Regulation; Young Adult

Optimal duration of anti-viral therapy in chronic hepatitis B virus (HBV) infection remains unclear.. To investigate factors that could predict relapse after stopping anti-viral agents.. Chronic hepatitis B patients who were treated with anti-viral agents (lamivudine, adefovir, entecavir) and have stopped the treatment were recruited. Anti-viral agents were stopped according to the recommendations of the Asian Pacific Association for the Study of the Liver. Virological relapse was defined as an increase in serum HBV DNA to >1000 copies/mL after discontinuation of treatment.. Eighty-four (69 treatment naïve and 15 lamivudine resistant) patients were eligible for this study. Thirty-seven patients developed virological relapse at 4.3 ± 2.9 (range 1-11) months after discontinuation of therapy. The 1-year cumulative probability of virological relapse was 42% and 47% in HBeAg (hepatitis B e antigen)-positive (n = 41) and HBeAg (hepatitis B e antigen)-negative (n = 43) patients, respectively. On multivariate analysis by Cox proportional hazard model, pre-existing lamivudine resistance, delayed suppression of HBV DNA to undetectable level during anti-viral therapy and to a higher HBsAg (hepatitis B surface antigen) level at the end of treatment were associated with virological relapse. Twelve of the 15 (80%) lamivudine resistant patients developed virological relapse. Among the 11 treatment naïve patients who had HBsAg ≤ 2 log IU/mL at the end of treatment, 1 (9%) of them had virological relapse.. Treatment cessation among lamivudine resistant patients is associated with high risk of virological relapse. Serum HBsAg level at the end of treatment and rate of HBV DNA suppression can provide supplementary information to guide the timing of stopping anti-viral drugs.

Topics: Adenine; Adult; Antiviral Agents; Female; Guanine; Hepatitis B Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Proportional Hazards Models; Real-Time Polymerase Chain Reaction; Recurrence; Time Factors

Drug resistance is a major limitation for the long-term efficacy of antiviral therapy with nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). Antiviral resistance mutations may pre-exist in the overall viral population of untreated patients. We aimed to assess the prevalence of such hepatitis B virus (HBV) variants in a large cohort of NAs-naïve patients with CHB and to explore possible association with viral and host variables. Serum samples from 286 NAs-naïve consecutive patients with CHB were tested for serum HBV-DNA, and 255 of them having HBV-DNA > 1000 IU/mL were further analysed for drug resistance mutations by INNO-LiPA HBV DRv2/v3. NAs-naïve patients analysed were mainly men (73%), Caucasians (85%), hepatitis B e Antigen (HBeAg) negative (79%) and genotype D (69%), with a mean age of 43.2 ± 13.4 years. HBV mutations associated with antiviral drug resistance were detected in 13 (5%) patients: three patients infected with HBV genotype C had the rtM204V + rtL180M mutations associated with lamivudine (LMV) resistance. Four patients had the rtI233V mutation that may reduce sensitivity to adefovir, and three patients had the rtM250L/V mutation typical of entecavir resistance. LMV compensatory mutations rtL80V and rtV173L were seen in two and one patients, respectively. No relationship was seen between presence of resistant or compensatory mutations and HBV-DNA levels, HBeAg/anti-HBe status or previous IFN therapy. These results confirm that HBV mutations, which confer resistance against currently available anti-HBV NAs, may already exist in patients who have never received the drug.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Gene Products, pol; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Mutation; Organophosphonates; Polyethylene Glycols; Recombinant Proteins

Complex mutants can be selected under sequential selective pressure by HBV therapy. To determine hepatitis B virus genomic evolution during antiviral therapy we characterized the HBV quasi-species in a patient who did no respond to therapy following lamivudine breakthrough for a period of 14 years.. The polymerase and precore/core genes were amplified and sequenced at determined intervals in a period of 14 years. HBV viral load and HBeAg/Anti-HBe serological profiles as well as amino transferase levels were also measured. A mixture of lamivudine-resistant genotype A2 HBV strains harboring the rtM204V mutation coexisted in the patient following viral breakthrough to lamivudine. The L180M+M204V dominant mutant displayed strong lamivudine-resistance. As therapy was changed to adefovir, then to entecavir, and finally to entecavir-tenofovir the viral load showed fluctuations but lamivudine-resistant strains continued to be selected, with minor contributions to the HBV quasi-species composition of additional resistance-associated mutations. At the end of the 14-year follow up period, high viral loads were predominant, with viral strains harboring the lamivudine-resistance signature rtL180M+M204V. The precore/core frame A1762T and G1764A double mutation was detected before treatment and remaining in this condition during the entire follow-up. Specific entecavir and tenofovir primary resistance-associated mutations were not detected at any time. Plasma concentrations of tenofovir indicated adequate metabolism of the drug.. We report the selection of HBV mutants carrying well-defined primary resistance mutations that escaped lamivudine in a fourteen-year follow-up period. With the exception of tenofovir resistance mutations, subsequent unselected primary resistance mutations were detected as minor populations into the HBV quasispecies composition during adefovir or entecavir monotherapies. Although tenofovir is considered an appropriate therapeutic alternative for the treatment of entecavir-unresponsive patients, its use was not effective in the case reported here.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Evolution, Molecular; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Middle Aged; Mutation; Organophosphonates; Tenofovir; Treatment Failure

Topics: Adenine; Adult; Aged; Antiviral Agents; Guanine; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Quality of Life; Young Adult

An increasing number of patients with chronic hepatitis B (CHB) have experienced treatment failure to adefovir (ADV) and their management poses a growing challenge. Very limited data are available on the efficacy of entecavir (ETV) in patients previously treated with ADV.. To examine the effect of ETV monotherapy on HBV DNA and ALT levels in CHB patients previously treated with ADV, but switched to ETV due to suboptimal response.. Study candidates were enrolled from five community gastroenterology clinics in the U.S. Each completed at least 12 months of ETV treatment after being previously treated with ADV and experiencing suboptimal response. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV DNA <100 IU/mL) and biochemical response (BR, ALT < 40 U/L), respectively.. A total of 60 patients were included in this analysis. Twelve were lamivudine (LAM)-experienced and none were LAM-resistant. At time of switch to ETV, no patients had experienced CVS. The CVS rate was 68% after 12 months of ETV therapy. The BR rate was 67% at switch to ETV and 80% after 12 months. There was no significant difference in response rates between LAM-experienced and naïve patients. Among the eight patients with ADV resistance, each achieved CVS after 12 months of ETV therapy and seven achieved BR.. In patients with suboptimal response to adefovir, complete viral suppression and biochemical response can be achieved in the majority by 12 months after switching to entecavir, including patients with prior exposure to lamivudine and those with adefovir resistance.

Topics: Adenine; Adult; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Regression Analysis; Time Factors; Treatment Outcome; Viral Load

In chronic hepatitis B (CHB) patients, adefovir is commonly used as a rescue therapy for lamivudine resistance, but often results in incomplete virological suppression.. To study the factors predicting response to adefovir rescue, and the treatment response of tenofovir and entecavir in suboptimal responders to adefovir in CHB patients.. Chronic hepatitis B patients who took adefovir for at least 6 months for lamivudine resistance were studied. Early virological response was defined as undetectable HBV DNA at month 6. Maintained virological response was defined as undetectable HBV DNA till the last follow-up.. Among 136 patients on adefovir for 39 (5-117) months, 30 (22%) had early virological response. The 3-year cumulative probability of maintained virological response was similar between patients on adefovir monotherapy (n = 53, 57.9%) and those on combination of lamivudine and adefovir treatment (n = 83, 56.5%). The month 6 HBV DNA was the only independent factor associated with maintained virological response (adjusted hazard ratio 0.49, 95% confidence interval 0.37-0.65, P < 0.001). Twenty-six of 30 (87%) early responders and 36 of 106 (34%) non-early responders had maintained virological response on adefovir (P < 0.001). Among 106 non-early responders, 18 and 11 were switched to tenofovir and entecavir, respectively. The 1-year cumulative probability of maintained virological response was higher in patients switched to tenofovir (87.5%) than those switched to entecavir (37.5%; P = 0.048) or continued with adefovir (8.7%; P < 0.001).. In adefovir rescue for lamivudine resistance, month 6 HBV DNA predicts maintained virological response in CHB patients. Switching to tenofovir achieved best viral suppression among suboptimal responders to adefovir.

Topics: Adenine; Adult; Antiviral Agents; Cohort Studies; DNA, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Retrospective Studies; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

No studies have reported the long-term effects of entecavir switching in patients with multidrug resistance who developed resistance after lamivudine/adefovir sequential therapy. We evaluated the efficacy of 96 weeks of entecavir therapy in patients with resistance to lamivudine/adefovir sequential therapy. In total, 33 patients with chronic hepatitis B virus (HBV) infection with evidence of active viral replication (HBV DNA levels ≥ 10(5) copies/mL) or a history of treatment failure to lamivudine/adefovir sequential therapy between April 2007 and July 2009 were treated with entecavir (1.0 mg daily) for at least 48 weeks. The rates of alanine transaminase (ALT) normalization and HBV DNA negativity were 66.7% (14/21) and 24.2% (8/33) at 48 weeks, respectively. The initial HBV DNA level was the only factor that was inversely associated with serum HBV DNA negativity after 48 weeks of entecavir therapy (P < 0.023). At 96 weeks, the rates of ALT normalization and HBV DNA negativity were 77.8% (7/9) and 16.7% (3/18), respectively. Viral breakthrough occurred in 21.2% (7/33) and 78.9% (15/19) of patients at 48 and 96 weeks, respectively. Patients who achieved a HBV DNA level of <4 log(10) copies/mL at 48 weeks maintained a similar HBV DNA level and a normal ALT level until 96 weeks. Entecavir monotherapy for 96 weeks was not efficacious for patients with lamivudine/adefovir-resistant HBV. The initial HBV DNA level was the only predictive factor for antiviral efficacy. However, patients who achieved a HBV DNA level of <4 log(10) copies/mL with a normal ALT level at 48 weeks should maintain, rather than stop, entecavir therapy.

Topics: Adenine; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Function Tests; Male; Middle Aged; Organophosphonates; Retrospective Studies; Treatment Outcome; Viral Load

This study aimed to evaluate the long-term efficacy of entecavir (ETV) in adefovir (ADV)-refractory chronic hepatitis B (CHB) patients with prior lamivudine (LMV) resistance. A total of 55 ADV-refractory CHB patients with prior LMV resistance, who received rescue therapy with ETV 1 mg daily for at least 12 months, were consecutively enrolled and analysed. Forty-four patients were men, and their median age was 47 (25-69). Ten patients had liver cirrhosis and 46 patients were positive for hepatitis B e antigen (HBeAg). Median hepatitis B virus DNA levels were 6.6 (4.3-8.0) log(10) copies/mL, and the median duration of ETV therapy was 24 (12-47) months. Cumulative virologic response rates at 6, 12, 24 and 36 months were 18%, 29%, 58% and 75%, respectively. HBeAg loss occurred in 10 (21.7%) of 46 HBeAg-positive patients. In multivariate analysis, only initial virologic response at 3 months remained as an independent predictor for virologic response (RR 3.143; 95% CI 1.387-7.120; P = 0.006). The patients with a virological response at 3 months had not only a significantly higher probability of achieving a virologic response (P < 0.001) but also lower probability of experiencing a virologic breakthrough (P = 0.043) than the patients without an early response. Viral breakthrough was observed in 29 patients during the follow-up period. Cumulative breakthrough rates at 6, 12, 24 and 36 months were 0%, 15%, 45% and 73%, respectively. ETV monotherapy may be considerably efficacious in cases with an initial virological response but its efficacy is attenuated by frequent emergence of ETV resistance in ADV-refractory CHB patients with prior LMV resistance.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Salvage Therapy; Treatment Outcome

We determined the virologic response, incidence of entecavir resistance, and evolution of lamivudine and adefovir-resistant mutants during entecavir (ETV) therapy in adefovir-refractory patients with prior lamivudine resistance. Forty adefovir-refractory chronic hepatitis B patients with prior lamivudine resistance who had received entecavir for > or = 6 months were included and monitored for virologic response and entecavir resistance. Ten per cent of patients achieved HBV DNA < 50 copies/mL by PCR after 24 weeks of ETV therapy, and an initial virologic response was observed in 12 of 40 patients (30%). Higher pretreatment ALT (P = 0.039) and the presence of the rtL180M mutation (P = 0.038) were associated with an initial virologic response. During a mean follow-up of 11.4 months, four patients (10%) experienced virologic breakthrough, while ETV-resistant mutants were detected in six patients (15%). YMDD and adefovir-resistant mutants were detected in 57 and 35% of patients at baseline, respectively. At 48 weeks of therapy, 96 and 4% of patients had YMDD and adefovir-resistant mutants, respectively. These data suggest an early development of ETV resistance and low antiviral response during ETV therapy in adefovir-refractory patients with prior lamivudine resistance.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Treatment Outcome; Viral Load

Recently, we reported on three patients with chronic hepatitis B virus (HBV) infection for whom adefovir (ADF) therapy virologically failed, most likely due to a preexisting rtI233V HBV polymerase mutation. Here, we describe two further patients with chronic HBV infection who were found to develop the rtI233V mutation after initiation of ADF therapy. These patients represent the first cases known so far in which the rtI233V ADF resistance mutation evolved under persistent HBV replication during HBV therapy with ADF. Interestingly, one of the previously described patients, who was initially successfully switched from ADF to tenofovir (TDF) and became virologically suppressed subsequently, experienced a moderate but remarkable rebound of HBV viremia after switching from TDF to entecavir, due to the emergence of renal toxicity. Thus, we provide evidence for the selection and counterselection of the rtI233V ADF resistance mutation during antiviral therapy.

Topics: Adenine; Adult; Amino Acid Sequence; Amino Acid Substitution; Antiviral Agents; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Molecular Sequence Data; Mutation, Missense; Organophosphonates; Selection, Genetic; Sequence Alignment; Tenofovir; Treatment Failure; Viremia; Young Adult

Topics: Adenine; Antiviral Agents; Biopsy; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis D; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Lamivudine; Liver Cirrhosis; Nucleotides; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir

Hepatitis B (HBV) is a public health problem worldwide; one-third of the population has already been in contact with HBV, and 350 million people are chronic carriers of virus. The appearance of hyperimmune gamma globulin and antiviral drugs has allowed that group to undergone hepatic transplantation, achieving satisfactory results to prevent a relapse. But the use of hyperimmune gamma globulin has an extremely high cost, and combined therapies with new antiviral drugs seem to be a therapeutic alternative. We analyzed 21 patients with hepatitis B associated or not with Delta hepatitis over a mean follow-up period of 19.5 months, concluding that use of only nucleotide analogues has sufficient to achieve satisfactory results.

Topics: Adenine; Adult; Aged; Antiviral Agents; Aspartate Aminotransferases; Female; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis D; Humans; Liver Transplantation; Male; Middle Aged; Organophosphonates; Polymerase Chain Reaction; Recurrence; Retrospective Studies; Young Adult

Hepatitis B is a DNA virus affecting hundreds of millions of individuals worldwide. As the clinical sequelae of cirrhosis and hepatocellular cancer are increasingly recognized to be related to viral levels, the impetus increases to offer treatment to those previously not treated. With the development of more robust antivirals with reasonable safety profiles, long-term treatment is becoming more common. The oral nucleos(t)ide analogs have become the preferred first-line therapies for most genotypes of hepatitis B. Five are now available, all with different potencies and resistance profiles. Long-term data spanning several years are now available for most compounds in this arena. This article focuses on the common natural variants and those secondary to nucleos(t)ide therapy, as well as diagnostic methods to detect resistance.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Genetic Testing; Genotype; Guanine; Hepatitis B; Humans; Lamivudine; Nucleosides; Organophosphonates; Phenotype; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

To reduce the incidence of drug resistance and to maintain viral suppression, patients chronically infected with HBV might require combination therapy using two or more drugs with different resistance profiles. We investigated the activity of clevudine (CLV) in combination with other nucleoside/nucleotide analogues to determine if these combinations were compatible in vitro.. Using the HepAD38 cell line, which expresses wild-type HBV, and a real-time PCR assay, we tested the anti-HBV activity of CLV in combination with entecavir, lamivudine, adefovir, tenofovir and telbivudine (TBV). We evaluated the uptake and phosphorylation of CLV in the presence of TBV, using HepAD38 cells and primary hepatocytes to determine the effect of TBV on the phosphorylation of CLV and vice versa. Phosphorylation of TBV and CLV to their corresponding monophosphate by deoxycytidine kinase, thymidine kinase-1 and thymidine kinase-2, and the phosphorylation of TBV monophosphate and CLV monophosphate by thymidylate kinase was evaluated and compared.. When CLV was combined with entecavir, lamivudine, adefovir or tenofovir, a synergistic antiviral effect was observed; however, the combination of CLV and TBV gave an antagonistic antiviral response. The results of in vitro metabolism and enzyme studies suggest that the antagonism observed with the CLV/TBV combination involves competition for uptake and phosphorylation.. The results of our studies demonstrate that combination treatments can provide enhanced antiviral activity and, when used in conjunction with appropriate metabolic investigations, provide a rational basis for the design and development of combination regimens for treating chronic HBV infection.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Arabinofuranosyluracil; Cell Line; Cells, Cultured; Drug Antagonism; Drug Synergism; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatocytes; Humans; Lamivudine; Microbial Sensitivity Tests; Nucleosides; Nucleotides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine

The aim of this study was to investigate the economic consequences of nucleoside analog therapy for hepatitis B treatment in China.. A cost-utility analysis of treatments for HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) was conducted using a Markov model, in which patients' yearly transitions between different health states were tracked. Patients were tracked as they moved between the following health states: CHB, HBeAg seroconversion (HBeAg-positive CHB patients can have this special health state), virologic resistance, virologic response, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. The transition parameters were derived either from systematic reviews of the literature or from previous economic studies. Cost and utility data came from studies based on a Chinese CHB cohort. One-way sensitivity analyses as well as second-order Monte Carlo and probabilistic sensitivity analyses were performed.. The entecavir strategy yielded the most quality-adjusted life years (QALYs) for both HBeAg-positive and HBeAg-negative patients when compared with the "no treatment," the lamivudine, the adefovir, and the telbivudine strategies. The risks of complications and mortality also decreased. In the economic analysis, the "no treatment" strategy was the least effective, whereas the entecavir strategy was both the least expensive and the most cost-effective option, followed by telbivudine and lamivudine. The probabilistic sensitivity analysis showed that the entecavir strategy would result in improved cost-effectiveness in >90% of cases at a threshold of $20,000 per QALY. In a one-way sensitivity analysis, the most influential parameters impacting the model's robustness were the utilities of the CHB and virologic response health states.. In China, when treating both HBeAg-positive and HBeAg-negative CHB populations, entecavir is the most cost-effective option when compared with lamivudine, adefovir, and telbivudine.

Topics: Adenine; Antiviral Agents; China; Cost-Benefit Analysis; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Markov Chains; Models, Economic; Models, Statistical; Monte Carlo Method; Nucleosides; Organophosphonates; Pyrimidinones; Quality-Adjusted Life Years; Reverse Transcriptase Inhibitors; Serologic Tests; Telbivudine; Thymidine

Antiviral treatment has improved the short-term outcome of kidney transplant recipients with chronic hepatitis B infection, but its long-term impact, especially in patients who have developed drug resistance, remains uncertain.. Sixty-three hepatitis B surface antigen positive (HBsAg+) and 63 HBsAg- patients who have undergone kidney transplantation from 1985 to 2008 were retrospectively reviewed and their clinical outcomes were compared.. With lamivudine as initial treatment, 62% of patients developed drug resistance after 4 years. Lamivudine resistance was associated with a higher incidence of chronic hepatitis but had no significant impact on liver stiffness score or patient survival during follow-up. Salvage treatment with adefovir or entecavir was well tolerated, and resulted in a three-log decrease in hepatitis B deoxynucleic acid after 6 months and normalization of alanine aminotransferase in 75% of patients. The survival rate of HBsAg+ patients transplanted in the recent era of antiviral treatment was 81% at 10 years. Treatment of hepatitis B with nucleoside/nucleotide analogues resulted in significantly improved patient survival (83% vs. 34% at 20 years, P=0.006). Although antiviral treatment was associated with reduced mortality because of liver complications (P=0.036), liver-related deaths still accounted for 40% of mortalities in HBsAg+ patients in the era of antiviral therapies and 22.2% of all deaths that occurred in patients who had received antiviral treatment.. Treatment of HBsAg+ renal transplant recipients with nucleoside/nucleotide analogues confers long-term survival benefit, and that rescue therapy with adefovir or entecavir is effective and well tolerated in patients who had developed resistance to lamivudine.

Topics: Adenine; Adult; Antiviral Agents; Biomarkers; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kidney Diseases; Kidney Transplantation; Lamivudine; Male; Middle Aged; Organophosphonates; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Viral Load

The detection of antiviral-resistant hepatitis B virus (HBV) mutations is important for monitoring the response to treatment and for effective treatment decisions. We have developed an array using peptide nucleic acid (PNA) probes to detect point mutations in HBV associated with antiviral resistance. PNA probes were designed to detect mutations associated with resistance to lamivudine, adefovir, and entecavir. The PNA array assay was sensitive enough to detect 10(2) copies/ml. The PNA array assay was able to detect mutants present in more than 5% of the virus population when the total HBV DNA concentration was greater than 10(4) copies/ml. We analyzed a total of 68 clinical samples by this assay and validated its usefulness by comparing results to those of the sequencing method. The PNA array correctly identified viral mutants and has high concordance (98.3%) with direct sequencing in detecting antiviral-resistant mutations. Our results showed that the PNA array is a rapid, sensitive, and easily applicable assay for the detection of antiviral-resistant mutation in HBV. Thus, the PNA array is a useful and powerful diagnostic tool for the detection of point mutations or polymorphisms.

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Microbial Sensitivity Tests; Mutation, Missense; Oligonucleotide Array Sequence Analysis; Organophosphonates; Peptide Nucleic Acids; Point Mutation; Sensitivity and Specificity

Pre-existing antiviral-resistant hepatitis B virus (HBV) has been associated with primary non-response to lamivudine treatment in patients with chronic hepatitis B, but little is known of the capacity for resistant HBV to cause primary infection.. The study was to investigate if Beijing patients with acute hepatitis B (AHB) are infected with drug-resistant HBV.. Sera were collected from 201 NA-untreated patients with AHB. Direct polymerase chain reaction (PCR) sequencing was used to screen HBV reverse-transcriptase (RT) domain and clonal sequencing were performed for all resistance-positive samples.. Direct PCR sequencing showed that 14 samples (7.0%) were positive for drug-resistant HBV variants, comprised of 11 with the lamivudine-resistant pattern rtM204I and/or rtM204V in the presence and absence of compensatory mutations rtL80I, rtV173L, and rtL180M; two with the adefovir-resistant pattern rtA181V; and one with the entecavir-resistant pattern rtL180M+rtS202G+rtM204V. Concomitance of resistance variants with wild-type HBV was observed in samples from 13 patients. Clonal sequencing verified direct sequencing results. Furthermore, variants associated with resistance to adefovir or entecavir were found in 3 samples.. Drug-resistant HBV strains, including those not resistant to lamivudine, are transmissible and can cause acute hepatitis B in China.

Topics: Adenine; Adult; Amino Acid Substitution; Antiviral Agents; China; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Organophosphonates; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; Sequence Analysis, DNA; Viral Proteins

Little is known about the optimal management of patients with chronic hepatitis B (CHB) who developed multiple-drug resistance.. We assessed 91 patients with compensated CHB who developed adefovir-resistant mutations during adefovir monotherapy for lamivudine-resistant CHB. Of these, 41 were treated with a combination of lamivudine plus adefovir (LAM+ADV group) and 50 were treated with entecavir monotherapy (ETV group).. There were no significant differences between the two groups in baseline characteristics, including serum HBV DNA levels (p>0.05). The rate of virologic non-response (HBV DNA reduction <1 log(10) IU/ml at 6 months) was significantly greater in the LAM+ADV than in the ETV group (51.2% vs. 16.0%, p<0.01). At 12 months, HBV DNA declined less in the LAM+ADV than in the ETV group (-1.49+/-1.78 vs. -3.47+/-2.13 log(10) IU/ml, p<0.01). Only 12.2% and 22.0% of patients in the LAM+ADV and ETV groups, respectively, achieved complete virologic response (HBV DNA <60 IU/ml) at 12 months. Multivariable analysis showed that LAM+ADV group (OR=0.08, CI=0.02-0.28) and the presence of the rtA181V/T mutation (OR=0.21, CI=0.05-0.91) were independently associated with a decreased rate of virologic response (HBV DNA <2000 IU/ml) at 12 months.. In patients with CHB resistant to lamivudine and adefovir, combination therapy with these two drugs was not effective and was inferior to entecavir monotherapy in suppressing HBV DNA. However, the response to entecavir monotherapy was also not optimal. These results emphasize the importance of preventing the development of multidrug-resistant HBV and of exploration for adequate combination therapy in treatment of multidrug-resistant CHB.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genes, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Viral Load

There have been no reports comparing the therapeutic results of adefovir (ADV) and entecavir (ETV) rescue therapy for patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB). We aimed to compare the cumulative efficacy and resistance of ETV 1.0 mg monotherapy, ADV monotherapy and ADV add-on LAM combination therapy in LAM-refractory patients.. One hundred and four patients were included in the following three treatment groups; group 1 (n = 24), LAM was switched to ETV (1.0 mg once a day); group 2 (n = 44), LAM was switched to ADV (10 mg once a day); and group 3 (n = 36), ADV was added to LAM (10 mg once a day).. After 6 months of rescue treatment, alanine aminotransferase normalization was observed in 75.0%, 65.9% and 74.3% of patients receiving ETV monotherapy, ADV monotherapy and ADV add-on therapy, respectively. A significantly higher log(10)HBV-DNA drop at 6 months occurred in the ADV add-on group compared with the ETV group. The rate of HBV-DNA polymerase chain reaction undetectability (<300 copies/mL) 6 months after initiation of ETV monotherapy, ADV monotherapy and ADV add-on therapy was 33.3%, 27.3% and 68.6%, respectively (P = 0.003). The cumulative HBeAg seroconversion rate was significantly higher in ADV add-on/ADV monotherapy groups compared with the ETV monotherapy group (P = 0.022). Viral breakthrough and genotypic resistance were detected in six (25.0%) and six (13.6%) patients in the ETV and ADV monotherapy groups, whereas no cases of genotypic resistance were detected in ADV add-on group 24 months after initiation of antiviral treatment (P < 0.01).. Adefovir add-on treatment in patients with LAM-resistant CHB suppresses HBV replication more effectively than ETV or ADV monotherapy. Additionally, no genotypic resistance was detected in the ADV add-on group.

Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; Biomarkers; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Republic of Korea; Retrospective Studies; Time Factors; Treatment Outcome; Viral Load; Virus Replication

Topics: Adenine; Antiviral Agents; Cross-Sectional Studies; Germany; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Long-Term Care; Organophosphonates; Patient Care Team; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load

As human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are acquired through the same routes of contamination, the prevalence of HBV serological markers found in the HIV-infected population is approximately 7%. Liver-related mortality and morbidity is higher in HIV/HBV co-infected patients than in HBV mono-infected patients. Both viruses must be considered before a treatment decision is made. According to the European consensus conference on the treatment of chronic hepatitis B and C in HIV coinfected patients, treatment is based on whether there is an existing indication of anti- HIV therapy or not. In patients with no indication of anti-HIV therapy, drugs with dual anti-viral activity (lamivudine, entecavir, tenofovir disoproxil fumarate) should not be used due to the risk of developing HIV-resistance. Interferon or adefovir in combination with telbivudine are recommended. In patients with an indication of anti-HIV therapy, a backbone of highly active anti-retroviral therapy should include tenofovir in combination with lamivudine or emtricitabine. The same regimen is recommended in patients who develop lamivudine resistance.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Antiviral Agents; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir

Early detection of antiviral drug-resistant mutations enables prompt initiation of rescue therapy. The aim of this study was to determine the accuracy and sensitivity of a new line probe assay in the detection of antiviral drug-resistant HBV mutations.. One-hundred samples from 54 patients with virologic breakthrough during entecavir, lamivudine or adefovir treatment and 21 samples from 21 nucleoside-naïve patients were tested by direct sequencing and an updated line probe assay (Innogenetics, HBV DR v.3) which incorporates probes that can detect mutations at 11 positions of the reverse transcriptase region of the HBV polymerase gene.. Complete concordance between line probe and sequencing results was observed for 90/121 samples (74.3%) and 1291/1331 amino acid positions (96.9%). Testing of follow-up samples and clonal analysis of discordant samples confirmed the presence of mutations where line probe assay but not direct sequencing detected mutations. HBV DR v.3 assay consistently detected mutations present in > or = 5% of the virus population when HBV DNA concentration was > or = 4 log10copies/mL.. The updated version of the line probe assay (HBV DR v.3) has high concordance with direct sequencing in detecting antiviral drug-resistant mutations but its sensitivity in detecting mutations at some positions needs to be improved.

Topics: Adenine; Adult; Antiviral Agents; DNA Probes; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Sensitivity and Specificity

We investigated the efficacy of entecavir in lamivudine-experienced and -naïve patients with persistently high HBV DNA during adefovir treatment.. Fourteen chronic hepatitis B patients (57% lamivudine-experienced) with a viral load above 5log(10)copies/mL after 12months of adefovir therapy and thereafter were treated with entecavir 1mg daily.. During a median follow-up of 15months (range: 8-23months) one of six lamivudine-naïve and none of the eight lamivudine-experienced patients achieved undetectable HBV DNA (<373copies/mL). HBeAg loss occurred in none of the subjects. Two lamivudine-experienced patients demonstrated the rtM204I mutation; no other entecavir-resistant substitutions were detected (rtI169, rtT184, rtS202, and rtM250). Two of three patients with genotypic adefovir resistance at baseline demonstrated a rapid virologic response to entecavir, but undetectable HBV DNA was not achieved. To attain a better antiviral response the dosage of entecavir was increased to 2mg daily in two patients, resulting in further viral load decline for both of them.. Entecavir monotherapy dosed at 1mg resulted in a slow reduction of viral load in both lamivudine-experienced and -naïve patients with persistently high HBV DNA during adefovir therapy. Increasing the dosage of entecavir led to further HBV DNA decline.

Topics: Adenine; Adult; Aged; Antiviral Agents; DNA, Viral; Female; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleosides; Nucleotides; Organophosphonates; Tenofovir

In patients receiving orthotopic liver transplantation, hepatitis B recurrence rates have decreased significantly with the use of various methods for prophylaxis. At present, a combination of hepatitis B immunoglobulin (HBIG) and lamivudine is the standard of care, resulting in recurrence rates of 0% to 11%. Recent data suggest that the addition of adefovir to lamivudine is successful in treating patients with recurrent hepatitis B infection. A Markov model was used to compare costs and outcomes of 2 strategies for hepatitis B prophylaxis 1 year after transplantation. The first consisted of prophylaxis with lamivudine and adefovir (strategy 1), whereas the second consisted of intramuscular HBIG and lamivudine (strategy 2) with the addition of adefovir in patients who subsequently developed hepatitis B recurrence. Patients who failed with adefovir and lamivudine were then treated with tenofovir and entecavir. 16.8% of liver transplant recipients had hepatitis B recurrence after 10 years of treatment with lamivudine and HBIG. The medical costs for strategy 1 and strategy 2 after 10 years of therapy were $151,819 and $166,246, respectively, and this resulted in cost savings of $14,427. The decision analysis model began 1 year after liver transplantation. A 1-way sensitivity analysis demonstrated that the model was most sensitive to cost changes of adefovir and HBIG injections as well as variations in the hepatitis B virus recurrence rate. The model was robust to costs of lamivudine, laboratory costs, administrative fees, and office visit fees. Our decision analysis model resulted in marked savings in costs with strategy 1 (lamivudine and adefovir), providing pharmacoeconomic support for the use of this strategy as first-line therapy in hepatitis B prophylaxis in liver transplant recipients 1 year after liver transplantation.

Topics: Adenine; Administration, Oral; Antiviral Agents; Cost Savings; Cost-Benefit Analysis; Decision Support Techniques; Drug Costs; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Health Care Costs; Hepatitis B, Chronic; Humans; Immunoglobulins; Injections, Intramuscular; Lamivudine; Liver Transplantation; Markov Chains; Models, Economic; Organophosphonates; Retrospective Studies; Salvage Therapy; Secondary Prevention; Tenofovir; Time Factors; Treatment Failure; Treatment Outcome

Long-term management of some chronic hepatitis B patients might require combination therapy using drugs with distinct resistance profiles to sustain viral suppression and to reduce the resistance-associated failure. Tenofovir disoproxil fumarate (TDF), approved for hepatitis B virus (HBV) and HIV-1 treatment, is active against wildtype HBV and HBV containing YMDD mutations, which confer resistance to emtricitabine (FTC), lamivudine (3TC) and telbivudine (LdT) and contribute to entecavir (ETV) resistance. We therefore evaluated the in vitro anti-HBV activity of tenofovir (TFV), the active parent drug of TDF, combined with FTC, 3TC, ETV, LdT and adefovir (AFV).. The anti-HBV activities of the compounds were tested using the AD38 cell line that expresses wild-type HBV from a tetracycline-controllable promoter. Intracellular HBV DNA levels were quantified using real-time PCR assay and cytotoxicities were assessed with XTT assays. The antiviral data of the drug combinations were evaluated using MacSynergy analyses on the basis of the Bliss independence model as well as isobologram analyses on the basis of the Loewe additivity theory.. All drug combinations tested, FTC+TFV, 3TC+TFV, ETV+TFV, LdT+TFV and AFV+TFV, showed additive antiviral interactions as analysed by MacSynergy. Isobologram analyses revealed that these combination pairs were additive, with the exception of FTC+TFV, which demonstrated slight synergistic activity. No cytotoxic or antagonistic effects were observed with any of the combinations tested.. The combination of TFV with FTC, 3TC, ETV, LdT or AFV had additive to slightly synergistic anti-HBV effects in vitro. These results support the use of TDF as a component in combination regimens with currently available anti-HBV nucleoside analogues.

Topics: Adenine; Antiviral Agents; Cell Line; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Nucleotides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine

The hepatitis B virus (HBV) reverse transcriptase (RT) plays an important role in viral replication. The aim of the present study was to characterize profiles of the RT region and to construct a database for further studies.. Serum samples were obtained from 328 treatment naive patients chronically infected with HBV in five Chinese cities. Mutation status, genotypes and deep sequence analysis were carried out by amplifying and sequencing the RT region.. The base usage in the RT region differed at the mono- and dinucleotide level and thymidine dominated. The higher the variability of the strain was, the more it replicated. No significant clustering was found between our HBV RT sequences and those isolated 10 years ago (achieved from genebank). Nucleotide analogue resistance related mutants exist. The M204V/I mutation was found in 1.8% of the strains, 1.2% had L180M+ M204V/I, 0.6% had A181T/V, and only one had all three mutations. Minor strain mutants were found in 9.3% of the samples studied. The genotype B patients made up 36.6% (88.7% B2) and were mostly found in southern China, 63.4% (92.2% C2) were genotype C, and only one was genotype D. The average age of HBeAg positive genotype B patients was 29.5 +/- 10.4 years, for genotype C it was 36.1 +/- 10.9 (P < 0.001).. Primarily antiviral resistance related mutant strains do exist in treatment naïve patients. Without antiviral pressure, HBV strains evolved at a normal speed. In depth sequence analysis implied that viral replication might be correlated with its variability, which needs to be further investigated.

Topics: Adenine; Adult; Antiviral Agents; Asian People; Base Composition; China; Computational Biology; Databases, Genetic; DNA, Viral; Drug Resistance, Viral; Female; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Phenotype; Phylogeny; RNA-Directed DNA Polymerase; Treatment Failure; Virus Replication; Young Adult

Pretreatment alanine transaminase (ALT) elevation may be used as a predictor for higher hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B patients. However, the role of dynamic changes of on-treatment ALT for seroconversion is unknown. A total of 170 naïve HBeAg-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogues (NA), either lamivudine, adefovir, entecavir, or telbivudine, for at least 2 years and followed up for 1 more year. Clinical characteristics were detected and analysed at baseline and at 3-month intervals. On-treatment ALT predicted HBeAg seroconversion more accurately than baseline ALT. Among the patients with on-treatment ALT 5 x UNL, HBeAg seroconversion was 11.4, 5.4, 24.4 and 65.0% (odds ratio = 1.0, 0.4, 2.5 and 14.4, respectively), respectively. Moreover, two models/types of seroconversion were observed. Type I was characterized by rapidly decreased ALT and HBV DNA during the first 3-month interval, but with high HBeAg reversion rate (50%) after consolidation treatment. Type II was a slow decreased DNA procedure accompanied by significant elevated ALT with less reversion (23%). Receiver operating characteristic curve analysis showed a 1.9-fold increased ALT ratio (present visit ALT: previous visit ALT) accompanied by at least a 0.8 log decreased HBV DNA may be used to classify these two seroconversion types. We conclude that on-treatment elevated ALT levels is a better predictor for seroconversion after NAs treatment, and HBV DNA profiles may help to identify different models of seroconversion.

Topics: Adenine; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Nucleosides; Organophosphonates; Prognosis; Pyrimidinones; Retrospective Studies; Telbivudine; Thymidine; Young Adult

Chronic hepatitis B affects 5-10% of HIV patients in Western countries. Lamivudine should no longer be used as a single anti-HBV agent in HIV-HBV co-infected patients, given its limited antiviral potency and high risk of selection of resistance, which further results in wide cross-resistance to all other nucleoside analogues. Recent reports of transmission of lamivudine-resistant HBV in HIV patients are of especial concern, and large surveillance studies suggest that it may occur in up to 10% of new HBV infections in Western countries. Another worrisome aspect of the selection of lamivudine-resistant HBV is the potential for selection of vaccine escape mutants. Currently, tenofovir must be viewed as the drug of choice in HIV-HBV co-infected patients in whom antiretroviral therapy is advised. Its co-formulation with emtricitabine (Truvada) is particularly convenient for treating both HIV and HBV in co-infected individuals. While pegIFN-alpha monotherapy for 1 year may be considered for HIV-HBV coinfected individuals with good spontaneous HIV control (elevated CD4 cell count, low plasma HIV-RNA), and certain HBV features (genotype A, HBeAg+, low serum HBV-DNA and elevated ALT), it is clear that very few coinfected patients fulfill these criteria. In HBeAg-negative HIV patients, adefovir may be an option but the relatively low antiviral potency of this drug discourages its wide use. Given its potential anti-HIV activity, both entecavir and telbivudine must only be prescribed with antiretroviral agents. Lack of information about potential pharmacodynamic interactions between entecavir and abacavir (both are guanosine analogues) or between telbivudine and zidovudine or stavudine (all are thymidine analogues) further discourages their concomitant use. At this time, most experts agree that early introduction of anti-HBV active HAART is the best strategy for the treatment of chronic hepatitis B in HIV patients, and Truvada must be part of the triple regimen.

Topics: Adenine; Antiviral Agents; Deoxycytidine; DNA, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine; Transaminases

The most serious problem of nucleoside/nucleotide analogue therapy for hepatitis B virus (HBV) infection is the emergence of drug-resistant mutant virus. Here, we describe a patient with chronic hepatitis B infection with a complex drug-resistant mutant virus during sequential therapy with lamivudine (3TC), entecavir (ETV) and adefovir dipivoxil (ADV). The patient was a 52-year-old male with positive hepatitis B e antigen and high HBV DNA (>7.6 log(10) copies/ml). Initial 3TC monotherapy offered little benefit and 3TC resistance was established by the virus with rtA181T and not rtM204V/I. HBV DNA was reduced slightly by replacement with ETV monotherapy and was followed by virological breakthrough. At that time, rtA181T was undetectable and the virus with rtM204V and rtL180M became predominant. ETV resistance was established by an additional rtS202G mutation. Efficacy of subsequent combination therapy with ADV and 3TC was limited because of reappearance of the virus with rtA181T, which might confer cross-resistance to 3TC and ADV. Final combination therapy with ETV and ADV reduced HBV DNA to 3.7 log(10) copies/ml for 5 months, which was the most effective therapy for this patient. Thus, two kinds of mutant viruses (rtM204V-related and rtA181T-related) appeared alternately in this patient. Combination therapy with ETV and ADV might have been effective because these drugs share therapeutic roles, that is, ETV affects the rtA181T-related virus and ADV affects the rtM204V-related virus. This is the first report suggesting clinical significance of combination therapy with ETV and ADV for controlling replication of the complex drug-resistant mutant HBV.

Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B; Hepatitis B virus; Humans; Male; Middle Aged; Organophosphonates

The efficacy of entecavir (ETV) monotherapy in treatment-experienced patients with chronic hepatitis B (CHB) is debatable.. A total of 22 hepatitis B e antigen (HBeAg)-positive CHB patients who had shown viral breakthrough or suboptimal response with lamivudine (3TC) and adefovir disoproxil (ADV) therapy were treated with 1.0 mg of ETV. Clinical and virological parameters were monitored every 3 months. Restriction fragment mass polymorphism assays were used to detect antiviral resistance.. During 3TC and ADV therapy, 11 patients had rtM204V/I mutations, 2 had rtA181V/T or rtN236T, 7 had both and 2 had no 3TC- or ADV-related mutations. After switching to ETV monotherapy, the median change in serum hepatitis B virus (HBV) DNA level was -2.1 log(10) copies/ml. Virological response (HBV DNA<300 copies/ml) was achieved in 1 of 18 patients with pre-existing rt204 mutations, whereas it was achieved in all 4 patients without pre-existing rt204 mutations regardless of the presence of rt181 or rt236 mutations. Changes in mutational patterns during ETV therapy showed that rt204 mutations persisted or re-emerged. Relative abundances of rtM204V/I mutations in total viral populations gradually increased under ETV rescue, whereas those with rtA181V/T and rtN236T mutations decreased. ETV resistance mutations (rtL180M+rtT184I/L[rtS202G]+rtM204V) were detected in five patients with pre-existing rt204 mutations.. ETV monotherapy resulted in a limited virological response in patients who had previously failed 3TC and ADV rescue therapy. The limited efficacy might be associated with residual or reselected rtM204V/I mutations leading to ETV resistance. Combination treatment including potent antiviral agents should be recommended for patients with pre-existing rtM204V/I mutations.

Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Multiple, Viral; Evolution, Molecular; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Treatment Outcome

The hepatitis B virus (HBV) pol gene overlaps the S gene encoding surface antigen (HBsAg). It has been reported previously that drug-induced changes in HBsAg alter its binding to sera from humans immunized against HBV. We investigate here the changes to specific epitopes in the a determinant (the major target of neutralizing antibody) caused by a number of drug-resistant mutations.. Recombinant HBsAgs, produced by transfection of Chinese hamster ovary cells with S gene plasmids into which lamivudine, adefovir and entecavir resistance and common antibody-escape mutations had been introduced, were probed with monoclonal antibodies to epitopes in the first and second loops of the a determinant.. The mutations rtF166L/sF158Y (lamivudine-associated, compensatory) and rtl169T/sF161L (entecavir-associated, primary) acting alone, and the mutations rtV173L/sE164D (lamivudine-associated, compensatory) and rtSilent/sD144E (antibody escape-associated) each when combined with rtM204V/sl195M (lamivudine-associated, primary) led to decreases in antibody reactivity to epitopes in the first or second loop, or in both loops. The rtM204V/sl195M + rtV173L/sE164D mutations yielded an epitope-antibody profile similar to the rtR153Q/sG145R vaccine escape mutant. The rtM204V/sl195M mutation combined with the rtF166L/sF158Y or rtR153Q/sG145R mutation restored reactivity to second-loop epitopes previously abrogated by single mutations.. Mutations associated with resistance to nucleos(t)ide analogue therapy, singly or in combination with each other or antibody escape-associated mutations, alter HBsAg immunoreactivity through concomitant amino acid substitutions at codons within and downstream of the a determinant. The findings have implications for understanding the native structure of HBsAg, optimizing treatment of chronic hepatitis B and evaluating the success of immunization programmes.

Topics: Adenine; Animals; Antibodies, Monoclonal; Antigen-Antibody Reactions; Antiviral Agents; CHO Cells; Cricetinae; Cricetulus; Drug Resistance, Multiple, Viral; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Viral; Gene Products, pol; Guanine; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunodominant Epitopes; Lamivudine; Mutagenesis, Site-Directed; Mutation; Organophosphonates; Transfection

The aim of our study was to assess the efficacy and safety of entecavir in kidney- and liver-transplant recipients with chronic hepatitis B virus (HBV) infection. Ten male transplant patients with chronic HBV infection (eight kidney- and two liver-transplant patients), who have become adefovir (n=9) or lamivudine-resistant (n=1) were given entecavir at 0.5 to 1 mg/d. All patients were HBs Ag positive: six were HBe Ag(-)/HBe Ab(+), and four were HBe Ag(+)/HBe Ab(-). After a median follow-up of 16.5 months, entecavir therapy was associated with a significant decrease in HBV DNA viral load, that is, 3.86 (2.71-6.46) log10 copies/mL at baseline down to 2.94 (2.15-4) log10 copies/mL at last follow-up (P=0.004). Rate of HBV DNA clearance was 50% in both HBeAg(+) and HBeAg(-) patients. There were no significant changes in renal function or hematological parameters. This study demonstrates that entecavir therapy is safe and efficient in HBV(+) organ-transplant patients.

Topics: Adenine; Adult; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Kidney Transplantation; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Organophosphonates; Pilot Projects; Prothrombin Time

The efficiacy of Entecavir and Adefovir for treatment of acute hepatitis B is not known.. Two women with severe acute hepatitis B (HB) complained about a skin rash as well as jaundice, nonspecific epigastric and joint discomfort.. Both patients had severe liver cell damage caused by the HB virus. Transaminases were elevated up to 150 times the normal range (normal: ALT up to 34 U/l, AST up to 31 U/l) and bilirubin was raised up to 35 times above normal (17 micromol/l). Liver synthesis, as measured by the Quick time test, was already impaired. High titers of HBs-antigen and HBV-DNA were detected.. Both patients were immediately admitted for antiviral therapy with lamivudine, in view of the prolonged prothrombin time. But there was no evidence of adequate recovery of liver function. Improvement followed after switching the antiviral therapy to entecavir or to an add-on with adefovir, respectively.. Recently available nucleos(t)ide analogs, such as entecavir and adefovir, seem to be efficacious in acute hepatitis B therapy when lamivudine has failed. When prothrombin time is substantially prolonged, antiviral therapy is recommended. However, there is no consensus on antiviral therapy of acute hepatitis B in general, because data from large studies are still lacking. The findings described here suggest that such patients with acute hepatitis B should be treated within the German GAHB study (German acute hepatitis B study: www.gahb.de).

Topics: Acute Disease; Adenine; Adult; Algorithms; Antiviral Agents; Bilirubin; DNA, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Lamivudine; Liver; Middle Aged; Organophosphonates; Prothrombin Time; Transaminases; Treatment Failure; Treatment Outcome

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Salvage Therapy

Development of hepatitis B virus (HBV)-resistant strains following nucleos(t)ide analog treatment is a major medical concern. This report describes a case of an adult patient with chronic HBV infection, sequentially treated with the nucleos(t)ide analogues, lamivudine, adefovir, and entecavir. During monotherapy with lamivudine, the patient developed lamivudine-resistant variants, which were undetectable during adefovir dipivoxil monotherapy. Twenty-two months after discontinuing lamivudine therapy, the resistant variants were again detected while the patient was receiving entecavir monotherapy. Genotypic analysis by sequencing the HBV polymerase was confirmed with the INNO-LiPA method. The results of this study suggest that entecavir treatment reselected residual lamivudine-resistant HBV variants, possibly because lamivudine-resistant HBV is less susceptible to entecavir than the wild-type virus. Despite the presence of these variants, the patient has had a complete virological response.

Topics: Adenine; Adult; Antiviral Agents; Drug Administration Schedule; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Mutation; Organophosphonates; Reverse Transcriptase Inhibitors

The new German and American guidelines on hepatitis B show similarities but also some discrepancies. In general, indication for therapy depends more on hepatitis B virus-(HBV-)DNA than alanine aminotransferase (ALT) values. Antivirals are recommended by German guidelines when HBV-DNA exceeds 10,000 copies/ml and ALT is increased more than twice the upper normal limit or when liver biopsy shows significant inflammation and fibrosis. By contrast, American guidelines recommend therapy only when HBV-DNA exceeds 100,000 copies/ml. American guidelines do not recommend lamivudine or telbivudine as initial monotherapy because of risk for resistance, but adefovir or entecavir. By contrast, according to German guidelines monotherapy with lamivudine, telbivudine, adefovir or entecavir may be initiated, if HBV-DNA is < 1 million copies/ml and cirrhosis is absent. Both guidelines recommend to monitor HBV-DNA even in the absence of therapy. Under antiviral therapy HBV-DNA should be measured more often than previously recommended to early identify lack of response and upcoming resistance. When resistance occurs, combination therapy is indicated. Risk for resistance is low as long as viral suppression is effective. In both guidelines liver biopsy should be considered when there are doubts on indication of therapy or selection of antiviral substances. In the presence of severe fibrosis and high HBV-DNA, antiviral substances should have high potency and low risk for resistance.

Topics: Adenine; Alanine Transaminase; Antiviral Agents; Biopsy; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Germany; Guanine; Hepatitis B; Humans; Lamivudine; Liver; Liver Cirrhosis; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pyrimidinones; Telbivudine; Thymidine; United States

Topics: Adenine; Antiviral Agents; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Organophosphonates

Emergence of a lamivudine (LAM)-resistant hepatitis B virus (HBV) with amino acid substitutions in the YMDD motif is a well-documented problem during long-term LAM therapy. Entecavir (ETV) is a new drug approved for treatment of HBV infection with or without LAM-resistant mutants. This report describes an ETV-resistant strain of HBV, which emerged after prolonged ETV therapy in a patient who did not respond to LAM therapy. Direct sequence analysis of the ETV-resistant strain showed appearance of amino acid substitution rtS202G in the reverse transcriptase (RT) domain, together with rtL180M + M204V substitution that had developed at the emergence of LAM-resistant mutant. In vitro analysis demonstrated that the rtL180M + M204V + S202G mutant strain displayed a 200-fold and a 5-fold reduction in susceptibility to ETV compared with the wild- type and the rtL180M + M204V mutant strain, respectively. Adefovir was effective against the ETV-resistant strain both in vitro and during the clinical course. In conclusion, this study showed that virological and biochemical breakthrough due to ETV could occur in patients infected with LAM-resistant HBV and confirmed that the addition of rtS202G substitution to the rtL180M + M204V mutant strain is responsible for ETV resistance and we could treat the resistant mutant successfully.

Topics: Adenine; Adult; Antiviral Agents; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Mutation; Organophosphonates; Viral Load

Topics: Adenine; Antiviral Agents; Disease Progression; Drug Resistance, Viral; Genotype; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immune Tolerance; Lamivudine; Organophosphonates

Hepatitis B virus (HBV) is an important cause of end-stage liver disease and hepatocellular carcinoma. Effective treatment can delay or prevent these outcomes. The decision to treat is based on the activity of liver disease and HBV replication status, and the likelihood of a long-term benefit. Approved therapies include standard and pegylated interferon-alfa and nucleoside analogues: lamivudine, adefovir and entecavir. Current therapies do not eradicate HBV so long-term treatment is usually required. Development of drug resistance is a major concern with long-term treatment. Even with successful therapy, patients remain at risk for reactivation of viral replication and require lifelong monitoring.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Organophosphonates

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B Antibodies; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Mutation; Organophosphonates; Viral Load

Nucleot(s)ide analogues are making milestones in the treatment of chronic hepatitis B (CHB) as safe oral therapy. FDA approved lamivudine in adult patients in 1998, adefovir dipivoxil in 2002, and entecavir in March 2005. Lamivudine is effective in viral suppression, ALT normalization, and improvement in histology in both HBeAg positive and HBeAg negative / HBV DNA positive patients. HBeAg seroconversion rates correlate directly with pretreatment ALT levels at 18-30% after one year of therapy. Hepatitis flares may occur if lamivudine is stopped before HBeAg seroconversion. Lamivudine resistant YMDD mutants emerge at a rate of 15-20% per year of therapy; often associated with the rebound viraemia, relapse of hepatitis or even hepatic decompensation. Durability of response off lamivudine therapy is not satisfactory and may be dependent on duration of therapy post-seroconversion. Lamivudine is well tolerated with few serious adverse events, even in patients with decompensated cirrhosis. Long term therapy in viraemic patients with advanced fibrosis or cirrhosis delays clinical progression. Adefovir dipivoxil is an oral prodrug of adefovir. 10 mg daily is effective in suppressing both wild-type HBV and YMDD mutants, normalising ALT and improving histology. Adefovir dipivoxil has been shown to be well tolerated in longterm therapy. Renal toxicity reported in higher dosages is rarely seen except among patients with creatinine clearance less than 50 ml/min. Adefovir resistance may emerge and the overall rate is much lower than lamivudine, reaching 18% after 4 years of therapy. Adefovir-resistant mutants (rt N236T) are susceptible to lamivudine and entecavir. Little data is available for durability of response off therapy. Entecavir is an oral nucleoside analogue with a recommended dosage of 0.5 mg daily for nucleoside-naive patients, and 1 mg daily for lamivudine-refractory patients. It is a potent antiviral and may also reduced intrahepatitic cccDNA. Entecavir resistance so far has only been detected in lamivudine resistant patients in the one-year studies. Patient counseling is very important to decide on the choice among available therapeutic options. The assessment of the risks/benefits of each option should be carefully explained to individual patient.

Topics: Adenine; Drug Resistance; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Transplantation; Nucleosides; Organophosphonates; Reverse Transcriptase Inhibitors; Time Factors