pyrimidinones and Hepatitis-B

The incidence of acute B hepatitis is decreasing due to socioeconomical changes and the implementation of vaccination programs. Nevertheless it is potentially severe, causing approximately 30% of acute liver failures in Spain. Pharmacological treatment of acute B hepatitis has become a matter of issue over the last decade. This text offers a review of the published data and international guidelines. Most published studies have a low methodological quality and lamivudine was used as treatment in all of them. A survival improvement with prompt treatment has been shown in acute liver injury and probably in severe acute hepatitis (total bilirubin>10mg/dl and INR>1.5). International guidelines support treatment in these cases, but there is no consensus on the drug to use or the length of treatment.

Topics: Acute Disease; Adenine; Antiviral Agents; Guanine; Hepatitis B; Humans; Lamivudine; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pyrimidinones; Spain; Telbivudine; Tenofovir; Thymidine; 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

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

It is estimated there are 350-400 million people worldwide chronically infected with HBV. Many of these are women and of reproductive age. As such, they may face therapeutic decisions regarding antiviral therapy and the implication this may have on future or current pregnancies. This article reviews the data of all antivirals licensed for use against hepatitis B infection regarding teratogenicity, carcinogenicity, clinical experience during pregnancy, placental transfer and excretion in breast milk.

Topics: Adenine; Antiviral Agents; Breast Feeding; Female; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

The ultimate goal of treatment is suppression of viral replication to undetectable HBV-DNA levels prior to and after liver transplantation (LT) to prevent infection of the newly transplanted liver. Most published data are available from therapy with lamivudine (LAM) in pre- and post-transplant HBV patients. Add-on therapy with adefovir dipivoxil (ADV) in pre-transplant LAM-resistant patients has been shown to represent an effective antiviral strategy leading to hepatic recompensation in many cases and, eventually, removal from the waiting list. Newer nucleos(t)ide analogues such as entecavir, tenofovir and telbivudine have shown lower resistance rates than LAM and more antiviral potency in studies in the non-transplant setting. Combined hepatitis B immune globulin (HBIG) and nucleos(t)ide analogue therapy have been widely adopted as the most effective treatment strategy against recurrent HBV disease after LT. Many programs have evaluated lower doses or a shorter duration of HBIG and intramuscular versus intravenous routes of administration. Active immunisation using recombinant HBV vaccines, including the S, pre-S1 and pre-S2 regions, and those with immunostimulatory adjuvants, seem to be more immunogenic than the currently available vaccines and have been used in studies to replace HBIG. Furthermore, it has been shown that immune memory against HBV can be adoptively transferred from organ donors to transplant recipients. Nucleos(t)ide analogue combination therapies might provide an alternative to the current treatment paradigm with costly HBIG; however, experience with this new treatment regimen is very limited and controlled clinical studies are urgently warranted to investigate its safety and efficacy and to determine which nucleos(t)ide analogue combinations will be the most promising in the long term after LT.

Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B; Hepatitis B Vaccines; Humans; Immunoglobulins; Lamivudine; Liver Transplantation; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

The US Food and Drug Administration (FDA) has approved several new drugs in the past 2 years. This article provides an overview of some of the newer drugs that are likely to find wider use in the future. The drugs reviewed in this article can be used to treat cardiovascular system problems, diabetes mellitus, multiple sclerosis, hepatitis B infection, hyponatremia, Parkinson's disease, rheumatoid arthritis, pain, constipation, and insomnia. Another drug discussed can be used to help a patient stop smoking. The article also discusses Gardasil, the recombinant vaccine against human papilloma virus (types 6, 11, 16, and 18).

Topics: Abatacept; Acetanilides; Amides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antiparkinson Agents; Antirheumatic Agents; Antiviral Agents; Apomorphine; Benzazepines; Cardiovascular Agents; Fumarates; Hepatitis B; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; Humans; Hypoglycemic Agents; Immunoconjugates; Multiple Sclerosis; Natalizumab; Nucleosides; Papillomavirus Vaccines; Pharmacology, Clinical; Piperazines; Pyrazines; Pyrimidinones; Quinoxalines; Ranolazine; Sitagliptin Phosphate; Smoking Cessation; Telbivudine; Thymidine; Triazoles; Varenicline; Viral Vaccines

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

Chronic hepatitis B virus infection affects approximately 10% of HIV-infected patients. There are an estimated 4 million patients with HIV/HBV coinfection. HIV infection has a deleterious effect on the natural history of chronic hepatitis B and increases the risk of progression to cirrhosis and terminal liver disease. Since the widespread use of highly active antiviral therapy (HAART), liver disease has emerged as one of the main causes of morbidity and mortality in HIV-positive patients. Therefore, all patients with HIV/HBV coinfection should be evaluated for treatment of hepatitis B, independently of the CD4 lymphocyte count. Six drugs are currently authorized for the treatment of chronic hepatitis B: standard interferon-alpha (2a and 2b), pegylated interferon alpha-2a, lamivudine, adefovir, entecavir and telbivudine. Other drugs with activity against HBV, such as tenofovir and emtricitabine, are used for the treatment of HIV infection. In patients not requiring HAART, treatment of hepatitis B should preferably consist of drugs without activity against HIV, such as pegylated interferon or adefovir. In contrast, in patients requiring HAART, a combination of drugs with activity against both viruses should be used, such as lamivudine, emtricitabine and tenofovir, with the aim of achieving maximal viral suppression and avoiding the development of resistance. Patients with HIV/HBV coinfection require periodic clinical and virological monitoring. Patients with cirrhosis should undergo ultrasonography and alphafetoprotein determination every 6 months for the early detection of hepatocellular carcinoma.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Comorbidity; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B; Hepatitis B Vaccines; Hepatitis B virus; HIV; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Virus Replication

Idenix (formerly Novirio) and Novartis are developing two beta-L-deoxynucleosides, telbivudine and torcitabine, for the potential treatment of hepatitis B virus infection. Phase III trials of telbivudine were underway by August 2002 and phase I/II trials of the torcitabine prodrug, valtorcitabine, were ongoing in November 2003.

Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Drugs, Investigational; Hepatitis B; Hepatitis B virus; Humans; Nucleosides; Pyrimidinones; Technology, Pharmaceutical; Telbivudine; Thymidine

To evaluate the efficacy and safety of telbivudine use during the second and third trimester of pregnancy for reducing hepatitis B virus (HBV) transmission from highly viremic hepatitis B e antigen-positive (HBeAg+) mothers to their fetuses.. Pregnant women, between weeks 20 to 32 of gestation, who were HBeAg+ and had HBV DNA more than 1.0*10(7) copies/mL were enrolled in our study. The women were offered inclusion into one of two treatment arms, based upon their personal preference: telbivudine or no telbivudine. The patients in the telbivudine treatment arm were administered 600 mg/d telbivudine at least until postpartum week 4. All delivered infants in both treatment arms were administered hepatitis B immune globulin (HBIG; 200 IU) within 12 hours of delivery and recombinant HBV vaccine (20 mug) at 0, 1 and 6 months. The HBV perinatal transmission rate was determined by measuring HBsAg and HBV DNA in infants at postpartum week 28.. A total of 220 pregnant women were enrolled in our study, 120 chose the telbivudine arm and 100 chose the control arm. All telbivudine treated subjects were registered in the Antiretroviral Pregnancy Registry. Telbivudine treatment was associated with a marked reduction in the mothers' serum HBV DNA, HBeAg and ALT levels before delivery. A striking decline of HBV DNA levels in treated mothers was observed at week 2 of treatment, which was followed by a gradual and steady decrease that continued until delivery. Thirty-seven (31%) of the telbivudine-treated mothers and none (0%) of the untreated controls had polymerase chain reaction-undetectable viremia at delivery. At week 28, 0% of the infants delivered from telbivudine-treated mothers were HBsAg+ or HBV DNA+, as compared to 8% HBsAg+ or HBV DNA+ in the untreated control arm (P = 0.002). No telbivudine discontinuations occurred from adverse events, and no congenital deformities were observed in the infants delivered to telbivudine-treated mothers. Eighty mothers discontinued telbivudine at week 4 postpartum, and there were no cases of severe hepatitis. There were no significant differences between the two treatment arms for postpartum hemorrhage, adverse events during pregnancy, cesarean section, gestational age, or infants' height/weight or Apgar scores.. Telbivudine use during the second and third trimester of pregnancy in HBeAg+ highly viremic mothers can safely reduce perinatal HBV transmission rates. Telbivudine was well-tolerated by our patient group. Furthermore, no safety concerns were observed in either the telbivudine-treated mothers or their delivered infants in short term follow-up.

Topics: Adult; DNA, Viral; Female; Hepatitis B; Hepatitis B virus; Humans; Infectious Disease Transmission, Vertical; Nucleosides; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Pyrimidinones; Telbivudine; Thymidine; Viral Load; Young Adult

Because drug-resistant strains of hepatitis B virus (HBV) have developed, and because serum HBV-DNA levels may rebound in patients who receive treatment with nucleoside/nucleotide analogues for up to 2 years, there remains a largely unmet clinical need for agents to induce potent virologic suppression in the initial stage of the disease course of HBV infection.. The aim of this work was to compare the early antiviral effectiveness of telbivudine and entecavir in the treatment of patients with hepatitis B e antigen (HBeAg)-positive HBV.. In this parallel-group, open-label trial, adult Chinese patients with previously untreated HBeAg-positive HBV (HBV-DNA concentration: >or=6 log(10) copies/mL; alanine aminotransferase [ALT] level: >or=2 times the upper limit of normal) were randomized to receive telbivudine 600 mg or entecavir 0.5 mg daily for 24 weeks. Blood samples were collected at the baseline and at 12 and 24 weeks after the treatment. The primary end point was the mean reduction from baseline in serum HBV-DNA concentration at week 24. Secondary end points included mean reduction from baseline in serum HBV-DNA concentration at week 12, the absence of serum HBV-DNA, absence of serum HBeAg, HBeAg seroconversion at week 24, the normalization of serum ALT at week 24, and occurrence of adverse events through week 24.. A total of 131 patients were enrolled in the study: 91 men and 40 women, with a mean (SD) age of 32.5 (8.9) years. All patients were ethnic Han Chinese. The baseline demographic characteristics and serum HBV-DNA concentrations in the 2 treatment groups were well matched. Sixty-five patients were randomized to receive telbivudine and 66 to receive entecavir. The mean reductions from baseline in serum HBV-DNA were 4.99 and 4.69 log(10) copies/mL at week 12, respectively, and 6.00 and 5.80 log(10) copies/mL at week 24 (both time points, P = NS between groups). At week 12, HBV-DNA was undetectable in 43.1% (28/65) of the telbivudine group and 34.8% (23/66) of the entecavir group (P = NS); at week 24, it was undetectable in 67.7% (44/65) of the telbivudine group and 57.6% (38/66) of the entecavir group (P = NS). At week 12, HBeAg absence and seroconversion rates were significantly greater in the telbivudine group than the entecavir group (absence: 20.0% [13/65] vs 3.0% [2/66], respectively [P = 0.002]; seroconversion: 13.8% [9/65] vs 3.0% [2/66] [P = 0.030]). However, at week 24, HBeAg absence and seroconversion rates were comparable between the telbivudine and entecavir groups (absence: 36.9% [24/65] vs 28.8% [19/66] [P = NS]; seroconversion: 24.6% [16/65] vs 13.6% [9/66] [P = NS]). In addition, the normalization of ALT levels was observed in 78.5% (51/65) and 74.2% (49/66) of patients treated with telbivudine and entecavir, respectively, at week 24 (P = NS). The adverse events were upper respiratory tract infection (12.3% of telbivudine patients vs 9.1% of entecavir patients), fatigue (6.2% vs 7.6%), diarrhea (1.5% vs 3.0%), and coughing (0% vs 1.5%), most of which were mild to moderate. Elevated creatinine phosphokinase was noted in 8 telbivudine-treated patients (12.3%). There were no statistically significant differences in rates of adverse events between groups except for creatinine phosphokinase.. In this study of ethnic Han Chinese adults with previously untreated HBeAg-positive HBV infection, there were no statistically significant differences in effectiveness or tolerability between telbivudine 600 mg and entecavir 0.5 mg at the end of 24 weeks of treatment. ChiCTR.org identifier: ChiCTR-TRC-00000341.

Topics: Adult; Antiviral Agents; China; DNA, Viral; Female; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

To investigate the efficacy of nucleosides as a prophylactic agent against reactivation of hepatitis B virus (HBV) in HBsAg-positive patients with non-hepatic tumors after chemotherapy.. Fifty-eight patients with non-hepatic tumors were divided into prevention group and control group. The patients of prevention group received nucleosides as a prophylactic agent before chemotherapy and were compared with the control ones about the clinical manifestation of HBV reactivation. Then, the patients of the control group were divided into three groups according to antiviral drugs, use or not and time of the use. The patients having HBV reactivation but never received nucleosides were included in the group A, the patients receiving nucleosides after having HBV reactivation were divided into the group B, and the patients receiving nucleosides before HBV reactivation were divided into the group C. The progression, prognosis and curative effect among the three groups were compared.. The rate of HBV reactivation, incidence of severe hepatitis, mortality rate of the control group (61.1%, 27.8%, 16.7%) were significantly higher than those of the prevention group (13.6%, 0, 0), and liver dysfunction was more serious than that in the prevention group. In the control group, all the 5 patients of group A died of liver failure. Of the 13 patients in the group B, 4 cases suffered from severe hepatitis and 1 of them died of the disease. Of the 18 patients in the group C, 4 cases suffered from HBV reactivation, but the clinical manifestation was milder than that of the group B.. Nucleosides can be used as a prophylactic measure to prevent HBV reactivation. If chemotherapy had begun, the use of nucleosides may reduce the risk of HBV reactivation. Even if patients had suffered from HBV reactivation, the use of nucleosides may still help the recovery of liver function and improve prognosis.

Topics: Adult; Antineoplastic Agents; Antiviral Agents; Breast Neoplasms; Female; Follow-Up Studies; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Lamivudine; Lung Neoplasms; Lymphoma; Male; Middle Aged; Nucleosides; Pyrimidinones; Retrospective Studies; Telbivudine; Thymidine; Virus Activation

The aim of this prospective study was to investigate the diagnostic value of ultrasound elastography for evaluating liver stiffness measurement (LSM) in 74 patients with hepatitis B virus (HBV) infection, treated with telbivudine (22 with chronic HBV infection, 32 with compensated cirrhosis and 20 with decompensated cirrhosis). Each patient underwent ultrasound elastography measurements and serum liver marker assays before and after 6 months' treatment with 600 mg telbivudine, orally, once daily. In the 22 patients with chronic HBV infection, LSM values measured by ultrasound elastography decreased significantly following the treatment period compared with baseline. The LSM values were significantly higher in the 20 patients with decompensated cirrhosis than in the 32 patients with compensated cirrhosis after treatment. Significant decreases in serum hepatic fibrosis indices occurred in all patients following treatment. The correlation between fibrosis index, hyaluronic acid level and LSM was statistically significant in all patients, whereas the correlation between alanine aminotransferase and LSM was not. The findings suggest that liver stiffness in patients with HBV can be measured simply with ultrasound elastography and that it is reduced within 6 months by treatment with telbivudine. The main adverse events noted during the study period were that creatine kinase levels were increased in seven patients and that seven patients had influenza-like symptoms.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antiviral Agents; Asian People; China; Demography; Elasticity; Elasticity Imaging Techniques; Female; Hepatitis B; Hepatitis B virus; Humans; Hyaluronic Acid; Liver Cirrhosis; Male; Middle Aged; Nucleosides; Prospective Studies; Pyrimidinones; Telbivudine; Thymidine; Young Adult

Topics: Antiviral Agents; Developing Countries; Female; Hepatitis B; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Nucleosides; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Vaccination

Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) represents a severe condition that requires prophylaxis with specific immunoglobulin and lamivudine. Few studies have addressed the efficiency of other effective antiviral drugs posttransplantation or their impact on early renal function after transplantation. Herein, we have reported experience among seven transplanted patients prescribed Telbivudin (600 mg/d) while on the waiting list followed by treatment for 3 months after OLT.. Our series consisted of men with HBV-related end-stage liver disease. Once the patient started antiviral treatment, the viral load decreased rapidly while on the waiting list. All patients were evaluated for liver and renal functions immunosuppressive drug trough levels, CPK before (T0), as well as at 1 month (T1), and 3 months after liver transplant (T3).. All patients received a CNI-based regimen. Their mean creatinine clearance (MDRD) was 72.5 mL/min at T0, 69.2 mL/min at T1, and 71.0 mL/min at T3. Neither CPK or serum transaminase levels increased throughout the study. Once HBV-DNA was cleared while on the waiting list, it remained negative throughout the follow-up period.. Telbivudin prophylaxis for HBV was safe and effective without any significant deleterious effect on liver or renal function tests after liver transplantation.

Topics: Adult; Case-Control Studies; Female; Hepatitis B; Humans; Liver Transplantation; Male; Middle Aged; Nucleosides; Pyrimidinones; Recurrence; Telbivudine; Thymidine; Viral Load

Telbivudine (beta-l-2'-deoxythymidine) is an orally administered nucleoside analog drug approved for the treatment of patients with chronic hepatitis B since 2006. Initially, it was regarded as being generally well tolerated, with low adverse reaction profiles and no dose-limiting toxicity. Recently, with the result of the telbivudine worldwide phase III GLOBE trial and other clinical experiments, cases of myopathy and neuropathy have been reported undergoing long-term telbivudine treatments. Telbivudine-induced myopathy has been characterized by muscle pain, weakness and moderately elevated creatine kinase levels during treatments, although no severe adverse events have been observed. Rhabdomyolysis has not reported in any patient.

Topics: Acute Kidney Injury; Antiviral Agents; Fatal Outcome; Fibrosis; Hepatitis B; Humans; Male; Middle Aged; Muscular Diseases; Nucleosides; Pyrimidinones; Rhabdomyolysis; Telbivudine; Thymidine; Treatment Outcome

Thirty-three persons became victims of a serial knife stabbing incident. One of the first victims one day later disclosed that he was HIV-infected. Thereafter thirty-one victims initiated HIV post-exposure prophylaxis (PEP), one exposed patient declined. None of the victims evaluated had seroconverted six months later. In most such incidents HIV exposure will be difficult to rule out as reliable information on the HIV serostatus of all serial victims will be lacking. It appears prudent, however, to inform serial stab victims about the potential risk of HIV transmission and to at least consider PEP in such scenarios.

Topics: Anti-HIV Agents; Crime Victims; Disease Transmission, Infectious; Drug Combinations; Hepatitis B; Hepatitis C; HIV Infections; Humans; Lamivudine; Lopinavir; Post-Exposure Prophylaxis; Pyrimidinones; Viral Load; Wounds, Stab; Zidovudine

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Biomarkers, Tumor; Cyclophosphamide; DNA; Hepatitis B; Hepatitis B virus; Humans; Lymphoma, B-Cell; Male; Middle Aged; Nucleosides; Prednisolone; Proto-Oncogene Proteins c-bcl-2; Pyrimidinones; Rituximab; Telbivudine; Thymidine; Vincristine

To evaluate the value of the hepatitis B virus (HBV) replication mouse model with regard to several aspects of the study of HBV biology.. To evaluate the HBV replication mouse model in detecting the efficacy of anti-HBV agents, the interferon inducer polyinosinic-polytidylin acid (polyIC) and nucleotide analogues adefovir and entecavir were administered to mice injected with wild type pHBV4.1, and the inhibiting effect of these agents on HBV DNA replication was evaluated. To identify the model's value in a replication ability study of HBV drug-resistant mutants and a HBx-minus mutant, telbivudine resistance mutants (rtM204I, ayw subtype), adefovir resistance mutants (rtA181V + rtN236T, ayw subtype) and HBx-minus mutants were injected respectively, and their corresponding HBV DNA replication intermediates in mouse liver were assessed.. Compared with the wild type HBV replication mouse model without antiviral agent treatment, the HBV DNA replication intermediates of the polyIC-treated group were decreased 1-fold; while in the entecavir- and adefovir-treated groups, the levels of HBV DNA replication intermediates were inhibited 13.6-fold and 1.4-fold, respectively. For the mouse models injected with telbivudine resistance mutant, adefovir resistance mutant and HBx-minus mutant, HBV DNA replication intermediates could still be detected, but the levels of HBV DNA replication intermediates of these mutants decreased 4.5-fold, 5.6-fold and 2.9-fold respectively, compared with the mouse model with wild type HBV plasmid.. The HBV replication mouse model we established was a useful and convenient tool to detect the efficacy of antiviral agents and to study the replication ability of HBV mutants in vivo.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Drug Resistance, Viral; Enzyme-Linked Immunosorbent Assay; Hepatitis B; Hepatitis B virus; Humans; Liver; Male; Mice; Mice, Inbred BALB C; Mutation; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Virus Replication

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

It is unknown if telbivudine causes muscle damage only in patients with pre-existing muscle pathology.. A 27 yo male of African origin received telbivudine for hepatitis B during 3 months. Three weeks after initiation of the drug he developed myalgia, and tiredness. Creatine-kinase increased from 278 U/l (n, <170 U/l) at baseline to 3243 U/l. Shortly after discontinuation of telbivudine muscle symptoms and hyper-CK-emia disappeared. The findings suggest that pre-existing muscle damage favored the myotoxic effect of telbivudine.. Telbivudine appears to cause accelerated muscle toxicity if given to patients who already have muscle damage. Patients under telbivudine should be closely monitored for muscular side effects and those with pre-existing muscle damage should not receive the drug.

Topics: Adult; Antiviral Agents; Creatine Kinase; Hepatitis B; Humans; Male; Muscle, Skeletal; Muscular Diseases; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Topics: Antiviral Agents; DNA, Viral; Global Health; Hepatitis B; Hepatitis B virus; Humans; Lamivudine; Nucleosides; Patient Selection; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine; Virus Replication

Tenofovir is a new effective treatment option for patients with chronic hepatitis B, but could be potentially hampered by mutations in the hepatitis B virus (HBV) polymerase conferring drug resistance. Drug resistance may occur preferentially if long-term administration is required, for example, in patients with hepatitis B e antigen (HBeAg)-negative HBV infection bearing precore (PC) and basal core promoter (BCP) mutations. The rtA194T polymerase mutation has been found in HBV/HIV coinfected patients during tenofovir treatment and may be associated with tenofovir resistance. We generated replication-competent HBV constructs harboring rtA194T alone or in addition to lamivudine (LAM) resistance (rt180M + rtM204V), PC mutations, and BCP mutations and assessed their replicative capacity after transient transfection in human hepatoma cells. The rtA194T polymerase mutation alone or in conjunction with LAM resistance reduced the replication efficiency as compared with wild-type (WT) HBV. In contrast, combination of rtA194T (+/- LAM resistance) with HBeAg-negative PC or BCP mutants increased the replication capacity of the drug-resistant polymerase mutants, thereby restoring the viral replication to similar levels as WT clones. Clones harboring rtA194T showed partial resistance to tenofovir in vitro and also to LAM but remained susceptible to telbivudine and entecavir.. The rtA194T polymerase mutation is associated with partial tenofovir drug resistance and negatively impacts replication competence of HBV constructs. Viral replication, however, can be restored to WT levels, if these polymerase mutations occur together with precore or basic core promoter substitutions as found in HBeAg-negative hepatitis B. Patients with HBeAg-negative chronic HBV infection may therefore be at particular risk when developing drug resistance to tenofovir. Telbivudine or entecavir should be considered as effective alternative treatment options for these patients.

Topics: Adenine; Anti-HIV Agents; Cell Line, Tumor; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; Humans; Lamivudine; Mutation; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Viral Proteins; Virus Replication

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: Antiviral Agents; Drug Resistance, Viral; Hepatitis B; Hepatitis B virus; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

To evaluate the risk factors for lopinavir/ritonavir (LPV/r)-related liver enzyme elevation (LEE) in HIV antiretroviral-experienced patients.. An open prospective observational study was carried out to analyse the incidence and time of LEE development during LPV/r treatment, and to determine whether LEE development was correlated with epidemiological, clinical and biochemical data, immune and virological profiles, concomitant hepatic diseases, antiretroviral therapy, or histological and ultrasonography liver examination results. A diagnosis of LEE was considered when LEE symptoms occurred after LPV/r introduction and was confirmed by a second control within 2 weeks.. A total of 782 HIV-positive outpatients have been enrolled in six different Infectious Diseases Departments in Northern Italy since August 2000. Of these patients, 71 (9.1%) developed LEE within 115+/-85 days (mean+/-standard deviation); 13 of these subjects discontinued LPV/r and four were hospitalized. Of the patients with LEE, 74.6% and 25.4% had grade 2 and > or =3 toxicity, respectively. No correlation between LEE and sex, baseline CD4 cell count, viral load, HIV stage, triglyceride values, histological and ultrasonography liver examination results, nevirapine use, or increase in CD4 cell count was observed. Higher baseline alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) values (P < 0.0001 and P=0.004, respectively), younger age (P=0.008), previous hepatitis B virus (HBV) infection (P=0.012), efavirenz use (P=0.04), and hepatitis C virus (HCV) and/or HBV coinfection (P < 0.0001, relative risk 4.78) were significantly related to LEE. No correlations between LEE and the same risk factors as investigated in the whole study population were found in subgroups of patients with HCV and/or HBV infection.. HCV and HBV testing and measurement of baseline ALT values are essential for screening subjects at risk of LEE before starting LPV/r. Strict monitoring of clinical and biochemical parameters should be performed in these patients.

Topics: Adult; Aged; Alanine Transaminase; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; Follow-Up Studies; gamma-Glutamyltransferase; Hepatitis B; HIV Infections; Humans; Liver; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Risk Factors; Ritonavir; Statistics, Nonparametric

Topics: Drug Therapy, Combination; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir