entecavir and HIV-Infections

More than 40 years into the pandemic, HIV remains a global burden and as of now, there is no cure in sight. Fortunately, highly active antiretroviral therapy (HAART) has been developed to manage and suppress HIV infection. Combinations of two to three drugs targeting key viral proteins, including compounds inhibiting HIV reverse transcriptase (RT), have become the cornerstone of HIV treatment. This review discusses nucleoside reverse transcriptase inhibitors (NRTIs), including chain terminators, delayed chain terminators, nucleoside reverse transcriptase translocation inhibitors (NRTTIs), and nucleotide competing RT inhibitors (NcRTIs); focusing on their history, mechanism of action, resistance, and current clinical application, including long-acting regimens.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; Humans; Nucleosides; Reverse Transcriptase Inhibitors

Despite the reciprocal inhibition exerted by HBV and HCV genomes, dual HBV/HCV infection is associated with more severe forms of liver disease and warrant effective treatment. Areas covered: A careful evaluation of disease progression to establish the predominance of one virus over another, concomitant HIV infection and comorbidities is essential to make the best therapy choices. In most virological conditions interferon (IFN)-based treatment has been replaced by a combination of different classes of second generation directly acting antivirals (DAAs), which offer better tolerability and HCV eradication in 95% of cases. Tenofovir or entecavir should be part of treatment for patients with active HBV production, for those coinfected with HIV and for those with cirrhosis. Expert opinion: DAAs have been successfully used to eradicate HCV infection in recent years, but the high cost may limit their use particularly in developing countries. Entecavir and tenofovir have been demonstrated to be effective for long-term inhibition of HBV replication. Careful monitoring of serum ALT and markers of HBV and HCV replication before and during treatment is essential for an early diagnosis and treatment of virus reactivation.

Topics: Anti-HIV Agents; Antiviral Agents; Coinfection; Guanine; Hepatitis C; HIV Infections; Humans; Tenofovir

Patients with chronic hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection are at a high risk of developing liver cirrhosis and hepatocellular carcinoma, and consequently, warrant effective treatment.. Effective treatment should eradicate HCV infection and inhibit HBV replication but without serious adverse reactions. Careful evaluation of disease progression, predominance of one virus over another, comorbidities and concomitant hepatitis delta virus and/or HIV infection are essential for better therapy choices. In the case of HCV predominance, Peg-interferon plus ribavirin with or without a first-generation directly acting antiviral (DAA) should be the first choice, but future treatments will be DAA-based and interferon-free. In the case of HBV predominance, tenofovir or entecavir should be part of treatment. Patients should be closely monitored for early identification and treatment of HCV or HBV reactivation.. High potency and high genetic barrier nucleos(t)ide analogues to inhibit HBV replication have been used for years, with no urgency for new drugs. Several DAAs for interferon-free therapy for HCV eradication will be available in the near future. We hope that the high cost of these drugs will not be a limitation to their use in developing countries. Further investigation of HBV/HCV interaction is needed before and during the administration of new therapies.

Topics: Adenine; Antiviral Agents; Coinfection; DNA, Viral; Drug Therapy, Combination; Guanine; Hepacivirus; Hepatitis B; Hepatitis B virus; Hepatitis C; Hepatitis C, Chronic; HIV Infections; Humans; Organophosphonates; Ribavirin; RNA, Viral; Tenofovir; Virus Replication

HCV-related liver disease is an important contributor to morbidity and mortality in the HIV-infected population. Successful treatment of HIV-HCV-coinfected patients is followed by favourable clinical outcomes. While the combination of pegylated interferon and ribavirin remains the mainstay in the treatment of non-1 HCV genotypes, the first generation of HCV protease inhibitors are being incorporated into existing HCV genotype-1 (HCV-1) treatment protocols. Although data are limited, the triple combination does improve the sustained virological response in HIV-HCV-1-coinfected subjects. However, with still very limited data in this setting, clinical decisions for triple therapy have to be individualized and made based on multiple considerations. Chronic HBV infection increases mortality in HIV-infected subjects. In the treatment of HIV-HBV coinfection, it is very important to coordinate HBV and HIV therapies. HBV-active HAART improves the outcome of patients with HIV-HBV coinfection and tenofovir has become a key component of the treatment for these patients, although a number of clinical situations require a case-by-case approach.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Antiviral Agents; Coinfection; Drug Therapy, Combination; Guanine; Hepatitis C; HIV Infections; Humans; Interferon-alpha; Organophosphonates; Polyethylene Glycols; Protease Inhibitors; Recombinant Proteins; Ribavirin; Tenofovir

This article reviews recent developments in the evaluation and treatment of chronic hepatitis B (CHB) based on articles published between December 2010 and January 2012.. The majority of patients infected with CHB have not been diagnosed and most at-risk individuals have not been immunized. Progression to cirrhosis depends on hepatitis B virus (HBV) genotype, hepatitis B e antigen (HBeAg) presence, persistently high levels of HBV DNA, and elevated alanine aminotransferase, although hepatitis B surface antigen (HBsAg) kinetics may help predict natural history and antiviral response. Antiviral resistance limits the success of nucleos(t)ide analogs and agents such as entecavir and tenofovir with high potency and high genetic barrier to resistance are considered first-line therapy. Specialized treatment of CHB in pregnancy, coinfection, decompensated cirrhosis, and posttransplant is safe and effective.. The complications of CHB can now be avoided and reversed with potent antiviral suppression of HBV DNA. For now, treatment is long-term and further studies are needed to discern whether sequential or combination therapy may be superior to current monotherapy for certain patients. Increased awareness should improve screening resulting in more frequent treatment and immunization of at-risk individuals toward eventual CHB eradication.

Topics: Adenine; Antiviral Agents; Coinfection; Disease Progression; Drug Resistance, Viral; Female; Guanine; Guidelines as Topic; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis D; HIV Infections; Humans; Interferons; Liver Cirrhosis; Organophosphonates; Pregnancy; Pregnancy Complications, Infectious; Risk Factors; Tenofovir

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

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

With highly active antiretroviral therapy, HIV-1 infection has become a manageable lifelong disease. Developing optimal treatment regimens requires understanding how to best measure anti-HIV activity in vitro and how drug dose-response curves generated in vitro correlate with in-vivo efficacy.. Several recent studies have indicated that conventional multiround infectivity assays are inferior to single cycle assays at both low and high levels of inhibition. Multiround infectivity assays can fail to detect subtle but clinically significant anti-HIV activity. The discoveries of the anti-HIV activity of the hepatitis B drug entecavir and the herpes simplex drug acyclovir were facilitated by single-round infectivity assays. Recent studies using a single-round infectivity assay have shown that a previously neglected parameter, the dose-response curve slope, is an extremely important determinant of antiviral activity. Some antiretroviral drugs have steep slopes that result in extraordinary levels of antiviral activity. The instantaneous inhibitory potential, the log reduction in infectivity in a single-round assay at clinical drug concentrations, has been proposed as a novel index for comparing antiviral activity.. Among in-vitro measures of antiviral activity, single-round infection assays have the advantage of measuring instantaneous inhibition by a drug. Re-evaluating the antiviral activity of approved HIV-1 drugs has shown that the slope parameter is an important factor in drug activity. Determining the instantaneous inhibitory potential by using a single-round infectivity assay may provide important insights that can predict the in-vivo efficacy of anti-HIV-1 drugs.

Topics: Acyclovir; Antiretroviral Therapy, Highly Active; Antiviral Agents; Dose-Response Relationship, Drug; Guanine; HIV Infections; HIV-1; Humans; Virus Replication

The main goal for treatment of chronic hepatitis B is to prevent complications such as liver cirrhosis or hepatocellular carcinoma. Knowledge from population studies of the long-term risk of chronic HBV infection, as well as the recent introduction of pegylated interferon and additional nucleoside analogues has changed the therapeutic situation. Recently, a Swedish expert panel convened to update the national recommendations for treatment. The panel recommends treatment for patients with active HBV infection causing protracted liver inflammation or significant liver fibrosis, verified by liver histology. In general, pegylated interferon alpha-2a is recommended as first-line treatment, in particular for HBeAg-positive patients with HBV genotypes A or B. Among nucleoside analogues, entecavir is the first choice and adefovir or tenofovir can be used as alternatives. Lamivudine monotherapy is not recommended due to the high risk of resistance development. Combinations of nucleoside analogues such as tenofovir and lamivudine or emtricitabine are alternatives for patients with non-response or infection with resistant variants, or as first choice for patients with advanced liver disease. Nucleoside analogue treatment should be monitored to detect primary non-response and virological breakthrough. Special recommendations are given for HBV/HIV coinfected patients, immunosuppressed patients, children, and for treatment before and after liver transplantation. The present guideline is translated from Swedish, where it is published on the MPA and RAV websites (www.mpa.se and www.rav.nu.se) including 7 separate papers based on thorough literature search. The complete reference list can be received from the Medical Products Agency upon request.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Immunocompromised Host; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Transplantation; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Sweden; Tenofovir

Chronic hepatitis B continues to be a serious problem worldwide. Because a high viral load is associated with greater progression to cirrhosis and hepatocarcinoma in these patients, new drugs that achieve rapid, potent and lasting suppression of viral replication must be sought. Entecavir is a new, highly potent antiviral agent; phase II and III studies have demonstrated this drug to be superior to placebo and lamivudine in patients with chronic hepatitis B virus in terms of histological improvement, efficacy in achieving suppression of viral replication and normalizing transaminase counts. The drug is well tolerated, since its adverse effects are usually mild or moderate and their incidence is similar to that found with placebo or lamivudine. Moreover, in treatment-naïve patients, no resistance has been observed after 3 years of therapy. However, in patients with prior resistance to lamivudine, the incidence of resistance is approximately 15% at 3 years. Further studies are required that compare this drug with other currently available therapeutic options, as well as longer term trials to evaluate its safety. It seems that entecavir will occupy a major place in the treatment of patients with chronic hepatitis B virus infection.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; Humans; Lamivudine; Liver Cirrhosis; Liver Transplantation; Multicenter Studies as Topic; Organophosphonates; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load; Virus Replication

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

Infection with hepatitis B virus (HBV) is extremely widespread - it infects two billion people out of the six billion world population. It is estimated that between 350 and 400 million people are chronically infected with HBV. Chronic HBV infection leads to development of complications, such as cirrhosis and hepatocellular carcinoma (HCC), which arise in 15-40% of patients. HBV-related liver disease and its complications result in approximately one million deaths each year. The ultimate goals of chronic hepatitis B (CHB) therapy are decreases in the incidence of cirrhosis, end-stage liver disease and HCC. The following six medications are currently approved by the U.S. Food and Drug Administration for the treatment of CHB: interferon (INF)-alpha2b, pegylated INF-alpha2a, lamivudine, adefovir dipivoxil, entecavir and, recently, telbivudine. Interferon therapy has many contraindications and commonly causes multiple intolerable adverse effects. Lamivudine therapy leads to increased development of resistant mutations with each year of use. Entecavir, a new guanosine nucleoside analogue with specific activity against HBV DNA polymerase, represents a third agent within the nucleoside/nucleotide HBV polymerase inhibitor class. It has distinct advantages over lamivudine and adefovir dipivoxil: it has a three-step mechanism of action, is the most potent inhibitor of HBV DNA polymerase, is not associated with any major adverse effects and has a limited potential for resistance. In clinical trials, entecavir was superior to lamivudine in all primary endpoints in both nucleoside-naive and lamivudine-refractory hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. Preliminary data support entecavir efficacy in patients with cirrhosis and HIV/HBV coinfected patients. No resistance occurred after two years of entecavir therapy in nucleoside-naive patients. Up to 9% resistance developed in patients with documented prior lamivudine resistance during 96 weeks of entecavir therapy. Currently, entecavir should be considered a first- or second-line treatment option for the management of HBeAg-positive or -negative nucleoside-naive or lamivudine-refractory CHB patients.

Topics: Animals; Antiviral Agents; Drug Interactions; Drug Resistance, Viral; Fibrosis; Guanine; Hepatitis B, Chronic; HIV Infections; Humans

Topics: Alanine Transaminase; Antiviral Agents; Aspartate Aminotransferases; DNA, Viral; Double-Blind Method; Drug Resistance, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; Humans; Lamivudine; Liver Cirrhosis; Liver Transplantation; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Recurrence; Treatment Outcome; Viremia

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

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

This article reviews the pharmacology/pharmacokinetics and therapeutic efficacy of entecavir, which was approved on March 29, 2005, for the management of adult patients with chronic hepatitis B virus (HBV) infection who have active viral replication and/or elevations in liver transaminases or signs of active liver disease on histologic examination. Potential drug interactions and adverse events associated with the use of entecavir are also reviewed.. Relevant literature was identified through searches of MEDLINE (1996-July 2005) and BIOSIS (1993-July 2005). Search terms included, but were not limited to, entecavir, BMS-200475, hepatitis B, pharmacology, pharmacokinetics, adverse events, and therapeutic use. Further publications were identified from the reference lists of the identified articles and through correspondence with the manufacturer of entecavir.. Entecavir is highly selective for the HBV and inhibits all 3 steps of viral replication. Results of early studies indicated a 6% resistance potential after 48 weeks of therapy, although the potential may be higher in patients who harbor lamivudine-resistant mutants. The approved dosage in treatment-naive patients is 0.5 mg/d p.o., administered on an empty stomach; in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg/d p.o.. The oral tablet and solution can be used interchangeably. Entecavir is well absorbed orally, achieving a dose-related Cmax between 0.6 and 1.5 hours after administration. It is metabolized to a small extent and is not a substrate for the cytochrome P450 enzyme system. The mean elimination t(1/2) ranges from 77 to 149 hours in patients with normal kidney function. Entecavir is eliminated primarily in the urine via glomerular filtration and tubular secretion (62%-73%). No dose adjustment appears to be necessary in patients with moderate to severe liver disease alone. The potential for drug interactions with entecavir appears to be minimal, although medications that inhibit tubular secretion of drugs (eg, probenecid) may be expected to prolong serum concentrations of entecavir. One of the Phase III studies of entecavir found statistically significant benefits compared with lamivudine in terms of improvements in liver histology after 48 weeks of therapy (72% vs 62%, respectively; P<0.009), the proportions of patients with undetectable HBV DNA titers on branched DNA signal amplification assay after 48 weeks of therapy (91% vs 65%; P<0.001), and the proportion with undetectable HBV DNA on polymerase chain reaction (PCR) assay after 48 weeks of therapy (69% vs 38%; P<0.001). In another Phase III study, patients who had failed to respond to lamivudine therapy responded to entecavir: after 48 weeks of therapy, significant differences between entecavir and lamivudine were seen in histologic improvement (55% vs 28%; P<0.001) and the proportion of patients with undetectable HBV DNA on PCR assay (21% vs 1%; P<0.001). Adverse events associated with entecavir therapy were similar in character, severity, and incidence to those associated with placebo or lamivudine therapy. The most common adverse events in clinical trials of entecavir were headache (17%-23% of patients), upper respiratory tract infection (18%-20%), cough (12%-15%), nasopharyngitis (9%-14%), fatigue (10%-13%),. Entecavir is a new antiviral agent for the management of chronic HBV infection. Questions concerning the ideal length of therapy, long-term efficacy, and resistance rates over time await the results of ongoing clinical trials.

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Viral; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Liver Transplantation; Molecular Structure

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

Chronic hepatitis B infection carries considerable risk for the development of cirrhosis and hepatocellular carcinoma. Treatment options are increasing but are limited to interferon alfa-2b, pegylated interferon alfa-2a, lamivudine, adefovir dipivoxil, and entecavir. Entecavir, a nucleoside analog, is the newest oral antiviral approved in the United States for treatment of chronic hepatitis B.. To review the available data for entecavir regarding its pharmacology, pharmacokinetics, safety, efficacy, and clinical use.. A MEDLINE, EMBASE, and Cochrane search of the English-language literature from January 1997-May 2006 was performed. Preapproval studies provided by the manufacturer and abstracts from recent scientific meetings on infectious disease and hepatology were also reviewed.. Three phase III clinical trials representing more than 1600 subjects established the superior efficacy and equivalent safety of entecavir compared with lamivudine for treating patients who are hepatitis B early antigen (HBeAg) positive, HBeAg negative, or refractory to lamivudine. Entecavir resistance has not occurred in nucleoside-naïve patients but may develop in those who already possess lamivudine resistance mutations.. Trial results, along with previously published response rates for adefovir dipivoxil and interferon monotherapy, make entecavir the preferred first-line treatment option for patients with chronic hepatitis B who are nucleoside naïve, HBeAg positive or negative, and have compensated liver disease. Both entecavir and adefovir dipivoxil maintain activity against hepatitis B virus in patients with chronic hepatitis B who are refractory to lamivudine, and both agents are reasonable first-line treatment options. Longer trials involving nucleoside-naïve, lamivudine-refractory patients are needed to determine entecavir's optimal treatment duration, long-term safety, and durability of response, including rate of resistance.

Topics: Animals; Antiviral Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Lamivudine

Topics: Adenine; Antiviral Agents; Comorbidity; Deoxycytidine; Drug Resistance, Viral; Emtricitabine; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Lamivudine; Organophosphonates; Organophosphorus Compounds; Tenofovir

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Guanine; Hepatitis B, Chronic; HIV; HIV Infections; Humans; Male; Middle Aged; Pilot Projects; Treatment Outcome; Viremia

We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy.. We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF.. At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 41-63 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m(2), which was most pronounced shortly after TDF therapy was initiated.. TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.

Topics: Adenine; Adult; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; Humans; Kaplan-Meier Estimate; Kidney; Male; Middle Aged; Organophosphonates; Prospective Studies; Tenofovir; Time Factors; Virus Replication

Prolonged use of lamivudine in patients coinfected with HIV and hepatitis B virus (HBV) leads to an increasing risk of lamivudine resistance in both diseases. We investigated the addition of entecavir, a potent inhibitor of HBV polymerase, to lamivudine-containing highly active antiretroviral therapy (HAART) in patients who experienced rebound in HBV viremia while maintaining suppression of plasma HIV RNA less than 400 copies/ml.. Sixty-eight patients were randomized to entecavir 1 mg (n = 51) or placebo (n = 17) once daily for 24 weeks; 65 patients continued the study with entecavir for an additional 24 weeks. Lamivudine-containing HAART was continued throughout.. At week 24, the mean HBV DNA in entecavir-treated patients was 5.52 log10 copies/ml versus 9.27 log10 copies/ml for placebo, and at week 48, it was 4.79 log10 copies/ml versus 5.63 log10 copies/ml, respectively. The mean HBV DNA change from baseline for entecavir was -3.65 log10 copies/ml (versus + 0.11 for placebo, P < 0.0001) and alanine aminotransferase normalization in 34% of patients (versus 8% for placebo, P = 0.08). At 48 weeks, mean change in HBV DNA reached -4.20 log10 copies/ml in patients who received entecavir for the entire 48 weeks. The frequency of adverse events with entecavir and placebo was comparable. Through 48 weeks, no clinically relevant changes in HIV viremia or CD4 cell counts were identified.. In this study, entecavir was associated with rapid, clinically significant reductions in HBV DNA, with maintenance of HIV viremia suppression, in HIV/HBV coinfected patients with HBV viremia while on lamivudine treatment.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV; HIV Infections; Humans; Lamivudine; Linear Models; Male; Middle Aged; Single-Blind Method; Virus Replication

Entecavir is a guanosine nucleoside analogue approved for the treatment of chronic hepatitis B virus (HBV) infection. The impact of human immunodeficiency virus (HIV) coinfection on the pharmacokinetics (PK) of entecavir was examined by nonlinear mixed-effects modeling. Plasma concentration data from HIV- and HBV-coinfected patients were analyzed in conjunction with data from HBV-monoinfected patients, and HIV coinfection was tested as a covariate on oral clearance (CL/F). The estimated population averages of intercompartmental clearance and the volumes of distribution in the central and peripheral compartments obtained with a 1-mg dose were 34.2 liters/h (interindividual variability, 30.2%), 115 liters (interindividual variability, 39.2%), and 1,830 liters (interindividual variability, 74%), respectively. CL/F was found to be a function of creatinine clearance, but HIV confection did not show any effect on CL/F. The geometric mean (GM) of individual Bayesian estimates of the steady-state area under the concentration-time curve following 1-mg daily doses were 39.3 and 38.8 ng x h/ml in HIV- and HBV-coinfected and HBV-monoinfected patients, respectively. The adjusted GM ratio (1.01; 90% confidence interval, 0.91 to 1.12) was within the bioequivalence criteria boundary (0.80 to 1.25). In conclusion, the proposed model adequately described the entecavir PK in HBV- and HIV-coinfected patients and HBV-monoinfected patients, and the entecavir exposures were comparable in the two patient populations.

Topics: Algorithms; Antiviral Agents; Area Under Curve; Guanine; Hepatitis B; HIV Infections; Humans; Metabolic Clearance Rate; Models, Biological; Randomized Controlled Trials as Topic

Topics: Antiretroviral Therapy, Highly Active; Antiviral Agents; Double-Blind Method; Drug Approval; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Placebos; United States; United States Food and Drug Administration; Viral Load

Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined.. In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antiviral Agents; Coinfection; Drug Therapy, Combination; Female; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; HIV Infections; Humans; Lamivudine; Liver; Male; Middle Aged; North America; Prospective Studies; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome; Young Adult

We report a case of HBV reactivation following belatacept treatment in a patient who underwent kidney transplantation in 2015 for HIV-associated nephropathy (HIVAN). Human immunodeficiency virus viral load was undetectable prior to transplantation, and CD4+ lymphocyte count was greater than 300/mL. Baseline HBV serology at transplantation was HBsAg negative, anti-HBcAb positive, anti-HBsAb 312 UI/L, and HBeAg negative/anti-HBeAb positive. Liver function tests were normal, and viral DNA was undetectable. Two years later, the patient presented with severe acute hepatitis after a progressive disappearance of anti-HbsAb, quickly followed by HBV reactivation. Immunosuppressive treatment was drastically reduced, and treatment with entecavir was started. The outcome was favorable, and HBV DNA became undetectable after 9 weeks of treatment. This is the first report of acute hepatitis related to HBV reactivation in a kidney transplant recipient treated with belatacept. The risk for HBV reactivation in patients treated with belatacept should not be underestimated, especially in those with resolved HBV infection.

Topics: Abatacept; Antiviral Agents; DNA, Viral; Graft Rejection; Guanine; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; HIV Infections; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Virus Activation

The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Consensus; Disease Management; Disease Progression; Female; Guanine; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; Humans; Immunization Programs; Interferon-alpha; Liver Cirrhosis; Liver Neoplasms; Male; Pregnancy; Societies, Medical; Taiwan; Viral Load

Topics: Adenine; Alanine; Anti-HIV Agents; Guanine; HIV Infections; Humans; Tenofovir

To compare the management of chronic hepatitis B (CHB) and its evolution over time in currently followed HIV-positive and HIV-negative patients.. A total of 709 consecutive patients with past or present positive HBs antigenemia seen in October 2012 in 19 French participating centres were included. The data were retrospectively collected from the first visit onwards through standardized questionnaires.. Chronic hepatitis B was less often assessed in the 299 HIV-positive patients, who were older, more likely to be male, excessive alcohol drinkers and HBe antigen-, HCV- and HDV-positive. They were also followed up for a longer time (11.3 +/-8.8 vs. 8.6 +/-6.9 years, P < 10(-3) ) and were more frequently treated for HBV (95.3% vs. 56.8%, P < 10(-3) ). HBV was undetectable at the last visit in 80.8% of HIV-positive vs. 55.1% of HIV-negative patients (P < 10(-3) ). In multivariate analyses, undetectable HBV was significantly associated with older age, lower baseline HBV DNA, longer HBV therapy and no previous lamivudine monotherapy, but not with HIV. Cirrhosis was associated with age, male gender, Asian origin, alcoholism, HCV, HDV, but not with HIV infection. Hepatocellular carcinoma, less frequently observed in HIV-positive patients (0.7% vs. 4.7%, P = 0.002), was positively associated with age, male gender, cirrhosis and negatively associated with HIV infection (OR 0.15, 95%CI 0.03-0.67, P = 0.01).. Although the assessment of CHB still has to be improved in HIV-positive patients, the negative impact of HIV on the virological, histological and clinical evolution of CHB seems to be disappearing, probably because of the immunovirological impact of HAART and the more frequent and longer use of HBV therapy.

Topics: Adult; Antiviral Agents; Cohort Studies; Comorbidity; Disease Progression; Female; France; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; HIV Infections; HIV Seronegativity; HIV Seropositivity; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Logistic Models; Male; Middle Aged; Multivariate Analysis; Reference Values; Retrospective Studies; Risk Assessment; Statistics, Nonparametric; Survival Analysis; Tenofovir; Treatment Outcome

Discovering the relevant therapeutic targets for drug-like molecules, or their unintended 'off-targets' that predict adverse drug reactions, is a daunting task by experimental approaches alone. There is thus a high demand to develop computational methods capable of detecting these potential interacting targets efficiently.. As biologically annotated chemical data are becoming increasingly available, it becomes feasible to explore such existing knowledge to identify potential ligand-target interactions. Here, we introduce an online implementation of a recently published computational model for target prediction, TarPred, based on a reference library containing 533 individual targets with 179 807 active ligands. TarPred accepts interactive graphical input or input in the chemical file format of SMILES. Given a query compound structure, it provides the top ranked 30 interacting targets. For each of them, TarPred not only shows the structures of three most similar ligands that are known to interact with the target but also highlights the disease indications associated with the target. This information is useful for understanding the mechanisms of action and toxicities of active compounds and can provide drug repositioning opportunities.. TarPred is available at: http://www.dddc.ac.cn/tarpred.

Topics: Antiviral Agents; Computational Biology; Databases, Pharmaceutical; Drug Repositioning; Drug-Related Side Effects and Adverse Reactions; Guanine; HIV; HIV Infections; Humans; Internet; Pharmaceutical Preparations; Software

Combination emtricitabine (FTC) or lamivudine (LAM) with tenofovir disoproxil (TDF) is the recommended first-line regime for treatment in chronic hepatitis B virus (HBV)/HIV co-infection. However, in those failing to suppress, few data exist regarding further management. In HBV/HIV co-infection, there are no published data describing outcomes when entecavir (ETV) is then added to TDF-based regimes in patients no longer suppressing their HBV. We report the first series of patients using ETV with truvada-based HAART in HBV/HIV co-infected patients with previous HBV therapy failure, including inadequate suppression.. A prospective observational study.. Thirteen HIV/HBV co-infected patients (all male, hepatitis B e antigen positive and hepatitis B e antibody negative) were commenced on ETV in addition to background truvada. All patients were previously exposed to LAM or FTC and TDF (median 53 months, range 6−123). Seven patients had LAM monotherapy prior to TDF/LAM or FTC combination; the remaining six patients were exposed to FTC or LAM and TDF combination. Median time of follow-up was 74 weeks (range 16−159) and median HBV decline was 2.53 log(10) IU/ml (range 1.28−7.36). Thirty-eight percent of patients achieved undetectable HBV DNA level by the end of the study and eight of 13 (62%) achieved normal alanine aminotransferase (ALT) levels with median reduction −28 U/l (range −152 to 37). TDF was stopped in one patient because of renal toxicity. ETV was well tolerated with no change of estimated glomerular filtration rate during the study.. Entecavir can be considered in addition to TDF/FTC in HBV/HIV co-infected treatment-experienced patients failing to fully suppress their HBV viral load.

Topics: Adenine; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Deoxycytidine; DNA, Viral; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; Humans; Male; Middle Aged; Organophosphonates; Prospective Studies; Tenofovir; Treatment Outcome

Most approved drugs with activity against hepatitis B virus (HBV) have activity against human immunodeficiency virus type 1 (HIV-1), which precludes their use in patients who are coinfected with HBV and HIV-1 and who are not receiving antiretroviral therapy due to the risk of inducing resistance. The activity of telbivudine, a highly selective HBV inhibitor, against temporally and geographically distinct wild-type and multidrug-resistant HIV-1 clinical isolates was evaluated in vitro. No inhibition was observed with up to 600 muM drug, which supports further exploration of telbivudine as a therapeutic option for the treatment of HBV infections in patients coinfected with HIV-1.

Topics: Anti-HIV Agents; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

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

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

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

A 45-year-old male active homosexual was given a diagnosis of HIV-1 and acute hepatitis B in August 2007. Since his liver function became rapidly impaired, anti-HBV therapy with oral administration of entecavir (ETV) was started, and resulted in a favorable outcome. However, serum concentration of HIV-RNA decreased by log 1.26 within 60 days, which strongly suggested the inhibition of HIV proliferation by ETV. To prevent the appearance of mutated HIV, novel therapeutic strategies should be established in HIV/HBV-coinfected patients.

Topics: Antiviral Agents; Guanine; Hepatitis B; HIV Infections; Homosexuality; Humans; Male; Middle Aged; RNA, Viral

Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.

Topics: Antiviral Agents; Cell Line; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans

The novel 2'-deoxyguanosine analog Entecavir (ETV) is a potent inhibitor of hepatitis B virus (HBV) replication and is recommended for treatment in human immunodeficiency virus type 1 (HIV-1) and HBV-co-infected patients because it had been reported that ETV is HBV-specific. Recent clinical observations, however, have suggested that ETV may indeed demonstrate anti-HIV-1 activity. To investigate this question at a molecular level, kinetic studies were used to examine the interaction of 5'-triphosphate form of ETV with wild type (WT) HIV-1 reverse transcriptase (RT) and the nucleoside reverse transcriptase inhibitor-resistant mutation M184V. Using single turnover kinetic assays, we found that HIV-1 WT RT and M184V RT could use the activated ETV triphosphate metabolite as a substrate for incorporation. The mutant displayed a slower incorporation rate, a lower binding affinity, and a lower incorporation efficiency with the 5'-triphosphate form of ETV compared with WT RT, suggesting a kinetic basis for resistance. Our results are supported by cell-based assays in primary human lymphocytes that show inhibition of WT HIV-1 replication by ETV and decreased susceptibility of the HIV-1 containing the M184V mutation. This study has important therapeutic implications as it establishes ETV as an inhibitor for HIV-1 RT and illustrates the mechanism of resistance by the M184V mutant.

Topics: Amino Acid Substitution; Antiviral Agents; Cells, Cultured; Drug Resistance, Viral; Guanine; Hepatitis B; Hepatitis B virus; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Kinetics; Lymphocytes; Mutation, Missense; Virus Replication

Recently, entecavir was introduced as a potent drug against hepatitis B virus infection. Initially, it was suggested not to have any effect on human immunodeficiency virus (HIV) infection. This guideline was revised in 2007 because of a report showing that the M184V mutation was selected in an hepatitis B virus and HIV-coinfected patient previously treated with lamivudine. Our investigation revealed findings similar to those preveiously reported but in an antiretroviral therapy-naive patient coinfected with HIV and hepatitis B virus. After 26 weeks of entecavir therapy, the M184V mutation dominated the plasma viral population. Thus, entecavir should only be used for coinfected patients who simultaneously receive suppressive therapy against HIV infection.

Topics: Aged; Anti-HIV Agents; env Gene Products, Human Immunodeficiency Virus; Guanine; HIV Infections; HIV Reverse Transcriptase; Humans; Male; Mutation; Phylogeny

Topics: Adult; Anti-Retroviral Agents; Guanine; Hepatitis D; Hepatitis Delta Virus; HIV Infections; HIV-1; Humans; Male; Mutation

Entecavir, an antiviral with potent anti-hepatitis B virus activity, was recently shown to have anti-HIV activity in three patients and the ability to select for the lamivudine-resistant HIV polymerase mutation M184V in a patient with prior antiretroviral therapy.. To further characterize entecavir's anti-HIV activity and identify risk factors for selection of the M184V.. Retrospective cohort study.. We evaluated the virological characteristics of HIV and hepatitis B virus in 17 HIV-hepatitis B virus coinfected patients (10 antiretroviral therapy-naive and seven antiretroviral therapy-experienced) prior to and during entecavir monotherapy. Descriptive statistics were used to assess changes in HIV RNA and hepatitis B virus DNA. Variables associated with development of the M184V were determined by univariate analysis.. Of the 17 patients, 13 (76%) demonstrated a reduction in HIV RNA by at least 0.5 log10 copies/ml. Of the remaining four patients, two had the M184V detected prior to entecavir therapy and the other two had wild-type HIV. The median reduction in HIV RNA for the cohort was 1.2 log10 copies/ml, which was similar in antiretroviral therapy-naive and antiretroviral therapy-experienced patients. The M184V mutation emerged in six patients receiving entecavir, including three antiretroviral therapy-naive patients. No other HIV mutations were consistently detected. Risk factors for the emergence of the M184V mutation were a decline in hepatitis B virus DNA (P = 0.04) and duration of entecavir use (P = 0.05).. Entecavir monotherapy in HIV-hepatitis B virus coinfected patients, including antiretroviral therapy-naive patients, has significant anti-HIV activity and can result in the development of the M184V variant. Entecavir should not be used in such co-infected patients without concomitant antiretroviral therapy.

Topics: Adult; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Evaluation; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Mutation; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; RNA, Viral

Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.

Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Drug Resistance, Viral; Guanine; Hepatitis B; Hepatitis B virus; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Middle Aged; Mutation; Phylogeny; Reverse Transcriptase Inhibitors; Reverse Transcription; RNA, Viral; Virus Replication; Zidovudine

Topics: Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Reverse Transcriptase Inhibitors; Reverse Transcription; Virus Replication

Topics: Antiviral Agents; Drug Industry; Guanine; HIV Infections; Humans; United States; United States Food and Drug Administration

Topics: Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B; HIV Infections; Humans

Topics: Antiviral Agents; Guanine; Hepatitis B; HIV Infections; Humans

Topics: Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B; HIV Infections; Humans; United States; United States Food and Drug Administration

Topics: Adult; Antiviral Agents; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; HIV; HIV Infections; Humans; Male; Treatment Failure

Topics: Antiviral Agents; Genotype; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Male; Middle Aged; Viral Load

Topics: Antiviral Agents; Drug Labeling; Drug Resistance, Viral; Guanine; Hepatitis B; HIV Infections; Humans; United States; United States Food and Drug Administration

Topics: Adult; Antiviral Agents; DNA, Viral; Guanine; Hepatitis B; HIV Infections; Humans; Immune System Diseases; Male; Syndrome

Topics: 2-Aminopurine; Anti-HIV Agents; Antiviral Agents; Deoxyguanosine; Famciclovir; Hepatitis B; HIV Infections; Humans; Lamivudine