Treatment paradigms on hepatitis B e antigen-negative chronic hepatitis B patients

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

Drugs in development for hepatitis B

The management of chronic hepatitis B (CHB) has improved dramatically over the last decade with the development of new drugs such as lamivudine and adefovir dipivoxil, in addition to the now standard interferon (IFN)-alpha therapy. These new drugs can achieve a significant reduction or inhibit replication of hepatitis B virus (HBV) DNA during therapy. However, in the majority of patients, particularly in those who are hepatitis B e antigen (HBeAg)-negative, the sustained off-therapy suppression of HBV DNA is rare. For this reason, several new antiviral and immunomodulatory agents are currently being evaluated. Among the immunomodulatory agents, pegylated IFNalpha (peginterferon-alpha) has been shown to be more effective for HBeAg-positive CHB than either lamivudine or standard IFNalpha monotherapy, particularly in those patients infected by HBV genotypes A and B. The new antivirals entecavir, tenofovir disoproxil fumarate and telbivudine exhibit a more potent viral inhibitory effect than the currently approved drugs (IFNs, lamivudine and adefovir dipivoxil). However, the emergence of viral resistance has been witnessed and this could be one of the major limitations to the clinical use of these new drugs, particularly during prolonged therapy. In HBeAg-negative patients it is more and more common for oral antiviral therapy to be administered for prolonged periods, as the sustained off-therapy response rates of short-term therapy are very low. Different studies are currently evaluating combination therapy, using lamivudine with adefovir dipivoxil or peginterferon-alpha with lamivudine; the preliminary results show virological responses no better than those achieved by monotherapy. However, as combination therapy is associated with a low likelihood of developing HBV drug resistance, this could result in a higher virological response during prolonged therapy. In the near future the most realistic therapeutic option for the majority of patients with CHB will be long-term use of these new, more potent antiviral drugs, if they can achieve good safety profiles while maintaining low resistance rates at affordable costs.     

Management options for lamivudine-resistant chronic hepatitis B patients with suboptimal virological suppression by adefovir

Aliment Pharmacol Ther 2011; 34: 972–981

Summary

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

A review of entecavir in the treatment of chronic hepatitis B infection

BACKGROUND: Infection with the hepatitis B virus (HBV) affects two billion people worldwide, and an estimated 400 million people are chronically infected. Currently, FDA-approved regimens for the treatment of chronic HBV include interferon-alpha2b, peginterferon-alpha2a, lamivudine, adefovir dipivoxil, and recently, entecavir. OBJECTIVE: The purpose of this review is to evaluate the pharmacokinetic and pharmacodynamic properties, and the clinical efficacy and safety of entecavir in the treatment of nucleoside-na?ve and nucleoside-resistant HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). SEARCH METHODOLOGY: Computerized searches of PubMed and International Pharmaceutical Abstracts from 1985 to July 10, 2005, were performed with the search headings: entecavir, BMS-200475, and chronic hepatitis B. FINDINGS: Entecavir, a new deoxyguanosine analog, represents a third agent within the nucleoside/nucleotide HBV polymerase inhibitor class with 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 phase II and III clinical trials, entecavir was found to be superior to lamivudine for all primary endpoints evaluated in both nucleoside-na?ve and lamivudine-resistant patients. Entecavir was effective in both HBeAg-positive and HBeAg-negative nucleoside-na?ve patients. At this time, optimal duration of entecavir therapy is unknown. CONCLUSION: Entecavir represents a new first- or second-line treatment option for patients chronically infected with HBV. Long-term efficacy and safety studies as well as studies of entecavir in combination with interferon products or other nucleoside/nucleotide analogs are eagerly awaited.     

Entecavir: a new nucleoside analogue for the treatment of chronic hepatitis B

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.     

Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 – 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in ～ 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-α. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 – 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.     

Pegylated interferons for the treatment of chronic hepatitis B

Five drugs are approved for the treatment of chronic hepatitis B: conventional interferon (IFN) alfa, lamivudine, adefovir dipivoxil, pegylated interferon (peginterferon) alfa-2a and entecavir. Conventional IFN monotherapy has a narrow range of efficacy, should be administered subcutaneously and is commonly associated with adverse effects. Lamivudine is cheaper and well tolerated, but the virological response may not be durable and prolonged lamivudine treatment is commonly associated with the emergence of drug-resistant mutants. Adefovir dipivoxil is potent but with nephrotoxicity at higher doses. Entecavir is active against both lamivudine- and adefovir dipivoxil-na?ve and -resistant HBV, however, its long-term efficacy remains to be evaluated. Peginterferon alfa-2a has recently been shown to be superior to conventional IFN and lamivudine in the treatment of both HBeAg-positive and -negative chronic hepatitis B. By using peginterferon alfa-2a monotherapy, the overall virological and serological responses are around 30%-44%. However, peginterferon alfa-2a in combination with lamivudine does not improve the results at the end of follow-up. Adverse effects are usually tolerable and comparable with conventional IFN. Similar efficacy of peginterferon alfa-2b has also been demonstrated in HBeAg-positive chronic hepatitis B. These observations suggest an important and even a primary role of peginterferon alfa in the treatment of chronic HBV infection.     

Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 - 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in approximately 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-alpha. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 - 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.     

优化方案治疗阿德福韦酯初治失败的慢性乙型肝炎患者的疗效分析

目的观察恩替卡韦单药序贯与拉米夫定联合阿德福韦酯治疗阿德福韦酯初治失败的慢性乙型肝炎患者的临床疗效及安全性。方法选择阿德福韦酯初治失败的慢性乙型肝炎患者213例．随机分为A组104例、B组109例;A组患者改用恩替卡韦单药治疗,B组患者予以拉米夫定联合阿德福韦酯治疗;至48周时分别观察、比较其血清HBV DNA水平中位数下降幅度、血清HBV DNA阴转率、HBeAg转阴率、生化学应答率。血清HBV DNA阴转患者继续原方案治疗至96周,并观察其维持血清HBV DNA阴转率、HBeAg转阴率、HBV基因耐药变异率及不良反应。结果治疗48周,两组患者血清HBV DNA水平中位数下降幅度、血清HBV DNA阴转率、HBeAg转阴率及生化学应答率,差异均无统计学意义（P均〉0．05）。血清HBV DNA阴转患者继续原方案治疗至96周．两组患者维持血清HBV DNA阴转率、HBeAg转阴率及HBV基因耐药变异率．差异均无统计学意义（P均〉0．05）。两组患者均无严重不良事件。结论阿德福韦酯初治失败的慢性乙型肝炎患者予以拉米夫定联合阿德福韦酯治疗或改用恩替卡韦单药治疗．均能取得较好的临床疗效;两种优化方案维持血清HBV DNA阴转率、HBeAg转阴率率及HBV耐药变异率均无明显差异,安全性良好均适用于患者临床治疗。     

Evaluating anti-viral drug selection and treatment duration in HBeAg-negative chronic hepatitis B: a cost-effectiveness analysis

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

Emerging treatments in chronic hepatitis B

Although the management of chronic hepatitis B has improved over the last decade, none of the available therapeutic agents, IFN-alpha, lamivudine and adefovir dipivoxil, can achieve sustained off-therapy responses in most cases. Therefore, several newer, mainly antiviral and immunomodulatory agents, are being evaluated. Pegylated IFN-alpha(2a) has been shown to be more effective than lamivudine or standard IFN-alpha monotherapy in achieving post-therapy biochemical and virological responses, and is expected to be licensed soon for the treatment of chronic hepatitis B. Newer antiviral agents, such as entecavir and telbivudine, appear to be quite effective initially, but their sustained off-therapy response rates remain unknown. The preliminary data of monotherapies with immunomodulatory agents, or of combination therapies, have been rather disappointing. Long-term maintenance treatment with antiviral agent(s) with good safety and tolerability profiles and low resistance rates appears to be the most realistic future therapeutic option for most chronic hepatitis B patients.     

Complications in treating chronic hepatitis B in patients with HIV

The management of chronic hepatitis B virus (HBV) poses specific problems in the presence of HIV infection, as therapeutic approaches have to consider both HBV and HIV. There are currently four drugs approved for the treatment of chronic HBV: IFN-α, lamivudine, adefovir and entecavir. Furthermore, the dual antiviral activity against HIV and HBV of antiretrovirals such as tenofovir and emtricitabine broadens the armamentarium against HBV in the HIV-coinfected population. Nucleotide analogues adefovir and tenofovir have the advantage of a higher genetic barrier for resistance when compared with the nucleoside analogues lamivudine and emtricitabine. Fortunately, the two families do not share resistance mutations, allowing salvage therapy and the consideration of combination therapy for drug-naive individuals. Although response to IFN-α is poorer in HBV/HIV-coinfected patients compared with HBV-monoinfected individuals, the more potent pegylated forms of IFN-α have brought new hopes.     

Complications in treating chronic hepatitis B in patients with HIV

The management of chronic hepatitis B virus (HBV) poses specific problems in the presence of HIV infection, as therapeutic approaches have to consider both HBV and HIV. There are currently four drugs approved for the treatment of chronic HBV: IFN-alpha, lamivudine, adefovir and entecavir. Furthermore, the dual antiviral activity against HIV and HBV of antiretrovirals such as tenofovir and emtricitabine broadens the armamentarium against HBV in the HIV-coinfected population. Nucleotide analogues adefovir and tenofovir have the advantage of a higher genetic barrier for resistance when compared with the nucleoside analogues lamivudine and emtricitabine. Fortunately, the two families do not share resistance mutations, allowing salvage therapy and the consideration of combination therapy for drug-naive individuals. Although response to IFN-alpha is poorer in HBV/HIV-coinfected patients compared with HBV-monoinfected individuals, the more potent pegylated forms of IFN-alpha have brought new hopes.     

Entecavir for chronic hepatitis B: a review

Three nucleotide/nucleoside analogs are currently used for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, and entecavir. Lamivudine and adefovir are beneficial for oral administration and safety, but only a few of the patients treated experience a sustained response after therapy withdrawal. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of chronic hepatitis B virus DNA polymerase, inhibiting both the priming and elongation steps of viral DNA replication. In phase II and phase III clinical trials, entecavir was found to be superior to lamivudine for all primary end points evaluated in both nucleoside-naive and lamivudine-resistant patients as well as being effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has shown evidence of cases of viral resistance to this drug. The approved dosage in treatment-naive patients is 0.5 mg per day orally, whereas in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg per day.     

Cost effectiveness of entecavir versus lamivudine with adefovir salvage in HBeAg-positive chronic hepatitis B

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

Review article: current management of chronic hepatitis B

Chronic hepatitis B can be diagnosed in patients with increased aminotransferases, hepatitis B virus viraemia and necroinflammation with fibrosis on liver biopsy. Although, ideally, all patients with chronic hepatitis B should be treated, therapeutic intervention is currently recommended for cases with a relatively satisfactory likelihood of response and/or advanced disease. A realistic therapeutic approach aims to sustain hepatitis B e antigen (HBeAg) loss and hepatitis B e antibody (anti-HBe) seroconversion in HBeAg-positive chronic hepatitis B and to sustain biochemical and virological remission in HBeAg-negative chronic hepatitis B. Currently, three drugs are licensed for chronic hepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. In patients with HBeAg-positive chronic hepatitis B, all of these drugs achieve HBeAg loss (24-33%) and anti-HBe seroconversion (12-30%) rates significantly superior to those observed in untreated placebo controls. In patients with HBeAg-negative chronic hepatitis B, the sustained off-therapy response rate is 20-25% after a > or =12-month course of interferon-alpha and minimal (<10%), if any, after a 12-month course of lamivudine or adefovir. Long-term lamivudine induces an initial response in 70-90% of patients, but only 30-40% of patients remain in remission after the third year due to progressively increasing viral resistance. Long-term adefovir achieves a response in approximately 70% of patients at 12 months, which is maintained at 24 months with rare (<2%) drug resistance. Adefovir is also effective against lamivudine-resistant strains. Many other anti-viral agents, immunomodulatory approaches and combination therapies are currently being evaluated in chronic hepatitis B.     

The efficacy of entecavir therapy in chronic hepatitis B patients with suboptimal response to adevofir

Aliment Pharmacol Ther 2011; 34: 767–774

Summary

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

Predictors of relapse in chronic hepatitis B after discontinuation of anti-viral therapy

Aliment Pharmacol Ther 2011; 34: 344–352

Summary

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

Comparison of the efficacy of thymosin alpha-1 and interferon alpha in the treatment of chronic hepatitis B: a meta-analysis

Chronic hepatitis B virus (HBV) infection is a serious problem because of its worldwide distribution and possible adverse sequelae, such as cirrhosis and hepatocellular carcinoma. Thymosin alpha-1 (Talpha1) is an immune modifier that has been shown to be effective for chronic hepatitis B (CHB) in some trials. But the trials comparing Talpha1 vs. interferon alpha (IFNalpha) treatment in CHB have been small and the results have been inconsistent. So we conducted a meta-analysis to compare the efficacy of Talpha1 and IFNalpha in the treatment of CHB. Generally, four randomized controlled trials including 199 CHB patients who received Talpha1 or IFNalpha treatment were identified through MEDLINE and EMBASE online search. Virological (for hepatitis B e antigen (HBeAg) positive patients, loss of HBV DNA and HBeAg; for HBeAg negative patients, loss of HBV DNA), biochemical (normalization of transaminases) and complete responses (fulfill criteria of biochemical and virological response simultaneously) were analyzed using the intention-to-treat method. The odds ratio (OR) was used to measure the magnitude of the efficacy. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of 6 months treatment were 0.62 (0.35, 1.10), 0.60 (0.34, 1.05) and 0.54 (0.30, 0.97), respectively. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of follow-up (6 months post-treatment) were 3.71 (2.05, 6.71), 3.12 (1.74, 5.62) and 2.69 (1.47, 4.91), respectively. These data showed that compared with IFNalpha, the benefit of Talpha1 was not immediately significant at the end of therapy, but virological, biochemical and complete response had a tendency to increase or accumulate gradually after the therapy. For three of the four trials that studied HBeAg-negative patients, the results are mostly applicable to HBeAg-negative CHB.