Telbivudine in the treatment of chronic hepatitis B

Treatment of chronic hepatitis B with oral nucleos(t)ide analogs is evolving rapidly with newer compounds gaining approval. Recently, the US FDA and European Medicines Agency (EMEA) have approved telbivudine, a potent anti-hepatitis B virus (HBV)-specific agent with a hitherto excellent safety profile. This review focuses on the efficacy of this agent in chronic hepatitis B compared with lamivudine, evaluated clinically in Phase II and a large Phase III study. Monitoring of the virologic response under treatment with sensitive HBV-DNA assays has been applied, aiming at increasing efficacy and reducing HBV resistance. The results are critically presented and the evolving concept of effective long-term telbivudine and other nucleos(t)ide analog therapy, predicted by the extent of suppression of HBV replication at week 24, are analyzed and discussed.     

Nucleos(t)ide analogues for hepatitis B virus: Strategies for long-term success

Nucleoside and nucleotide analogues are potent HBV suppressors, but these agents rarely eradicate HBV. Therefore, the durability of viral response is a problem, and long-term therapy is usually required to ensure maintained HBV suppression. Studies have shown that long-term therapy starting with lamivudine may significantly improve survival, reduce the risk of liver-related major complications, and prevent the development of cirrhosis and HCC in chronic hepatitis B patients. However, drug resistance is a critical challenge during long-term nucleos(t)ide analogue maintenance therapy. The emergence of these mutants is characterized by an increasing level of serum HBV DNA, elevation of ALT level, and even hepatitis flare or decompensation. The prevention and proper management of drug resistance are crucial to ensure long-term success. To start treatment in the right patients at the right time with the right drug is essential in minimizing the problem of drug resistance. Each of these agents has a different profile of resistant mutations. In choosing a direct antiviral agent to initiate therapy, resistance profile is a crucial factor to consider, apart from potency and cost. In the case of drug resistance emerging, timely institution of a drug without cross-resistance may rescue the adverse effects of drug resistance and ensure the long-term success of nucleos(t)ide analogue therapy. To develop strategies for enhancing the therapeutic response and shortening the duration of therapy is an ultimate goal to avoid the problems of drug resistance.⁶⁸

• nucleos(t)ide analogues for hepatitis B virus (HBV) are highly effective in suppressing HBV replication but rarely eliminate the virus

• long-term therapy is usually required

• emergence of drug-resistant HBV mutations is a critical challenge

• to treat the right patient at the right time with the drug with highest genetic barrier to drug resistance is essential to minimize the problem with drug resistance

• the strategy of on-treatment adjustment based on level of suppression of HBV DNA needs to be clarified

• studies are needed to find the optimal combination therapy for both better therapeutic efficacy and less drug resistance

• oral antiviral agents able to attack cccDNA are urgently needed

Telbivudine protects renal function in patients with chronic hepatitis B infection in conjunction with adefovir‐based combination therapy

Previous studies have demonstrated that the treatment of chronic hepatitis B (CHB) infection with adefovir (ADV) can impair renal function. In contrast, treatment with telbivudine (LdT) improves renal function in CHB patients. The aim of this study was to evaluate the renoprotective effect of LdT in CHB patients receiving ADV‐based combination therapy. The effects of treatment with ADV + LdT on renal function were compared to those resulting from treatment with ADV + entecavir (ETV), ADV + lamivudine (LAM), ADV alone and ETV alone. The consecutive cohort analysis included 831 CHB patients who received ADV + LdT, ADV + LAM, ADV + ETV, ADV alone or ETV alone for 96 weeks. Alterations in estimated glomerular filtration rate (eGFR) were compared between the five groups using a linear mixed‐effects model. HBV DNA levels were also compared between the five groups during the 96‐week period. Among the five treatment groups, significant improvements in eGFR were observed in the ADV + LdT and ADV + LAM groups over time (P < 0.001 for each group compared with baseline eGFR). In patients with a baseline eGFR between 50 and 90 mL/min, the change in eGFR was the most significant in the ADV + LdT group (+0.641 mL/min; P < 0.001). Age, gender, baseline eGFR and treatment option were significant predictive factors for eGFR changes. In conclusion, our results suggest that the combination therapy of LdT and ADV is significantly associated with renoprotective effects in CHB patients when compared with other ADV‐based combination or single therapies.     

Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B

Chronic hepatitis B is one of the leading causes of cirrhosis and hepatocellular carcinoma globally. At present, seven drugs, including two interferons and five oral nucleos(t)ide analogues (NAs), have been approved for the treatment of chronic hepatitis B. Interferon works by immunomodulation, but is successful in less than a third of treated patients and is a relatively weak antiviral. NAs directly suppress the hepatitis B virus but have limited durability. Based on current data, combination of NA and interferon results in greater viral suppression but does not translate to off‐treatment sustained response. Concomitant or sequential treatment also does not make a difference. Combining telbivudine and interferon also runs the risk of severe peripheral neuropathy. On the other hand, interferon switch or additional therapy in patients well controlled with NAs appears to improve the durability of off‐treatment response. This article reviews current data on interferon and NA combination and discusses potential future developments.     

Use of telbivudine in kidney transplant recipients with chronic hepatitis B virus infection: A preliminary experience

Telbivudine is a relatively novel oral nucleoside analogue with favourable efficacy and tolerability in treatment‐naïve chronic hepatitis B virus (HBV) infection, but its data in kidney transplant recipients (KTRs) was lacking. The efficacy and tolerability of telbivudine in four treatment‐naïve HBsAg‐positive KTRs were reviewed (treatment duration 54 (36–72) months) HBV DNA declined from 2.6 × 10⁵(7.8 × 10³–1.5 × 10⁷) copies/mL at baseline to 170 (0.0–3.2 × 10⁴) copies/mL at 12 months, and became undetectable at 24 and 36 months (P = 0.060, 0.118 and 0.005 compared with baseline). Alanine aminotransferase levels dropped from 46.5 (30–48) IU/mL at baseline to 28 (13–45) IU/mL, 34.5 (15–71) IU/mL and 26 (12–41) IU/mL at 12, 24 and 36 months, respectively (P = 0.109, 0.715 and 0.068 compared with baseline). Serum creatinine level and estimated glomerular filtration rate (eGFR) remained stable after 36 months of treatment (P all > 0.05 compared with baseline). No virological breakthrough, cirrhosis or hepatocellular carcinoma occurred. Our pilot data suggests that telbivudine has favourable efficacy and renal safety profiles in HBsAg‐positive KTRs.     

六味五灵片联合替比夫定治疗慢性乙型肝炎肝纤维化疗效分析

目的：观察六味五灵片联合替比夫定（ LdT）治疗慢性乙型肝炎（ CHB）肝纤维化的临床疗效。方法：将120例CHB肝纤维化患者随机分为观察组和对照组。观察组（64例）患者口服六味五灵片和LdT,对照组（56例）患者单用LdT,疗程均为24周。比较两组患者治疗前后的临床症状、肝功能及肝纤维化指标变化情况。结果：治疗24周后,观察组患者ALT、 AST、 TBil分别为（25.4±16.3） U/L、（28.4±15.9） U/L、（22.8±10.7）μmol/L,均明显低于对照组（44.7±19.6） U/L、（40.1±17.1） U/L、（35.2±11.5）μmol/L ,差异有显著性意义（ P＜0.05）。治疗后两组患者肝纤维化指标均显著下降,且观察组下降幅度优于对照组（P＜0.05）。结论：六味五灵片联合LdT能够明显改善CHB肝纤维化患者的肝功能,促进HBV DNA转阴,同时还能显著降低患者的血清肝纤维化指标,提高临床疗效。     

抗乙型肝炎病毒新药特必夫定

特必夫定（telbivudine）是一种选择性抗乙型肝炎病毒新药，可快速且显著地抑制乙型肝炎病毒（HBV）复制，降低并发肝硬化甚至肝癌的几率。临床试验研究表明特必夫定能够有效且选择性地抑制人肝肿瘤细胞株中的HBV病毒，而不会对体内其他正常细胞产生不良影响，具有优于其他抗病毒药物的特性。在迄今为止的试验中，特必夫定显示了良好的安全性及有效性，且较拉米夫定有更强的抗病毒活性。现主要对特必夫定的药理作用机制、药动学、临床应用进展及前景等进行综述。     

Treatment of chronic hepatitis B

In the last years, marked progress has been made in the treatment of chronic hepatitis B. The efficacy of lamivudine, the first nucleoside analogue available, is limited by the high incidence of resistance. Adefovir, which was recently approved has a comparable efficacy with a very low frequency of resistance. However, adefovir needs to be indefinitely administered as withdrawal of therapy is generally associated with reactivation and sustained response is uncommon. Recent large randomized controlled trials showed that PEG IFNs induce relatively high sustained response rates both in HBeAg positive and HBeAg negative chronic hepatitis B. So far, the combination of PEG IFN with lamivudine, used simultaneously, is disappointing in terms of short-term efficacy. However, long-term efficacy needs to be assessed and different schedules of combination (for example sequential) need to be evaluated. A number of nucleoside analogues, with favourable toxicity profiles and a promise of increased effectiveness against HBV, are at various stages of clinical development. Results of phase III trials of entecavir and emtricitabine confirmed their efficacy. However, while entecavir is associated with a low incidences of resistance, emtricitabine is associated with a relatively high incidence of resistance which limits its use as a monotherapy. The efficacy and safety of new and more potent drugs like telbivudine and clevudine need to be confirmed. The future of chronic hepatitis B therapy seems to be in the combination of different drugs. Ideally, the optimal drugs to combine would meet the following criteria: they should have different sites of action on HBV DNA replication, a potent antiviral effect, an excellent safety profile and they should induce a sustained response with a limited duration of therapy. Indeed, the concept of combination therapy has been recently developed in order to increase efficacy and to decrease the occurrence of viral resistance. However, so far few combinations have been evaluated. No combination therapy demonstrated a benefit as compared with monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are important challenges to improve the efficacy of treatment and decrease in the future the global burden related to chronic hepatitis B.     

Current treatments for patients with HBeAg‐positive chronic hepatitis B virus infection: a comparison focusing on HBeAg seroconversion

HBeAg seroconversion, in association with undetectable levels of hepatitis B virus DNA as determined by polymerase chain reaction, is an important goal in the treatment of patients with HBeAg‐positive chronic hepatitis B (CHB). Achievement of sustained HBeAg seroconversion at an early age (<40 years) is associated with a reduced incidence of hepatic complications, increased rates of HBsAg loss and seroconversion and improved survival rates, whether the seroconversion is spontaneous or treatment induced. Patients with HBeAg‐positive CHB who achieve sustained HBeAg seroconversion and complete 6–12 months of consolidation therapy are eligible for stopping therapy. In randomized clinical studies involving patients with HBeAg‐positive CHB, treatment with pegylated interferon (PegIFN)‐ α is associated with higher and more durable HBeAg seroconversion rates than are lamivudine and adefovir. More recently, newer generation oral nucleos(t)ide analogs (NAs) have become available. These include entecavir, telbivudine and tenofovir, and they demonstrate superior antiviral potency and efficacy. This review examines the importance of HBeAg seroconversion as an end point for therapy in the treatment of patients with HBeAg‐positive CHB, and examines the rates and durability of HBeAg seroconversion with PegIFN and oral NA therapy. The mechanisms for enhanced HBeAg seroconversion rates with new‐generation NAs are also discussed.