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.     

聚乙二醇干扰素联合恩替卡韦治疗慢乙肝观察

目的 探究聚乙二醇干扰素联合恩替卡韦治疗慢性乙肝疾病的效果,以供临床参考以及研究.方法 选取2014年10月至2015年10月于本院就诊的慢性乙肝患者98例,通过动态化随机分组的方法将其分为对照组和观察组,各49例.对照组聚乙二醇干扰素治疗,观察组聚乙二醇干扰素联合恩替卡韦治疗,分析两组治疗后24周、48周相关指标的差异.结果 治疗24周、48周后,观察组相关指标均优于对照组,差异具有统计学意义(P＜0.05).结论 聚乙二醇干扰素联合恩替卡韦治疗慢性乙肝疾病效果显著,能够有效延长患者生存期限,安全性较好,具有较高临床价值,可推广应用.     

Pegylated IFNs for chronic hepatitis C: an update

For over a decade, IFN-α₂ has been the standard treatment for chronic hepatitis C. However, the drug’s rapid clearance and short half-life have led to low rates of sustained virological response. Pegylation is a well-established method of modifying the pharmacological properties of IFNs, causing significant improvements in pharmacokinetics, which in turn lead to improved efficacy. Two pegylated forms of IFN-α₂ have been developed: PEG-IFN-α_2b and PEG-IFN-α_2a, and their efficacy has been established in randomised, -controlled trials. However, the two differ significantly in structure, invitro activity and pharmacological properties, and this may translate into -differences in clinical efficacy. Comparative trials have been initiated that will provide insight into relative importance of pharmacokinetics, bioactivity and dosing regimen.     

Pegylated IFNs for chronic hepatitis C: an update

For over a decade, IFN-alpha(2) has been the standard treatment for chronic hepatitis C. However, the drug's rapid clearance and short half-life have led to low rates of sustained virological response. Pegylation is a well-established method of modifying the pharmacological properties of IFNs, causing significant improvements in pharmacokinetics, which in turn lead to improved efficacy. Two pegylated forms of IFN-alpha(2) have been developed: PEG-IFN-alpha(2b) and PEG-IFN-alpha(2a), and their efficacy has been established in randomised, controlled trials. However, the two differ significantly in structure, in vitro activity and pharmacological properties, and this may translate into -differences in clinical efficacy. Comparative trials have been initiated that will provide insight into relative importance of pharmacokinetics, bioactivity and dosing regimen.     

Pegylated interferon with ribavirin therapy for chronic infection with the hepatitis C virus

Chronic infection with the hepatitis C virus is common. In the past, therapy involved a combination of thrice-weekly interferon (IFN) injections combined with oral ribavirin. This therapy was expensive, poorly tolerated and poorly effective, only curing approximately 40% of treated patients. Long-acting IFNs have recently been developed by linking IFN to polyethylene glycol and these 'pegylated' IFNs are now the standard of care for patients with chronic hepatitis C (CHC). Two pegylated (PEG) IFNs are available; 40 kDa PEG-IFNalpha(2a) (Pegasys, Hoffmann-La Roche) and the 12 kDa PEG-IFN-alpha(2b) (Peg-Intron, Schering-Plough). They have different physicochemical, pharmacokinetic and pharmacodynamic properties. The 40 kDa PEG-IFN-alpha(2a) is dispensed as a solution and used at a fixed dose whereas the 12 kDa PEG-IFN-alpha(2b) is a dry powder, which is reconstituted prior to administration, and the dose is dependent upon body weight. Both PEG-IFNs are given by a once-weekly injection and as monotherapy, they are more effective than standard IFN-alpha. The 40 kDa PEGIFN-alpha(2a) cures 36 - 39% of patients and the 12 kDa pegylated-IFN-alpha(2b) cures 23 - 25%. When combined with ribavirin, the two PEG-IFNs have acceptable safety profiles and cure > 50% of treated patients (56 and 54% for the 40 kDa PEG-IFN-alpha(2a) and 12 kDa PEG-IFN-alpha(2b), respectively). For the 40 kDa PEG-IFN-alpha(2a) it is possible to predict the outcome of therapy after 12 weeks of treatment. The new PEG-IFNs are a significant advance in the therapy of CHC infection. Their ease of administration, coupled with their improved efficacy, is likely to lead to an increase in the proportion of infected patients who wish to receive treatment.     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix, Epivir, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-alpha. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix^®, Epivir^®, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-α. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.     

Treatment of chronic hepatitis B

Infection with the hepatitis B virus has switched over the last 20 years from the classical HBeAg positive serologic pattern to a HBeAg negative form that is linked, in the Mediterranean basin, with the epidemiologic replacement of the causative wild-type of virus B with mutant variants, whereby mutations in the core-promoter and in the pre-core region prevent the secretion of HBeAg. The wild-type pattern of infection (characterized by relatively high steady level ALT, high HBV-DNA levels and clinically overt liver disease) responds relatively well to Interferon: 3 to 5 mega units daily or 10 mega units every other day for 16 weeks induce anti-HBe seroconversion, normalize the ALT and possibly also eliminate the HBsAg in some 40% of the adults with a minimal (7%) risk of relapse. However, the mutant type infection (anti-HBe positive / HBe Ag negative) is less responsive to Interferon; this has led to the search for novel nucleoside analogues which has currently culminated in the advent of Lamivudine. This competitor of cytidine is 80% bioavailable and devoid of side-effects at the oral dose of 100 mg daily; tolerance continues for therapies up to 3 years. Lamivudine therapy shares with Interferon a rapid decline of ALT accompanied by improvement of histology; at variance with Interferon there is a delayed accumulating seronconversion to anti-HBe and the switch to anti-HBs is rare. Over the long term its activity is abolished by the emergence of specific viral mutations (YMDD mutants) that rekindle the disease. The indications to Lamivudine therapy in HBeAg negative chronic hepatitis B are currently under investigation. Lamivudine is highly efficacious in preventing HBV reinfection in liver transplants.     

慢性乙型肝炎治疗的研究进展

慢性乙型病毒性肝炎是一个严重威胁人类健康的疾病,呈世界性流行。抗病毒治疗是减少肝硬化、肝癌等严重肝病发生的关键治疗,目前公认有效的抗病毒药物包括干扰素和核苷(酸)类似物。抗病毒药物治疗的持续应答率仅有20%-30%,病毒耐药率高,且停药后容易反弹或复发。那么对CHB的抗病毒治疗时机的把握、药物的选择、治疗的目标、治疗效果的评价及终点的界定就显得尤为重要。     

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.     

Telbivudine for the treatment of chronic hepatitis B

The hepatitis B virus (HBV) has a complex natural history and causes a wide spectrum of disease. Choices of therapy depend on a number of factors predictive of treatment response, clinical circumstances and stage of disease, and the likelihood and consequences of resistance to treatment. Telbivudine (beta-L-2'deoxythymidine) is a thymidine analogue that belongs to a new class of beta-L-configuration nucleoside analogues with specific activity against hepadnavirus. Phase III studies of telbivudine versus lamivudine in hepatitis B e antigen (HBeAg) and anti-HBe have been completed. In HBeAg-positive patients, HBV DNA was not detectable by polymerase chain reaction (PCR) assay in 56% of the HBeAg-positive patients receiving telbivudine after two years of treatment. In HBeAg-negative patients, at two years, HBV DNA was undetectable by PCR in 82% of HBeAg-negative patients (versus 52% of lamivudine recipients). Patients who were PCR-negative after 24 weeks were less likely to develop resistance. HBeAg seroconversion rates were also greatest in patients whose HBV DNA was undetectable at 24 weeks. These results are promising and could be used to devise a strategy to utilize combination therapy or to adjust therapy if an inadequate early viral response is observed. However, resistance is a potential shortcoming of the use of single agents for the treatment of HBV.     

肝复乐胶囊治疗慢性乙型肝炎、肝硬化临床疗效观察

目的 观察中药复方制剂肝复乐胶囊治疗慢性乙型肝炎、肝硬化患者的疗效.方法 慢性乙型肝炎、肝硬化患者102例,分为3组：对照组A（34例）采用常规保肝治疗加安慰剂胶囊,对照组B（34例）采用常规保肝治疗加肝友胶囊,治疗组（34例）采用常规保肝治疗加肝复乐胶囊,疗程均为8周.治疗前后测定血清中透明质酸（HA）、IV型胶原（CIV）、层粘连蛋白（LN）.结果 治疗组用药后HA为（87.3±36.6）μg·L-2,CIV为（5.2±0.7）μg·mL-1,LN为（373.2±49.6）μg·L-1,与对照组A比有显著性差异（P〈0.05）.肝功能复常情况治疗组ALT为（35.9±3.3）U·L-1,AST为（35.8±5.4）U·L-1,Tbil为（16.6±4.2）μmol·L-1;治疗组第8周后的主要症状改善率（100.0%）显著高于对照组A（82.4%）（P〈0.05）,略高于对照组B（91.2%）（P〉0.05）.结论 肝复乐胶囊具有减轻肝细胞炎症及抗肝纤维化的作用,可以作为慢性乙型肝炎、肝硬化综合治疗用药选择.     

Pharmacoeconomics of entecavir treatment for chronic hepatitis B

Background: Entecavir is a new antiviral agent for chronic hepatitis B virus (HBV) infection with potent HBV suppression and a low rate of viral resistance. Objective: To review published studies on the pharmacoeconomics of entecavir for treatment of chronic HBV. Methods: A literature search on Medline and Embase over the period of 1998 – 2008 was performed in April 2008 using keywords ‘entecavir’ and ‘cost’. Results/conclusion: Four studies comparing the cost effectiveness of entecavir with lamivudine and/or adefovir for treatment with chronic HBV infection using either decision tree or Markov modeling were reviewed. All four studies showed that entecavir was cost-effective in the treatment of chronic HBV with the incremental cost per QALY (quality-adjusted life-year) gained below the commonly accepted benchmark. The results are mainly due to the lower complication rates and better quality of life of patients using entecavir which can offset the higher acquisition cost of the drug. Patient characteristics, comparing agents and model assumptions were different among the four studies and they should be taken into account when applying the results to real life situations.     

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.     

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-α 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.     

阿德福韦酯治疗慢性乙型肝炎的长期疗效

目的观察应用阿德福韦酯治疗慢性乙型肝炎重度患者的长期疗效,并探讨对重型肝炎及肝炎后肝纤维化发展的阻断作用。方法将164例慢性乙型肝炎重度患者随机分为对照组82例(常规治疗组),治疗组82例(在常规治疗基础上加用阿德福韦酯。结果在治疗组中,23.2%(19/82)的患者发展至慢性重型肝炎,显著低于对照组46.3%(38/82)(P<0.01,对照组52.6%(20/38)的慢性重型肝炎患者死亡,而在治疗组,仅26.3%(5/19)的患者死亡(P<0.01.两组患者肝性脑病、感染、出血、肾病等并发症发生率差异有统计学意义(P<0.05.治疗组患者肝纤维化、肝功能指标及乙型肝炎e抗原转阴率、乙型肝炎e抗原/抗-Hbe转换率明显优于对照组,乙型肝炎病毒DNA持续保持阴性水平。结论阿德福韦酯的长期疗效是可靠、稳定的,对重型肝炎及肝炎后肝纤维化发展有阻断作用.     

Antiviral therapy for chronic hepatitis B: a review

Chronic hepatitis B virus (HBV) infection is a well-recognized risk factor for the development of hepatocellular carcinoma (HCC), which is becoming a more prevalent clinical problem, especially in HBV-endemic areas. It is estimated that 1.25 million people in the United States and more than 300 million people worldwide are chronically infected with HBV. Despite the introduction of universal vaccination against hepatitis B in over 100 countries, persistent HBV infection is still a serious problem worldwide, causing an estimated annual death rate of one million. It may take several decades until the effect of vaccination will be translated into reduced transmission and morbidity. Meanwhile, patients with persistent HBV infection require better antiviral therapeutic modalities than are currently available. It is well accepted that antiviral therapy for chronic hepatitis B is effective to improve prognosis of patients with HBV by preventing development of hepatitis state and HCC. The therapeutic endpoints for hepatitis B treatment are: 1) sustained suppression of HBV replication, as indicated by HBsAg and HBeAg loss, 2) decrease of serum HBV DNA of an undetectable level by a non-PCR method, 3) remission of disease, as shown by normalization of ALT, 4) improvement in liver histology, and 5) reduction of the acute exacerbation, cirrhosis, and HCC. In the present, the antiviral treatment of hepatitis B consists of either interferon alpha or oral lamivudine alone or in combination with existing therapy. Each major antiviral drug of interferon alpha and lamivudine has pros and cons, and effect of combination therapy of both drugs is also still limited. More powerful and safe new antiviral therapies are required to achieve final goal of these therapeutic endpoints. Management of chronic hepatitis B requires significant knowledge of approved pharmacotherapeutic agents and their limitations. Therapeutic options for managing hepatitis infection after liver transplantation (LT) are also evolving.