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.     

Clevudine for the treatment of chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is a major health problem that is responsible for < or = 1 million deaths and 500,000 cases of hepatocellular carcinoma worldwide each year. Drugs that are currently approved by the FDA for the treatment of chronic HBV consist of two groups: the immunomodulators, such as conventional IFN-alpha and pegylated IFN-alpha2a; and nucleoside/nucleotide analogues, such as lamivudine, adefovir dipivoxil and entecavir. However, due to the limitations of these agents, newer agents with improved efficacy are currently being developed. One nucleoside/nucleotide analogue that is drawing a wide range of interest is clevudine, which is an analogue of the unnatural beta-L configuration. In the woodchuck hepatitis virus (WHV), clevudine 10 mg/kg has proven to be effective in suppressing viral replication with < or = 9 log10 decreases in WHV. At this dose, a significant reduction of intrahepatic WHV RNA and covalently closed circular WHV DNA levels can also be observed. Treatment with clevudine 10 mg/kg can confer additional antiviral benefit in the form of a more sustained reduction in WHV replication, serum woodchuck hepatitis surface antigen and intrahepatic woodchuck hepatitis core antigen expression following the withdrawal of clevudine. In humans, clevudine 10, 50, 100 or 200 mg/day for 28 days can reduce the median HBV DNA by -2.5, -2.7, -3 and -2.6 log10, respectively. More importantly, this suppression of antiviral activity is maintained at 12 and 24 weeks post treatment. Based on the early results of clevudine, more large-scale human studies with clevudine monotherapy or combination therapy is eagerly awaited.     

Clevudine for the treatment of chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is a major health problem that is responsible for ≤ 1 million deaths and 500,000 cases of hepatocellular carcinoma worldwide each year. Drugs that are currently approved by the FDA for the treatment of chronic HBV consist of two groups: the immunomodulators, such as conventional IFN-α and pegylated IFN-α2a; and nucleoside/nucleotide analogues, such as lamivudine, adefovir dipivoxil and entecavir. However, due to the limitations of these agents, newer agents with improved efficacy are currently being developed. One nucleoside/nucleotide analogue that is drawing a wide range of interest is clevudine, which is an analogue of the unnatural β-L configuration. In the woodchuck hepatitis virus (WHV), clevudine 10 mg/kg has proven to be effective in suppressing viral replication with ≤ 9 log₁₀ decreases in WHV. At this dose, a significant reduction of intrahepatic WHV RNA and covalently closed circular WHV DNA levels can also be observed. Treatment with clevudine 10 mg/kg can confer additional antiviral benefit in the form of a more sustained reduction in WHV replication, serum woodchuck hepatitis surface antigen and intrahepatic woodchuck hepatitis core antigen expression following the withdrawal of clevudine. In humans, clevudine 10, 50, 100 or 200 mg/day for 28 days can reduce the median HBV DNA by -2.5, -2.7, -3 and -2.6 log₁₀, respectively. More importantly, this suppression of antiviral activity is maintained at 12 and 24 weeks post treatment. Based on the early results of clevudine, more large-scale human studies with clevudine monotherapy or combination therapy is eagerly awaited.     

Recent developments in the treatment of chronic hepatitis B virus infection

Infectious diseases are the major cause of death worldwide; in developing countries such diseases are responsible for nearly half the burden of premature death and disability. Therefore, the need for the development of new vaccine strategies aimed at preventing or limiting disease is extremely urgent. Important successes have been achieved against some infectious diseases that were once endemic or, even, epidemic (e.g., polio, smallpox, diptheria). Advances in our knowledge of the pathogenesis and immune correlates of protections are needed to develop novel vaccinal approaches to diseases such as hepatitis C, AIDS and malaria. In this review we will analyse the biological problems associated with the prevention of development and/or improvement of vaccine strategies for infectious diseases, focusing on the difficulties facing the creation of new effective vaccines for HIV infection and malaria.     

Evolving therapies for the treatment of chronic hepatitis B virus infection

Despite the availability of prophylactic vaccines lamivudine and IFN-alpha, chronic hepatitis B remains an enormous global health problem. Several promising nucleosides/nucleotides are undergoing clinical trials, including adefovir dipivoxil, the latter of which is active against lamivudine-resistant hepatitis B virus (HBV). In addition to nucleosides/nucleotides, it will be important to develop new agents with different modes of action. Novel small molecule inhibitors, as well as gene therapy approaches, have produced encouraging results in vitro and in animal models. Additional immunomodulatory therapies, including thymosin-alpha 1, IL-12 and several therapeutic vaccines, are also being explored. Combination therapy with multiple nucleosides/nucleotides and other agents will play an important role in the treatment of hepatitis and may help achieve complete viral suppression, host-mediated elimination of infected cells and lasting immunity.     

Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection

Introduction: In April 2017 tenofovir alafenamide (TAF) was added to the list of first-line therapies recommended for chronic hepatitis B (CHB). TAF has pharmacology similar to tenofovir disoproxil fumarate (TDF) with higher cell delivery to the hepatocytes but less systemic exposure.

Areas covered: We review here studies leading to TAF’s approval and comparing it to TDF. In two major clinical trials, TAF was non-inferior to TDF in achieving HBV DNA levels below 29 IU/ml. TAF-treated patients had significantly smaller decreases in bone mineral density (BMD) at the hip and spine in both HBeAg-positive and HBeAg-negative patients, and smaller mean increases in serum creatinine, although the difference was only statistically significant in HBeAg-positive patients. Patients treated with TDF for 96 weeks and then switched to TAF had improvements in renal and BMD measures only 24 weeks after switching.

Expert commentary: With clear evidence from major studies showing that TAF is safe, tolerable, and non-inferior to TDF, its recommendation as a first-line therapy is appropriate. Longer term follow up will be required to determine if the differences in adverse bone and kidney effects seen with TAF in comparison to TDF will be clinically relevant.     

双环醇治疗慢性乙型肝炎25例

目的:研究双环醇治疗慢性乙型肝炎的疗效。方法:慢性乙型肝炎46例,随机分成两组:治疗组25例,在一般保肝治疗(水飞蓟宾)基础上加用双环醇25mg,tid,疗程6个月;对照组21例,使用一般保肝(水飞蓟宾)治疗,疗程6个月。两组均停药后继续观察3个月。结果:治疗组在HBV-DNA阴转、HBeAg阴转、HBeAg/HBeAb转换率上均较对照组高,差异有显著性(P<0.05)。结论:双环醇具有明显的降酶和一定的抗病毒疗效,其抗病毒作用随时间延长而增高。     

恩替卡韦联合胸腺肽肠溶片治疗慢性乙肝的疗效及安全性评价

目的探讨恩替卡韦联合胸腺肽肠溶片治疗慢性乙肝的疗效。方法 90例慢性乙肝患者,分成观察组和对照组。对照组给予恩替卡韦治疗,观察组给予恩替卡韦联合胸腺肽肠溶片治疗。结果观察组总有效率82.22%高于对照组62.22%,差异有统计学意义（P〈0.05）。结论恩替卡韦联合胸腺肽肠溶片治疗慢性乙肝疗效较佳,具有良好的安全性。     

Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon

BACKGROUND: Pegylated interferon-alpha has been shown to be more efficacious than conventional interferon in treating chronic hepatitis C. The use of peginterferon in chronic hepatitis B virus infection with positive hepatitis B e antigen has also been tested in a number of trials since 2003. AIM: To systematically summarize and compare the results of these studies. METHODS: Four studies were identified from PubMed, Medline and reference lists. Data from the trials were extracted and analysed. Where appropriate, combined odds ratio of different trials was calculated. Safety data including serious adverse events and emergence of drug-resistant mutants were recorded. RESULTS: Three of the four trials contained predominantly Asian patients. Peginterferon is found to be superior to lamivudine monotherapy and induced sustained biochemical and virological responses in about one-thirds of patients after 12 months of therapy. Coadministration of lamivudine did not result in improvement in viral suppression. Peginterferon appears to reduce the emergence of YMDD mutation in the combination treatment groups. It was well tolerated with serious adverse events reported in <10% of patients in most trials. CONCLUSIONS: Peginterferon-alpha treatment of at least 6 months should be considered as one of the first-line therapeutic options for hepatitis B virus infection.     

苦参素联合胸腺肽治疗慢性乙型肝炎34例

目的:探讨苦参素联合胸腺肽治疗慢性乙型肝炎的疗效。方法:选择66例慢性乙型肝炎患者,随机分为2组,治疗组34例,对照组32例。治疗组采用肌内注射苦参素600mg·d~(-1),qd,1个月后改为qod,与胸腺肽50mg·d~(-1)加入10％葡萄糖250mL中静滴联合治疗1个月后改为胸腺肽25mg肌内注射,qod。对照组采用促肝细胞生长素120mg·d~(-1)等综合治疗,2组均3个月为1个疗程,共2个疗程。结果:治疗组肝功能的复常率明显优于对照组(P<0.05),治疗组HBeAg和HBV-DNA的阴转率分别为47.1%和50.0％,而对照组则分别为28.1％和31.3％,2组比较差异有显著性(P<0.05),2组均未见明显不良反应。结论:苦参素联合胸腺肽具有改善肝功能和抑制乙肝病毒复制等功效,二者联用可治疗慢性乙型肝炎。     

Antiviral therapeutic efficacy of foscarnet in hepatitis B virus infection

Foscarnet (PFA), a viral DNA polymerase inhibitor, is a clinical agent for herpes viruses. The goal of the study was to evaluate the therapeutic efficacy of PFA in hepatitis B virus (HBV) infection. Intravenous infusion of PFA (1 g/day) for 4 weeks significantly reduced serum HBeAg (p<0.01) and HBV DNA copies (p<0.05) in 31 patients who were diagnosed with active chronic HBV infection (CHB) and had not received antiviral treatment previously. Alanine aminotransaminase (ALT), aspartate aminotransaminase (AST) and gamma glutamyl transpeptidase (gamma-GT) of the patients declined (p<0.001, 0.001 and 0.01, respectively). Kidney function (blood creatinine and urea nitrogen) remained unchanged. Another 21 lamivudine-resistant CHB patients with mutations at the tyrosine-methionine-aspartate-aspartate motif (YMDD) displayed a response to PFA similar to that mentioned above, with reductions in HBeAg (p<0.05), HBV DNA (p<0.01) and liver enzymes (ALT and AST, p<0.001; gamma-GT, p<0.05). Moreover, PFA reduced serum HBeAg (p<0.01), HBV DNA (P<0.05), AST (p<0.05) and ALT (p<0.02) in a cohort of 13 severe CHB patients with advanced liver damage. PFA was also evaluated in vitro and in vivo. PFA inhibited HBV DNA replication in HBV-transfected human HepG2 cells (2.2.15 cells) with reduced amount of HBV RC-DNA and DS-DNA. In the duck HBV-infected ducklings, PFA reduced viral DNA and duck HBsAg in the serum (p<0.01 for both).     

胸腺素联合乙肝疫苗对慢性乙型肝炎患者人血蛋白的影响

目的探讨胸腺素(胸腺肽)联合乙肝疫苗选择性对HBV-DNA阴性、HBeAg阴性、HBsAg阳性、ALT<100U*L-1的无黄疸慢性乙肝患者的免疫调节治疗.方法70例患者随机分为治疗组(36例)与对照组(34例),对照组采用一般常规治疗,治疗组在一般常规治疗的基础上加用胸腺肽联合乙肝疫苗,胸腺肽每次40mg,im,隔日1次,乙肝疫苗每次10μg,每月2次;2组疗程均为3个月.结果治疗组人血白蛋白及球蛋白有不同程度的改善,治疗组白蛋白的改善率明显高于对照组(P<0.05),未发现明显不良反应.结论此疗法在免疫调节抗病毒的同时,能改善肝细胞的蛋白代谢.     

阿德福韦酯联合胸腺肽α1治疗慢性乙型肝炎临床观察

目的：观察阿德福韦酯联合胸腺肽α1治疗慢性乙型肝炎的疗效。方法：将入选病例随机分为阿德福韦酯组和联合治疗组，阿德福韦酯组给予阿德福韦酯10mg&#183;d^-1，连续用48周；联合治疗组在阿德福韦酯组治疗的基础上加用胸腺肽α1 1．6mg，皮下注射，每周2次，连用48周。观察2组患者的生化应答率，病毒应答率，HBeAg阴转率。结果：阿德福韦酯组24周时生化应答率为56％，病毒应答率44％，HBeAg转阴率为13％；48周时生化应答率为72％，病毒应答率59％，HBeAg阴转率为41％。联合治疗组24周时生化应答率为87％，病毒应答率73％，HBeAg转阴率为40％；治疗48周时生化应答率为93％，病毒应答率87％，HBeAg阴转率为70％。结论：阿德福韦酯与胸腺肽α1联合治疗慢性乙型肝炎具有较好疗效。     

Safety of telaprevir for chronic hepatitis C virus infection: a meta-analysis of randomized controlled trials

Background: Previous studies have reported telaprevir is effective for chronic hepatitis C virus infection, but the safety of a telaprevir-based regimen remains uncertain. Objective: A meta-analysis was performed to assess the safety of the addition of telaprevir to a standard regimen of pegylated interferon (peginterferon) plus ribavirin (combination telaprevir with peginterferon plus ribavirin, the TPR group) compared with the standard regimen group (peginterferon plus ribavirin, the PR group). Methods and Results: Seven randomized controlled trials involving a total of 2808 patients were included in the meta-analysis. The addition of telaprevir to the standard regimen was associated with a significantly increased risk of serious adverse events compared with the standard PR group (relative risk [RR]?=?1.56; 95% confidence interval [CI] 1.21, 2.03; p?=?0.0007; I2?=?0%). Telaprevir was also associated with increased risk of treatment discontinuation (RR?=?2.10; 95% CI 1.56, 2.83; p?相似文献   

Novel treatment options for hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection affects between 350 and 400 million people globally. Interferon-alpha, lamivudine and adefovir (Hepsera) are approved for the treatment of chronic hepatitis B; however, the use of interferon-alpha is limited. Lamivudine and adefovir have excellent antiviral activity and oral bioavailability, although viral rebound after cessation of therapy and development of resistance after long-term therapy with lamivudine are major clinical limitations. Adefovir has proven to be effective against lamivudine-resistant strains in vitro and in vivo. The various steps of HBV replication provide opportunities for new antiviral drugs to interact with the virus. Recent developments, including new antivirals that interfere with viral DNA replication, hold promise for the future. Sustained reduction in viral load and improved treatment of chronic HBV infection could, in future, be achieved by the development of new drugs with different mechanisms of action and resistance profiles, and with combination therapy involving two or more nucleosides with or without immunomodulators.     

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

BACKGROUND: 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. OBJECTIVE. To review the available data for entecavir regarding its pharmacology, pharmacokinetics, safety, efficacy, and clinical use. METHODS. 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. RESULTS. 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-na?ve patients but may develop in those who already possess lamivudine resistance mutations. CONCLUSION. 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 na?ve, 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-na?ve, lamivudine-refractory patients are needed to determine entecavir's optimal treatment duration, long-term safety, and durability of response, including rate of resistance.     

Therapeutic strategies for a functional cure of chronic hepatitis B virus infection

Treatment of chronic hepatitis B virus (HBV) infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc) DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus–host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection.KEY WORDS: Hepatitis B virus, cccDNA, Antiviral agents