Combined antiviral options for the treatment of chronic hepatitis C

In the absence of antiviral treatment, chronic hepatitis C virus (HCV) infection is a liver disease characterized by the development of necroinflammatory changes and progressive liver fibrosis, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). The approval of ribavirin in combination therapy regimens with interferon (IFN) dramatically improved therapy. Another advance was the introduction of pegylated IFNs, which allow a once-weekly subcutaneous administration and show more favorable pharmacokinetics and greater efficacy. Two forms are available: pegylated IFN alpha-2b (12 kDa) (1.5 microg/kg) and pegylated IFN alpha-2a (40 kDa) (fixed dosage of 180 microg). Ribavirin is administered orally, at doses > or =10.6 mg/kg, resulting in higher sustained virological responses (SVR) than IFN monotherapy. The highest SVR rates are attained with pegylated IFNs in combination with ribavirin. Factors associated with treatment outcome include HCV genotype, viral load, body weight, age, cirrhosis or bridging fibrosis, coinfection with HIV or hepatitis B virus, and treatment adherence and tolerance. Currently, the main therapeutic challenges ahead are: (a) the dosage optimization of pegylated IFNs and ribavirin according to the patients' characteristics; and (b) to evaluate the efficacy and safety of this combination therapy for difficult-to-treat patients, such as nonresponders, cirrhotics, transplant recipients, renal disease patients or those coinfected with HIV.     

The combination of interferon alpha-2b and n-butyl deoxynojirimycin has a greater than additive antiviral effect upon production of infectious bovine viral diarrhea virus (BVDV) in vitro: implications for hepatitis C virus (HCV) therapy

Interferon alpha-2b (IFN) alone or in combination with Ribavirin is approved in the United States for the treatment of chronic hepatitis C virus (HCV) infection. We have previously reported that the glucosidase inhibitor, n-butyl deoxynojirimycin (nB-DNJ) inhibits the production of infectious bovine diarrhea virus (BVDV) (Proc. Natl. Acad. Sci. 96 (1999) 11878). Since BVDV has been used as a model for HCV and grows productively in tissue culture, and IFN and glucosidase inhibitors are thought to act at different steps in the virus life cycle, it was of interest to determine the antiviral impact of combining nB-DNJ with IFN. Using plaque reduction and single-step growth analyses of the cytopathic BVDV strain NADL, data are presented that shows human IFN inhibited BVDV production in a dose dependent manner, with 3 IU/ml inhibiting 50% of the yield of virus (IC50) when added within 1 h post infection. Under the same conditions, the glucosidase inhibitors nB-DNJ and castanospermine (CST) also prevented BVDV production in a dose dependent manner with IC50s of 226 microM and 47 microM, respectively. In combination with 138 microM nB-DNJ the apparent IC50 for IFN was 0.056 IU/ml. This 54-fold increase in IFN potency suggests that nB-DNJ can synergize with IFN. Two additional independent analyses were performed to measure combination effects which demonstrated that the combined antiviral effect of nB-DNJ and IFN were greater than would be expected for a simple additivity. These data are consistent with an interpretation that glucosidase inhibitors and IFN have a synergistic antiviral effect in tissue culture. The relevance of these finding to treatment of HCV infection is discussed.     

Assessment of adverse reactions and pharmacokinetics of ribavirin in combination with interferon alpha-2b in patients with chronic hepatitis C

Ribavirin has recently been demonstrated to be efficacious in combination with interferon (IFN) alpha-2b for the treatment of relapsed hepatitis C infections. The aim of this study was to evaluate the relationship between the pharmacokinetics and adverse reactions of ribavirin when ribavirin plus IFN alpha-2b were administered to patients affected with chronic hepatitis C. Nineteen patients received intramuscular IFN alpha-2b at a dose of 6 or 10 million units and oral ribavirin at 600 mg or 800 mg daily for 24 weeks. The pharmacokinetic profiles of ribavirin were assessed by the measurement of plasma concentrations. Twelve patients were continuously given both ribavirin and IFN alpha-2b, whereas in 7 patients the therapy was discontinued due to severe adverse drug reactions such as skin eruption, anemia and depression. There were no significant differences in ribavirin dose, Hb, ALT and AST values between the continued and the discontinued therapy groups. In contrast, the pretreatment platelet level and patient age of the discontinued therapy group were significantly different to the continued group. The trough plasma concentration of ribavirin in the discontinued therapy group was significantly higher than that in the continued group at week 1. These results suggest that the monitoring of plasma ribavirin concentrations may be valid for predicting the early phase of adverse drug reactions, thereby providing useful information for the adjustment of the ribavirin dosing for each patient.     

丙型肝炎抗病毒药物治疗的现状与研究进展

干扰素(IFN)是丙型肝炎抗病毒治疗中一种非常重要的药物,单药治疗以及与利巴韦林联合用药都表现出较好的抗病毒疗效。IFN与利巴韦林联合用药已成为丙型肝炎的标准治疗方案,对丙型肝炎病毒(HCV)基因型和应答指标的研究有助于个体化给药。本文对聚乙二醇IFN、人血清清蛋白融合IFN以及特异性靶向HCV治疗药物的研究进展做一综述。     

丙型肝炎病毒NS5B RNA聚合酶抑制剂研究进展

丙型肝炎病毒（hepatitis C virus,HCV）是引起慢性肝炎并进而发展为肝硬化和肝细胞癌的主要病原体之一。目前,临床上采用α-干扰素（IFN-α）和利巴韦林（RBV）联合用药治疗丙型肝炎,但有效率仅为40%~50%。寻找HCV特定靶向抗病毒治疗药物是抗HCV研究的重要方向,相应靶点包括NS2和NS3蛋白酶,NS4A、NS4B、NS5A和NS5B,其中以NS5B RNA依赖性RNA聚合酶（NS5B RdRp）为靶标的抗HCV药物研究近年来颇受关注。本文在介绍NS5B及NS5B RdRp结构和功能的基础上,总结归纳以NS5B RdRp为靶点的HCV特定靶向抗病毒治疗药物研究的主要策略,以及近年来相关NS5BRdRp抑制剂的研究进展。     

The role of ribavirin in the combination therapy of hepatitis C virus infection

Ribavirin is a very broad-spectrum anti-viral agent used clinically to treat infections by Lassa fever virus, respiratory syncytial virus (RSV) and, in combination with Interferon-alpha (IFN-alpha), hepatitis C virus (HCV). Although it was originally synthesized over 30 years ago, the precise mechanisms of its therapeutic activities are still not fully understood. Ribavirin was shown to possess both direct and indirect action mechanisms against several DNA and RNA viruses. These include direct inhibition of viral RNA-dependent RNA polymerases, inhibition of the host inosine monophosphate dehydrogenase, modulation of the host immune response and inhibition of viral capping enzymes. More recently, ribavirin was demonstrated to be able to act as an RNA virus mutagen, increasing mutations in the RNA virus genome and reducing their infectivity. Still the real challenge is to identify which of its biological properties is responsible for the observed clinical efficacy on specific infections. Under this aspect, renewed interest results from its synergistic enhancement of interferon-alpha (IFN-alpha) therapy, which could open the way to develop more powerful anti-HCV compounds. This work purpose is to provide a broad overview of all the recognized ribavirin action mechanisms against HCV, which can possibly also explain its synergistic behavior with IFN-alpha. An overview on the corresponding HCV treatment clinical observations is also provided in the second part of this work.     

Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase

The global prevalence of hepatitis C virus (HCV) infection and the serious consequences associated with the chronic state of the disease have become a worldwide health problem. A combination therapy comprising Interferon-alpha and Ribavirin represents the current standard treatment for chronic HCV infection, although it has demonstrated limited success and causes serious side effects. Promising alternative approaches toward the control of HCV infection include the development of small molecule inhibitors of viral enzymes interfering with the essential steps in the life cycle of the virus. In this review we will focus on inhibitors of the HCV-encoded NS5B RNA-dependent RNA polymerase (NS5B RdRp) which is essential for viral replication and has been recognized as a prime target for therapeutic intervention.     

Management of chronic hepatitis C in patients co-infected with HIV: focus on safety considerations.

Hepatitis C virus (HCV) infection is a significant public health problem and one of the most important causes of chronic liver disease worldwide. Co-infection with HCV and HIV occurs frequently, mainly because both viruses share the same transmission routes. In recent years, the life expectancy of patients with HIV disease has been increased due to the introduction of highly active antiretroviral therapy (HAART). Furthermore, several studies have established that HIV infection is associated with a major progression of the HCV-related liver disease. Thus, end-stage liver disease has become a leading cause of morbidity and mortality in this population, emphasising the importance of treatment of chronic hepatitis C in HIV-infected persons.The biological and histological benefit of interferon-alpha (IFNalpha) therapy in patients co-infected with HCV/HIV is not significantly different from that noted in similar patients without HIV when the HIV infection is adequately controlled. However, patients with low CD4+ cell counts tend to respond poorly to anti-HCV therapy.Given the relatively low sustained virological response rate to IFN alone, the use of IFNalpha monotherapy has been largely abandoned in favour of combination therapy with ribavirin. In the last 2 years, IFN plus ribavirin combination therapy has been the standard care for the treatment of chronic hepatitis C. Although information on the safety and efficacy of this dual therapy in HCV/HIV co-infected patients is scarce, recent trials have reported that the combination of IFN plus ribavirin is well tolerated and feasible in patients co-infected with HCV/HIV. However, the rates of sustained virological response seem to be worse than those observed in patients without HIV infection. New IFN formulations (e.g. pegylated interferon) plus ribavirin appear to be way of the future for the treatment of chronic hepatitis C in patients both with and without HIV co-infection.     

Peginterferon alpha-2b: a new approach to improving response in hepatitis C patients

Chronic hepatitis C infection affects approximately four million Americans. Over the last decade, Type 1 interferons (IFNs) have been the mainstay of therapy for suitable patients. Recently, the combination of IFN plus ribavirin, with enhanced response rates, has replaced IFN monotherapy for treatment of these patients. The addition of a polyethylene glycol (peg) moiety to IFN alpha-2b has provided a drug with reduced clearance whilst retaining biological and antiviral activity. This formulation allows once-weekly dosing and enhances sustained response rates, without significantly changing the safety and tolerability of IFN. Clinical trials indicate a doubling of sustained virological response rates for regimens utilising pegIFN alpha-2b, compared with standard IFN-alpha 2b. The combination of pegIFN alpha-2b and ribavirin further increases the sustained virological response rates to > 50% for suitable patients. Future pegIFN alpha-2b studies will need to examine drug profiles in patients with co-morbid conditions (e.g., renal impairment, liver transplantation), as well as safety and efficacy issues in different ethnic groups. Further clinical trials are also required to determine the benefits of pegIFN alpha-2b in previous non-responders or relapse patients and as maintenance therapy to prevent disease progression. Finally, careful cost effectiveness analyses will need to be performed.     

Digestive disease week 2001. American association for the study of liver diseases. 19-23 May 2001, Atlanta, GA, USA

All aspects of hepatology were represented at this year's meeting of the American Association for the Study of Liver Diseases (AASLD), although the meeting was dominated by a proliferation of information in the arena of viral hepatitis. In an international multicenter study of over 1000 treatment-naive patients with hepatitis C virus (HCV) infection, sustained virological response was found in 56% of patients who received PEGylated interferon (IFN) alpha-2a (Pegasys; F Hoffmann-La Roche) in combination with ribavirin (Virazole; ICN Pharmaceuticals), versus 45% in patients who received IFN alpha-2b and ribavirin therapy, and 30% of patients who received PEG. This is a significant improvement on currently licensed therapy and will define practice patterns for the next decade. In other areas, novel therapies such as silymarin for cholestatic liver disease, L-dT (Novirio Pharmaceuticals Inc), herbal therapy, combination therapies including amantadine and mycophenolate mofetil (Roche Holding) for viral hepatitis, and long-acting octreotide (Sandostatin LAR Depot; Novartis) for portal hypertension, were presented. This review represents the best of AASLD at DDW 2001.     

利巴韦林注射液体内外抗流感病毒作用研究

利巴韦林具有广谱抗病毒活性, 对多种DNA或RNA病毒体内外都有抑制作用。本文对利巴韦林注射液的体内外抗流感病毒活性进行研究, 体外实验采用细胞病变 (CPE) 法研究了利巴韦林注射液对流感病毒甲乙型的活性, 体内实验采用小鼠模型研究了利巴韦林注射液对流感病毒A/FM/1/47 (H1N1) 鼠肺适应株感染小鼠的保护作用。结果显示, 在体外实验中, 利巴韦林注射液对所检测的7种病毒株均有显著的抑制活性; 在体内实验中, 利巴韦林注射液可以显著提高感染小鼠的存活率和平均生活日, 显著改善感染小鼠的肺病变和肺指数。     

Ribavirin and inosiplex: a review of their present status in viral diseases

A considerable amount of information has accumulated during the past 10 years in the search for antiviral agents. Ribavirin and inosiplex are 2 interesting developments to come out of this search. Ribavirin, a synthetic nucleoside, has an unusually wide spectrum of antiviral activity, especially when tested in vitro. A large number of RNA and DNA viruses are sensitive, especially herpes viruses, poxvirus, influenza, parainfluenza, reovirus, togavirus, and RNA tumour viruses. The in vivo antiviral spectrum of activity is much narrower, with activity against herpes virus, influenza, parainfluenza, measles and adenoviruses. However, controlled clinical trials have not been uniformly successful in treating influenza, hepatitis, herpes simplex and herpes zoster. Inosiplex has been shown to have antiviral activity in vivo against influenza, herpes simplex, rhinovirus and vaccinia virus infections. However, antiviral activity has not been consistently demonstrated, and this observation led to further studies which revealed its immunomodulating effects. The accumulated evidence has indicated that inosiplex is more a prohost agent rather than an antiviral drug. Immune functions which are depressed during viral infection can be restored to normal by inosiplex therapy. At present, neither ribavirin nor inosiplex alone has been shown to be uniformly successful in the treatment of human viral diseases. Nevertheless, their potential place in chemotherapy should not be neglected, although further data are needed to determine what this place will be. Whether combining them with other antiviral agents such as interferon, acyclovir, Ara-A, and so on, would produce a potentiation of action and improved antiviral chemotherapy, will be an interesting area for further study.     

The exploding field of the HCV polymerase non-nucleoside inhibitors: summary of a first generation compounds

The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) is strictly essential for viral replication and it has been used as viral target for anti-HCV drug development. All small molecules which have been identified to be selective non-nucleoside inhibitors (NNI) of the HCV RdRp to date are reported.     

Introducing treat-to-target strategies of autoimmune extrahepatic manifestations of chronic hepatitis C virus infection

Introduction: The hepatitis C virus (HCV) is recognized as one of the hepatic viruses most often associated with extrahepatic manifestations (EHMs). It is currently accepted that cryoglobulinemic vasculitis (CV) is the key autoimmune extrahepatic disease associated with HCV infection. Therapeutic approaches have mainly been based on the use of old antiviral interferon (IFN)-based regimens and immunosuppressive therapies, often with an inadequate balance between therapeutic benefits and excess side effects.

Areas covered: Therapeutic management of HCV patients with EHMs, including both non-autoimmune (cardiovascular, hematological, general features) and autoimmune complications (organ-specific and systemic autoimmune diseases). Therapies included antiviral (IFN, ribavirin, direct-acting antivirals – DAAs-) and non-antiviral (immunosuppressive agents, rituximab, plasma exchanges) options. The review analyses the current evidence for proposing a treat-to-target (T2T) approach for HCV-related autoimmune EHMs based on an organ-by-organ strategy.

Expert commentary: Eradication of HCV must be considered the key T2T in the therapeutic approach to HCV-related EHMs, as there has been a disruptive change due to the appearance of direct-acting antivirals (DAAs) as game-changers in HCV therapy, with an efficacy reaching nearly 100%. In this scenario, the central role played until now by IFN and ribavirin is not currently supported and they will not be used in the future.     

Cost effectiveness of peginterferon alpha-2a plus ribavirin versus interferon alpha-2b plus ribavirin as initial therapy for treatment-naive chronic hepatitis C

INTRODUCTION: In adults with previously untreated chronic hepatitis C (CHC), the combination of peginterferon alpha-2a plus ribavirin produces a higher rate of sustained virological response (SVR) than interferon alpha-2b plus ribavirin, but it is still unproven whether this increase is cost effective. The objective of this study was to determine if the gain in SVR with peginterferon alpha-2a plus ribavirin is worth the incremental cost. METHODS: We constructed a Markov model of disease progression in which cohorts of patients received peginterferon alpha-2a plus ribavirin or interferon alpha-2b plus ribavirin for 48 weeks (hepatitis C virus [HCV] genotype 1 and non-1 patients with fibrosis) or 24 weeks (genotype non-1 patients without fibrosis), and were followed for their expected lifetimes. The reference patient was a 45-year-old male with CHC without cirrhosis. The SVRs with peginterferon alpha-2a plus ribavirin and interferon alpha-2b plus ribavirin used to populate the model were 46% and 36% for patients infected with HCV genotype 1 and 76% and 61% for patients infected with HCV non-1 genotypes, respectively. QOL and costs for each health state were based on literature estimates and on Italian treatment patterns. Costs were in 2002 euros and benefits were discounted at 3%. Sensitivity analyses on key clinical and economic parameters were performed. The analysis was reported from the perspective of the Italian National Health Service. RESULTS: In patients infected with HCV genotype 1, peginterferon alpha-2a plus ribavirin increased life-years (LYs) by 0.78 years and QALYs by 0.67 years, compared with interferon alpha-2b and ribavirin. The incremental cost per LY and QALY gained was euro9433 and euro10 894, respectively. In patients infected with HCV non-1 genotypes, peginterferon alpha-2a plus ribavirin increased LYs by 1.17 and QALY by 1.01 years, compared with interferon alpha-2b plus ribavirin. The incremental cost per LY and QALY gained was euro3261 and euro3766, respectively. Using genotype distribution estimates, the weighted average ICER for all genotypes was euro6811 per LY gained and euro7865 per QALY gained. CONCLUSION: Our model suggests that peginterferon alpha-2a plus ribavirin is cost effective compared with conventional interferon alpha-2b plus ribavirin for treatment of naive adults with CHC, regardless of HCV genotype, under a wide range of assumptions regarding treatment effectiveness and costs.