Antiviral activity of telaprevir and boceprevir for the treatment of hepatitis C virus infection in treatment-experienced patients

Around 50% of hepatitis C virus (HCV)-positive patients infected with genotype 1 are nonresponders to the combination of pegylated interferon (pegIFN) and ribavirin, including relapsers, and partial and null responders and, as such, are exposed to the risk of progression to cirrhosis and its complications, resulting in HCV-related morbidity and mortality. Repeat treatment using the same combination in such patients results in <5% viral eradication and there are no therapeutic prospects for patients who fail, as maintenance therapy has not proved efficacious. The triple association of direct-acting antivirals specific of HCV, and especially the first-generation protease inhibitors boceprevir and telaprevir, increases this percentage to around 65%, with variations according to the previous response to therapy of patients (85% of relapsers, 50% of partial responders and 30% of null responders). These encouraging results extend the therapeutic indications and costs of therapy during virological follow-up, and influence the rules of discontinuation. Information on the management of these new molecules also allows a larger number of patients to be cured and reduces the occurrence of viral resistance. Thus, the aim of the present review is to summarize the efficacy of the triple association of pegIFN, ribavirin and telaprevir or boceprevir in treatment-experienced patients who failed to respond to dual pegIFN and ribavirin therapy.     

Antiviral treatment of hepatitis C virus infection and factors affecting efficacy

Hepatitis C virus(HCV)infection is the leading cause of chronic liver-related diseases,including cirrhosis,liver failure,and hepatocellular carcinoma.Currently,no effective vaccine is available for HCV infection.Polyethylene glycol interferon-α(PegIFN-α)in combination with ribavirin(RBV)is the standard of care(SOC)for chronic hepatitis C.However,the efficacy of PegIFN-αand RBV combination therapy is less than 50%for genotype 1HCV,which is the dominant virus in humans.In addition,IFN and RBV have several severe side effects.Therefore,strategies to improve sustained virological response(SVR)rates have been an important focus for clinical physicians.The serine protease inhibitors telaprevir and boceprevir were approved by the United States Food and Drug Administration in 2011.The addition of HCV protease inhibitors to the SOC has significantly improved the efficacy of treatments for HCV infection.Several direct-acting antiviral drugs currently in late-stage clinical trials,both with and without pegIFN and RBV,have several advantages over the previous SOC,including higher specificity and efficacy,fewer side effects,and the ability to be administered orally,and might be optimal regimens in the future.Factors affecting the efficacy of anti-HCV treatments based on IFN-αinclude the HCV genotype,baseline viral load,virological response during treatment,host IL28B gene polymorphisms and hepatic steatosis.However,determining the effect of the above factors on DAA therapy is necessary.In this review,we summarize the development of antiHCV agents and assess the main factors affecting the efficacy of antiviral treatments.     

Antiviral strategies in hepatitis C virus infection

Resolution of the three-dimensional structures of several hepatitis C virus (HCV) proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for direct-acting antiviral (DAA) agents. Numerous families of drugs that potently inhibit the HCV lifecycle in vitro have been identified, and some of these molecules have reached early to late clinical development. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment-na?ve and treatment-experienced patients. Sustained virological response rates in the range of 6675% and 5966% (2988% if the response to the first course of therapy is taken into account) have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. A number of other DAAs are at the clinical developmental stage in combination with pegylated IFN-α and ribavirin or with other DAAs in IFN-free regimens, with or without ribavirin. They include second-wave, first-generation, and second-generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non-nucleoside inhibitorsof HCVRNA-dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host-targeted compounds, such as cyclophilin inhibitors and silibinin. The proof of concept that IFN-free regimens may lead to HCV eradication has recently been brought. However, new drugs may be associated with troublesome side effects and drugdrug interactions, and the ideal IFN-free DAA combination remains to be found.     

HBV/HCV重叠感染的抗病毒治疗

从全球范围看,乙型肝炎病毒(hepatitis B virus,HBV)和丙型肝炎病毒(hepatitis C virus,HCV)重叠感染估计约有700-2000万人口感染.重叠感染和单一HBV或HCV感染比较,更易发展为肝硬化、肝细胞癌甚至肝衰竭的比例也高,HBV和HCV重叠感染可有四种不同的临床模式,即HCV活动...     

Antiviral therapy and resistance with hepatitis B virus infection

Hepatitis B virus (HBV) infection is still the most common cause of hepatocellular carcinoma and liver cirrhosis world wide. Recently, however, there has been quite dramatic improvement in the understanding of HBV associated liver disease and its treatment. It has become clear that high viral replication is a major risk factor for the development of both cirrhosis and hepatocellular carcinoma. Early studies have shown lamivudine lowers the risk of HBV associated complications. There are currently three nucleos(t)ides licensed, in addition to interferon, and there are more drugs coming to the market soon. Interferon or its pegylated counterpart are still the only options for treatment with defined end points,while nucleos(t)ides therapy is used mostly for long term treatment. Combination therapies have not been shown to be superior to monotherapy in na(i)ve patients, however, the outcome depends on how the end point is defined. Interferon plus lamivudine achieves a higher viral suppression than either treatment alone, even though Hbe-seroconversion was not different after a one year treatment. HBV-genotypes emerge as relevant factors,with genotypes "A" and "B" responding relatively well to interferon, achieving up to 20% HBsAg clearance in the case of genotype "A". In addition to having a defined treatment duration, interferon has the advantage of lacking resistance selection, which is a major drawback for lamivudine and the other nucleos(t)ides. The emergence of resistance against adefovir and entecavir is somewhat slower in na(i)ve compared to lamivudine resistant patients. Adefovir has a low resistance profile with 3%,9%, 18%, and 28% after 2, 3, 4, and 5 years, respectively, while entecavir has rarely produced resistance in na(i)ve patients for up to 3 years.     

Molecular virology of the hepatitis C virus

Infection with the hepatitis C virus (HCV) is the major cause of nonA-nonB hepatitis worldwide. Although this virus cannot be cultivated in vitro, several of its key features have been elucidated in the past few years. The viral genome is a positive-sense, single-stranded, 9.6 kb long RNA molecule. The viral genome is translated into a single polyprotein of about 3000 amino acids. The viral polyprotein is proteolytically processed by the combination of cellular and viral proteinases in order to yield all the mature viral gene products. The genomic order of HCV has been shown to be C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. C, E1 and E2 are the virion.structural proteins. The function of p7 is currently unknown. These proteins have been shown to arise from the viral polyprotein via proteolytic processing by the host signal peptidases. Generation of the mature nonstructural proteins, NS2 to NS5B, relies on the activity of viral proteinases. Cleavage at the NS2/NS3 junction is accomplished by a metal-dependent autocatalytic proteinase encoded within NS2 and the N-terminus of NS3. The remaining cleavages downstream from this site are effected by a serine proteinase also contained within the N-terminal region of NS3. NS3 also contains an RNA helicase domain at its C-terminus. NS3 forms a heterodimeric complex with NS4A. The latter is a membrane protein that has been shown to act as a cofactor of the proteinase. While no function has yet been attributed to NS4B, it has recently been suggested that NS5A is involved in mediating the resistance of the hepatitis C virus to the action of interferon. Finally, the NS5B protein has been shown to be the viral RNA-dependent RNA polymerase.     

Antiviral therapies for chronic hepatitis C virus infection with cirrhosis

Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents(DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5 A inhibitors and HCV NS5 B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatmentnave patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in nullresponders and in patients with cirrhosis. Interferonfree regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-nave, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferonis contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCVinfected patients with advanced liver diseases.     

Molecular virology of the hepatitis C virus: implication for novel therapies

With the advent of second-generation agents that for the first time specifically target individual HCV proteins, HCV-specific therapy has arrived.The study of HCV molecular virology has helped make this possible and is helping us to identify additional new antiviral targets that will be targeted by third-generation drugs. Key to these efforts is the development of high-efficiency HCV replicons. The future effective pharmacologic control of HCV will likely consist of a cocktail of simultaneously administered virus-specific agents with independent targets. This should minimize the emergence of resistance against any single agent. The way we treat HCV should change dramatically over the next few years.     

Molecular virology of the hepatitis C virus: implication for novel therapies

The study of hepatitis C virus (HCV) molecular virology is helping to shape the future of our anti-HCV strategies by identifying new antiviral targets. With the advent of agents that specifically target individual HCV proteins, HCV-specific therapy has arrived. Key to these efforts is the development of high-efficiency HCV replicons. The future effective pharmacologic control of HCV will likely consist of a cocktail of simultaneously administered virus-specific agents with independent targets. This should minimize the emergence of resistance against any single agent. The way we treat HCV should change dramatically over the next few years.     

Occult hepatitis C virus infection： A new form of hepatitis C

INTRODUCTION The etiology of liver disease is unknown in approximately 10% of patients with abnormal results on liver function tests. Some authors have reported that occult hepatitis B virus could be the cause of a proportion of these cryptogenic chronic …     

Daclatasvir for the treatment of hepatitis C virus infection

Daclatasvir was pivotal to the trial that established proof-of-concept that an interferon-free regimen could induce a sustained virologic response in patients with chronic HCV infection. This NS5A inhibitor is not currently licensed for the treatment of HCV, but has shown promising efficacy and minimal side-effects in clinical trials to date, where it has been tested in combination with a variety of different HCV therapies. An all-oral, interferon-free curative combination therapy for HCV is now tantalizingly close to becoming part of routine clinical practice, with multiple highly-efficacious direct-acting antiviral agents emerging virtually simultaneously. In this article we will discuss daclatasvir’s background and review the clinical trials published to date, concluding with our predictions regarding its future place in the treatment armamentarium against HCV.     

Antiviral treatment for hepatitis C virus infection: Effectiveness at general population level in a highly endemic area

BackgroundPeginterferon plus ribavirin treatment induced a sustained virological response in >50% of HCV-RNA-positive individuals enrolled in published clinical trials.AimTo determine anti-HCV treatment effectiveness at a general population level.Patients and methodsIn 2002, a 1:5 random sample of >11 years old inhabitants of a small Italian town (Cittanova) was invited for HCV screening. HCV-RNA-positive individuals were evaluated for antiviral treatment.Results1645 of 1924 invited individuals (85.5%) participated in the screening. 84 HCV-RNA-positive individuals were detected: median age was 65 years (range: 32–87); 67% was infected with genotype 1 or 4. Antiviral treatment was judged unnecessary for 43 (51.2%), due to persistently normal alanine aminotransferases, mild disease at liver biopsy or age >70 years without cirrhosis. Twenty-eight of the remaining 41 patients (68.3%) were ineligible for treatment, because of medical/psychiatric contraindications (42.9%), alcohol/drug abuse (17.9%), decompensated cirrhosis/hepatocellular carcinoma (17.9%), not attending official appointments (10.7%), previous intolerance/non-response to interferon plus ribavirin (10.7%). 5 of 13 eligible patients (38.5%) did not receive treatment (4 refused and 1 accidental death). 3 of 8 treated patients (37.5%) reached a sustained virological response.ConclusionsAlthough efficacy of anti-HCV therapy improved in recent years, we found that low eligibility to treatment still limited its effectiveness at general population level in a highly endemic town.     

Peginterferon and ribavirin treatment for hepatitis C virus infection

Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, ...     

Sofosbuvir treatment and hepatitis C virus infection

Hepatitis C virus (HCV) infection is a serious problem worldwide. The use of interferon-based therapy has made HCV eradication challenging. The recent appearance of direct-acting antiviral agents (DAAs) has changed HCV therapy. Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy. Furthermore, the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety. In particular, sofosbuvir, a nucleotide-based NS5B inhibitor, prevents HCV RNA synthesis by acting as a “chain terminator”. Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response. The current review summarizes the efficacy and safety of sofosbuvir therapy.     

Current treatment of hepatitis C virus infection

New strategies have led to better results in the treatment of HCV infection during the last few years. At present the recommended treatment for patients with chronic hepatitis C is a combination of pegylated interferon and ribavirin. The sustained virological response rate of this combination therapy is 42 - 48 % for patients with genotype 1 after a course of 48 weeks and 80 % for patients with genotype 2 or 3 after a course of 24 weeks. New nucleoside analogs may lead to a better tolerance and better outcomes. A new approach is the long term monotherapy with pegylated interferon in order to reduce the progression of fibrosis and the incidence of cirrhotic complications. At present the effectivity of protease inhibitors and of a therapeutic immunisation with the E1 envelope protein of the hepatitis C virus are being examined. Because the optimal treatment strategy for patients with an acute hepatitis C infection is still unclear, these patients should be included in clinical studies.     

慢性乙型肝炎病毒感染特殊人群抗病毒治疗的几个问题

对于慢性乙型肝炎患者,抗病毒治疗目的 是阻断肝炎-肝硬化-肝癌"三部曲"进程,减低和防止终末期肝病的发生.抗病毒治疗的有效性及可行性已勿容置疑,但其是否可改变慢性HBV感染者的最终结局,影响疾病长期转归还需更多循证医学证据支持.     

Insulin resistance and steatosis in hepatitis C virus infection

The relationship between hepatitis C virus (HCV), steatosis, and insulin resistance is genotype specific, and steatosis and insulin resistance are closely linked to the progression of liver disease in HCV infected patients.