Drugs in development for chronic hepatitis C: a promising future

INTRODUCTION: The approval of the first direct-acting antiviral (DAA) drugs for treatment of HCV in 2011 has lead to improved sustained viral response rates of up to 79% in treatment-na?ve or relapse genotype 1 patients. AREAS COVERED: Clinical trial data, the clinical skills required for the use of DAA drugs, the use of genetic tests and HCV RNA assays, new small molecules, resistance-associated variants, combinations of two or more DAAs, treatment of special populations, and future directions. The results of the pivotal Phase III trials with telaprevir and boceprevir, including the efficacy, safety and tolerability, drug-drug interactions and management of the most common side-effects. Resistance-associated variant data and treatment strategies implemented to minimize the development of resistance with these first-generation protease inhibitors. EXPERT OPINION: Combination therapies of protease inhibitors with nucleoside or non-nucleoside polymerase inhibitors, non-structural protein 5A (NS5A) inhibitors and cyclophylin inhibitors are currently underway in regimens that use pegylated interferon and ribavirin or are interferon-free. The explosion of new drug development will probably move the field forward and offer both improved efficacy and tolerability to patients with hepatitis C infections. The use of these drugs ushers in a new era for the treatment of HCV but must be done with care and caution.     

Drugs in development for chronic hepatitis C: a promising future

Introduction: The approval of the first direct-acting antiviral (DAA) drugs for treatment of HCV in 2011 has lead to improved sustained viral response rates of up to 79% in treatment-naïve or relapse genotype 1 patients.

Areas covered: Clinical trial data, the clinical skills required for the use of DAA drugs, the use of genetic tests and HCV RNA assays, new small molecules, resistance-associated variants, combinations of two or more DAAs, treatment of special populations, and future directions. The results of the pivotal Phase III trials with telaprevir and boceprevir, including the efficacy, safety and tolerability, drug–drug interactions and management of the most common side-effects. Resistance-associated variant data and treatment strategies implemented to minimize the development of resistance with these first-generation protease inhibitors.

Expert opinion: Combination therapies of protease inhibitors with nucleoside or non-nucleoside polymerase inhibitors, non-structural protein 5A (NS5A) inhibitors and cyclophylin inhibitors are currently underway in regimens that use pegylated interferon and ribavirin or are interferon-free. The explosion of new drug development will probably move the field forward and offer both improved efficacy and tolerability to patients with hepatitis C infections. The use of these drugs ushers in a new era for the treatment of HCV but must be done with care and caution.     

New antivirals against hepatitis C virus

Recently, first direct acting antiviral (DAA) against hepatitis C virus (HCV) has just approved in Japan. It is a first generation protease inhibitor, telaprevir. Telaprevir inhibits HCV NS3 & 4A serine protease, and combination with pegylated-interferon and ribavirin has now become a standard of care (SOC) for patients with genotype 1 high viral load hepatitis C. Fortunately, more than 50 new antivirals against HCV are under development including antivirals in preclinical trials. New antivirals are classified into several categories; (1) NS3 & 4A protease inhibitor, (2) NS5B polymerase inhibitor, (3) NS5A inhibitor, (4) host factor targeting antivirals, (5) interferon-related antivirals, and others. Combination of different classes of antivirals without interferon is expected to become a future SOC for hepatitis C.     

Dasabuvir (ABT333) for the treatment of chronic HCV genotype I: a new face of cure,an expert review

Hepatitis C virus (HCV) affects nearly 1.3% of US population and around 2% of people worldwide. It is associated with serious complication of Cirrhosis and Hepatocellular carcinoma leading to significant morbidity and mortality. Until now the only treatment option for this serious disease was interferon based therapy which had poor tolerance and at best SVR (Sustained virological response) in only 50% of cases. With the introduction of other direct – acting antiviral agents the treatment of HCV has been revolutionized with significantly high rates of cure. Among novel Direct acting antivirals are non-nucleoside inhibitor NS5B which is highly effective in treatment of HCV genotype 1 a and 1b including those with compensated cirrhosis achieving high cure rates with SVR more than 97 % in pooled analysis from six different phase 3 trials. This review will discuss the DAA – Dasabuvir, a non – nucleoside NS5B inhibitor, its mechanism of action, efficacy, safety & tolerance, and drug resistance. Dasabuvir is approved by FDA in combination with other DAA agents called as the 3D(Viekira Pak) in various interferon free regimens achieving high cure rates (SVR >95%) with low adverse effects. In Europe, it is approved by European medicines agency for use in combination with Ombitasvir, Paritaprevir, and ritonavir with or without ribavirin. The drug is used in treatment naive as well as previously treated patient with high success rates. It is also approved in patients with compensated cirrhosis, patients with HIV co-infection and liver transplant recipients which were in the past were excluded from treatment with interferon based therapy. Dasabuvir is extensively evaluated in large clinical trials and shown excellent SVR among HCV genotype1 patient population in combination with other oral DAAs, with good safety profile and tolerance. Its drawback is its genotype restriction, need for ribavirin (RBV) for 1a genotype, low resistance barrier and high cost. It is well tolerated with less than 1 % of patients permanently discontinuing treatment and 2% of patient experiencing a serious adverse reaction. It is contraindicated in patients with known hypersensitivity to ritonavir (e.g. Steven – Johnson syndrome) and strong inducers of CYP3A and CYP2CB.     

New pharmacotherapy for hepatitis C

Chronic hepatitis C infection remains a major global public health burden associated with substantial morbidity and mortality. Recent advances in antiviral therapy with the US Food and Drug Administration (FDA) approval of the oral protease inhibitors boceprevir and telaprevir introduce a new era of treatment for hepatitis C based on directly acting antiviral agents, which are associated with significant improvements in viral eradication rates in combination with pegylated interferon plus ribavirin. Newer classes targeting the hepatitis C virus (HCV) protease, polymerase, NS5A, and other components of the viral genome demonstrate great promise to further enhance viral eradication with superior efficacy, improved tolerability, shorter duration of therapy, and diminished requirement for interferon. Current and future strategies for HCV pharmacotherapy are reviewed.     

Directly acting antivirals against hepatitis C virus

The approval of directly acting antivirals (DAA) for the treatment of chronic hepatitis C virus (HCV) infection will represent a major breakthrough for the 180 million persons infected worldwide. Paradoxically, hepatitis C is the only human chronic viral disease that can be cured, as all other pathogenic viruses infecting humans either display self-limited courses or establish non-eradicable persistent infections. Until now, treatment of chronic hepatitis C consisted of the combination of peginterferon-α plus ribavirin, which provided limited rates of cure and was associated with frequent side effects. Several DAA have been identified that inhibit the NS3 protease, the NS5B polymerase or the NS5A replication complex, and have entered the final steps of clinical development. These molecules, coupled with significant progress made in the recognition of more potent and safe interferon forms (e.g. interferon-λ) and host protein targets (e.g. alisporivir), are opening a new era in hepatitis C therapeutics. The expectations are so great that, to some extent, it is reminiscent of what happened in 1996 in the HIV field when the introduction of the first protease inhibitors as part of triple combinations revolutionized antiretroviral therapy. To maximize treatment success and reduce the likelihood of drug resistance selection, a proper individualization of hepatitis C therapy will be required, choosing the most convenient drugs and strategies according to distinct viral and host profiles. The complexity of HCV therapeutics has reached a point that presumably will lead to the birth of a new specialist, the HCV doctor.     

Serine protease inhibitors as anti-hepatitis C virus agents

Approximately 3% of the worldwide population (i.e., more than 170 million people) are chronically infected with the hepatitis C virus (HCV). An estimated 20% of these patients will develop liver cirrhosis within a mean of 20 years, and 2–5% of cirrhotic patients will die of end-stage liver disease or hepatocellular carcinoma. The currently approved antiviral therapy with pegylated interferon (pegIFN) and ribavirin induces a sustained virological response (SVR) in 40–50% of patients infected with genotype 1, the most prevalent HCV type. In this review, we focus on the development and clinical application of serine protease inhibitors as anti-HCV agents. Although highly active in inducing a significant decline of serum HCV RNA, the rapid development of resistance must be counteracted in combination with other antiviral agents, currently pegIFN-α and ribavirin. Two serine protease inhibitors have reached clinical Phase III trials, increasing SVR rates and shortening treatment duration when combined with pegIFN and ribavirin. Trials of interferon-free targeted combination therapies are currently underway.     

Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study

Summary. Background: Hepatitis C is a major co‐morbidity in patients with hemophilia. However, there is little information on the efficacy of antiviral therapy and long‐term follow‐up after treatment.Objectives: To assess the effect of interferon‐based (IFN‐based) therapy on hepatitis C virus (HCV) eradication, to identify determinants associated with treatment response, and to assess the occurrence of end‐stage liver disease (ESLD) after completing antiviral therapy.Patients and methods: In a multicenter cohort study, 295 treatment‐naïve hemophilia patients chronically infected with HCV were included. The effect of therapy was expressed as sustained virological response (SVR). Determinants associated with treatment response were expressed as odds ratios (ORs). Cumulative incidence of ESLD was assessed using a Kaplan–Meier survival table.Results: Among human immunodeficiency virus (HIV) negative patients (n = 235), SVR was 29% (29/101) for IFN monotherapy, 44% (32/72) for IFN with ribavirin, and 63% (39/62) for pegylated IFN (PegIFN) with ribavirin. In patients co‐infected with HIV (n = 60), IFN monotherapy, IFN with ribavirin, and PegIFN with ribavirin eradicated HCV in 7/35 (20%), 1/2 (50%), and 11/23 (48%), respectively. SVR increased with genotype 2 and 3 [OR 11.0, 95% CI: 5.8–20.5], and combination therapy (IFN and ribavirin OR 3.7, 95% CI: 1.7–8.4), PegIFN and ribavirin (OR 4.2, 95% CI: 1.8–9.5). Up to 15 years after antiviral treatment, none of the patients with a SVR relapsed and none developed ESLD. In contrast, among unsuccessfully treated patients the cumulative incidence of ESLD after 15 years was 13.0%.Conclusions: Successful antiviral therapy appears to have a durable effect and reduces the risk of ESLD considerably.     

Treatment options for nonresponders and relapsers to initial therapy for hepatitis C

As treatment for chronic hepatitis C virus (HCV) infection has advanced over the past decade, efforts have evolved to retreat patients who did not achieve a sustained virologic response to previous antiviral regimens. Retreating nonresponders to interferon alfa monotherapy with a combination of interferon and ribavirin yields a sustained virologic response in 9% to 32% of patients, whereas retreatment with peginterferon alfa plus ribavirin yields a sustained virologic response in up to 30% to 40% of patients. Sustained virologic response is more likely in retreated patients with HCV genotype 2 or 3, low serum HCV RNA levels, and lack of response to prior interferon monotherapy. Retreatment of nonresponders to interferon-ribavirin combination therapy is associated with lower response rates (< or = 20%). Despite treatment advances, the efficacy of current antiviral regimens for nonresponders remains inadequate. The next few years will see more-targeted antiviral regimens for these patients and therapies focused on slowing the progression of liver disease rather than viral eradication.     

New antiviral therapies in the management of HCV infection

Improved knowledge of the HCV life cycle and of structural features of HCV proteins have led to the discovery of numerous potential targets for antiviral therapy. Viral replication and polyprotein processing have been tagged as promising viral targets. Clathrin-mediated endocytosis, fusion of HCV with cellular membranes, translation of viral RNA, virus production and release as well as several host cell factors may provide alternative targets for future anti-HCV therapies. Several compounds are currently under investigation in clinical trials and showed high antiviral activity in patients with chronic hepatitis C. Recently, Phase III studies for two protease inhibitors, telaprevir and boceprevir, each given in combination with pegylated interferon (standard of care [SOC]), were completed. In HCV-genotype-1-infected patients, the addition of telaprevir or boceprevir to SOC increased sustained virological response rates from <50% to >70%. Nucleoside/nucleotide inhibitors of the HCV NS5B polymerase have shown antiviral activity against different HCV genotypes, and have a higher barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. Inhibitors of NS5A are potentially active against all HCV genotypes. Among the different host cell-targeting compounds, cyclophilin inhibitors have shown promising results. Future hope lies in the combination of direct-acting antiviral agents with the possibility of interferon-free treatment regimens.     

Boceprevir: an oral protease inhibitor for the treatment of chronic HCV infection

Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to affect sustained elimination of the virus (a sustained virological response [SVR]). The success and duration of therapy with interferon is dependent on HCV genotype. The current standard of care comprises combined treatment with pegylated interferon and ribavirin. Rates of SVR in patients with genotype 1 infection, the least responsive group, are less than 50%. Boceprevir is a ketoamide protease inhibitor that binds reversibly to the HCV nonstructural NS3 protease active site inhibiting intracellular viral replication. Phase III clinical studies have demonstrated that, in combination with the current standard of care, boceprevir significantly increases the SVR rate in both treatment-naive and previously treated patients with genotype 1 CHC. Both the US FDA and EMA have approved boceprevir for the treatment of genotype 1 CHC: the first directly-acting antiviral drug to be licensed for this indication. This article will review the pharmacology and pharmacodynamics of boceprevir, the efficacy and safety of the drug, and explore possible future developments in the management of CHC.     

Effects of mutagenic and chain-terminating nucleotide analogs on enzymes isolated from hepatitis C virus strains of various genotypes

The development of effective therapies for hepatitis C virus (HCV) must take into account genetic variation among HCV strains. Response rates to interferon-based treatments, including the current preferred treatment of pegylated alpha interferon administered with ribavirin, are genotype specific. Of the numerous HCV inhibitors currently in development as antiviral drugs, nucleoside analogs that target the conserved NS5B active site seem to be quite effective against diverse HCV strains. To test this hypothesis, we examined the effects of a panel of nucleotide analogs, including ribavirin triphosphate (RTP) and several chain-terminating nucleoside triphosphates, on the activities of purified HCV NS5B polymerases derived from genotype 1a, 1b, and 2a strains. Unlike the genotype-specific effects on NS5B activity reported previously for nonnucleoside inhibitors (F. Pauwels, W. Mostmans, L. M. Quirynen, L. van der Helm, C. W. Boutton, A. S. Rueff, E. Cleiren, P. Raboisson, D. Surleraux, O. Nyanguile, and K. A. Simmen, J. Virol. 81:6909-6919, 2007), only minor differences in inhibition were observed among the various genotypes; thus, nucleoside analogs that are current drug candidates may be more promising for treatment of a broader variety of HCV strains. We also examined the effects of RTP on the HCV NS3 helicase/ATPase. As with the polymerase, only minor differences were observed among 1a-, 1b-, and 2a-derived enzymes. RTP did not inhibit the rate of NS3 helicase-catalyzed DNA unwinding but served instead as a substrate to fuel unwinding. NS3 added to RNA synthesis reactions relieved inhibition of the polymerase by RTP, presumably due to RTP hydrolysis. These results suggest that NS3 can limit the incorporation of ribavirin into viral RNA, thus reducing its inhibitory or mutagenic effects.     

Effect of ribavirin on the hepatitis C virus (JFH-1) and its correlation with interferon sensitivity

BACKGROUND: The consensus therapy for chronic hepatitis C infection is based on a synergistic combination of pegylated interferon and ribavirin. The therapy leads to a sustained virological response in around 60% of infected patients. The mechanism by which this synergy occurs has not yet been elucidated. Several mechanisms of action have been proposed; one suggests that ribavirin, which is a nucleoside analogue, is incorporated into the RNA strand and generates an increase in the error rate. Such an accumulation of mutations would threaten the integrity of the virus's genetic information. METHODS: The effects of ribavirin on the new infectious hepatitis C virus cell culture (HCVcc) system were investigated using Huh-7 cells. Cells were cultured for 1 month in either 0 microM, 20 microM or 50 microM ribavirin. The HCV interferon sensitivity and the NS5A quasispecies were analysed. RESULTS: An increase in the mutation rate in the HCV NS5A gene was observed when the infected cells were treated with 50 microM ribavirin for 1 month. Amino acid sequence analysis revealed that ribavirin exerts an increase in G to A transition events as predicted by its mutagenic effect and a selective pressure on the HCV NS5A sequence. Furthermore, ribavirin treatment modified the efficacy of interferon (IFN) treatment. The IFN half-inhibition concentration (IC50) was significantly lower for viruses obtained after 1 month's exposure to 50 microM ribavirin than for viruses cultured in the absence of ribavirin. CONCLUSIONS: Ribavirin's mutagenic effect could explain in part its synergistic action with interferon.     

Nouveaux traitements de l’infection chronique par le virus de l’hépatite C

Treatment of hepatitis C virus (HCV) infection by the combination of pegylated interferon and ribavirin has been the standard of care since 1998 and has helped to achieve a sustained virologic response (SVR) in more than 50% of patients with chronic infection. SVR represents a complete recovery from the infection, but more than 50% of genotype-1-infected patients do not achieve SVR. Progress in the understanding of the viral cycle and the characterization of the viral enzymes which are possible targets have resulted in the development of new molecules including direct-acting antivirals targeted against HCV with specificity for either genotype-1 (protease inhibitors NS3/NS4A) or wider spectrum (NS5A inhibitors, polymerase inhibitors NS5B or entry inhibitors), and nonspecific antivirals (new interferons, cyclophilin inhibitors). We review the results of phase III trials, which have clearly shown a 20% to 30% increase in the SVR rate of genotype-1-infected patients, both naive and who have received previous treatments. These new drugs have been approved at the end of 2011, after an early compassionate access to cirrhotic patients who have experienced a previous relapse or partial response to the combination therapy. In the future, the main limitations of the triple therapy will be safety against adverse effects (including skin rash and anemia, which may be easily controlled), cost, adherence, viral resistances, and drug-drug interactions that we have to avoid by therapeutic education of patients and physicians.     

Evolution of hepatitis C virus quasispecies during ribavirin and interferon-alpha-2b combination therapy and interferon-alpha-2b monotherapy

OBJECTIVE: Ribavirin and interferon combination therapy is more effective than interferon monotherapy in patients with chronic hepatitis C virus (HCV) infection. To test the hypothesis that ribavirin induces nucleotide substitutions in the viral genome and reduces viral load by forcing it into error catastrophe in the combination therapy, we investigated the molecular evolution of HCV quasispecies in 3 patients who received combination therapy and 2 patients who received interferon monotherapy. METHODS: The quasispecies were analyzed before and after therapy by sequencing at least 8 clones in five regions of the HCV genome; 5' untranslated region, EI, E2, NS5A and NS5B. RESULTS: Marked genetic drift was observed in the NS5A and NS5B regions in patients treated with combination therapy. However, genetic distances between clones obtained after therapy were closer than those obtained before therapy. CONCLUSION: Our results suggest that the combination therapy modified HCV quasispecies, but that this did not reflect the induction of error catastrophe by ribavirin. Modification of quasispecies by this therapy requires further investigation in a larger number of patients to elucidate the possible mechanism of viral resistance against the combination therapy.     

A case of successful treatment with telaprevir-based triple therapy for hepatitis C infection after treatment failure with vaniprevir-based triple therapy

Recently direct-acting antiviral agents, such as hepatitis C virus (HCV) non-structural 3/4A (NS3/4A) protease inhibitors (PI), have been introduced, and triple therapy regimens that include PI with conventional pegylated interferon α and ribavirin have significantly improved the sustained virological response (SVR) rate, up to 80% for both treatment-naïve and treatment-experienced patients with HCV genotype 1. We here report for the first time a case of the successful treatment of HCV genotype 1 infection with a first generation PI drug (telaprevir) based triple therapy after treatment failure with a second generation PI drug (vaniprevir) based triple therapy. A 67-year-old treatment-naïve Japanese man with HCV genotype 1b infection took part in a phase III clinical trial of vaniprevir-based triple therapy. His serum HCV RNA had become undetectable at week 2 and SVR was highly expected, but HCV RNA reappeared at week 4 after vaniprevir treatment. Polymerase chain reaction direct sequence of the HCV NS3/4A gene at week 8 after vaniprevir treatment showed the emergence of a vaniprevir-resistance mutation (D168V), the probable reason for the treatment failure. Six months later, retreatment with telaprevir-based triple therapy was started. Although the dosages of telaprevir and ribavirin had to be reduced due to severe anemia, the patient achieved an SVR. This case shows the value of repeating PI-based triple therapy with a different drug, a process that would reduce the chance of drug resistant mutation.     

The prevalence, clinical features and response to antiviral therapy of patients with chronic hepatitis C who are seropositive for liver-kidney microsome type 1 antibodies

BACKGROUND: Antibodies to liver-kidney microsome type 1 (anti-LKM-1), which are a marker of autoimmune hepatitis, are found in a minority of patients with chronic hepatitis C virus (HCV) infection. Whether interferon/ribavirin therapy is safe and effective in these patients is unclear. AIM: To describe the prevalence, clinical features and response to interferon/ribavirin therapy of anti-LKM-1 seropositive patients with chronic hepatitis C. PATIENTS AND METHODS: All anti-LKM-1 seropositive patients with chronic hepatitis C who between 1997 and 2002 underwent a diagnostic liver biopsy at the Liver Center Maggiore Hospital, Milan, were studied. Serum HCV RNA was tested by in-house PCR with a limit sensitivity of 50 IU/ml. Tissue antibodies were assessed by indirect immunofluorescence on cryostat sections from rat liver, kidney and stomach. Liver biopsies were graded and staged by the Ishak score. Autoimmune hepatitis was defined according to the International Autoimmune Hepatitis Grading (IAHG) score. RESULTS: Forty-eight (1.8%) of 2675 HCV patients circulated anti-LKM-1 (30 females, 55 years of age). Twenty-eight had genotype 2, 18 genotype 1, and two genotype 3. Aminotransferase levels had been high for 23 + 12 years, on average. Using IAHG, autoimmune hepatitis was excluded in 44 patients (92%) and found to be probable in 4 patients (8%). Chronic hepatitis was histologically mild in 34 patients (70%), moderate to severe in 7 patients (15%) and with cirrhosis in 7 patients (15%). A sustained virological response (SVR) was achieved in 20 of the 27 patients who received interferon/ribavirin (13 genotype 2c with 87% SVR, and 7 genotype 1b with 58% SVR). None of the patients had serum aminotransferases, immunoglobulins or anti-LKM-1 levels flaring following therapy. CONCLUSIONS: LKM-1 antibodies rarely occur in patients with chronic hepatitis C and do not predict autoimmune hepatitis, interferon/ribavirin hyporesponsiveness or immune-related reactions to therapy.     

Antiviral treatment of hepatitis C: present status and future prospects

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis. A substantial proportion of patients with chronic hepatitis C eventually develop hepatocellular carcinoma (HCC), which is one of the leading causes of death worldwide. Therefore, efficient antiviral treatments for HCV have long been needed. A recently developed combination therapy of pegylated interferon and ribavirin has dramatically improved the outcome of antiviral therapy for HCV infection. In genotype 1b HCV infection, 48 weeks of the combination therapy achieved eradication of the virus in 50% of patients, and in genotype 2 HCV infection, 24 weeks of the therapy resulted in viral eradication in 80%–90% of patients. By this eradication, an improvement in the hepatic fibrosis, an inhibition of HCC development, and an improvement in life expectancy were attained. Patients who did not respond to the combination therapy may be treated with long-term interferon monotherapy, which is not intended to eradicate HCV, but will lower the serum alanine aminotransferase (ALT) level. Thus, the treatment for HCV infection has progressed significantly, but therapies with new modalities, such as inhibitors of viral protease or RNA polymerase, are still being awaited.     

MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants

HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.     

Structure–Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA‐Dependent RNA Polymerase Inhibitors: Ten Years of Research

Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA‐dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct‐acting antivirals). In the last 10 years, a growing number of non‐nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure–activity relationships.¹ In this review, we will discuss the reported non‐nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure–activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp.