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1.  Advances in the Treatment of Hepatitis C Virus Infection 
Gastroenterology & Hepatology  2012;8(2):91-101.
Therapy for chronic hepatitis C virus (HCV) infection with pegylated interferon α and ribavirin leads to suboptimal rates of viral eradication in patients with genotype 1 HCV, the most common viral strain in the United States and many other countries. Recent advances in the study of viral kinetics, host factors that predict response to antiviral therapy, and viral protein structure have established the foundation of a new era in the treatment of HCV infection. The HCV NS3/4A protease inhibitors boceprevir and telaprevir, the first 2 agents in a new and promising generation of direct-acting antiviral agents to have completed phase III studies, were approved by the US Food and Drug Administration in May 2011. The addition of these HCV protease inhibitors to standard therapy has been demonstrated to dramatically improve sustained virologic response rates, both in treatment-naïve patients and in prior relapsers and nonresponders. These novel agents represent only the beginning of a revolution in HCV therapy, which will include additional protease inhibitors as well as other classes of drugs currently under investigation, such as polymerase inhibitors, NS5A inhibitors, and host factor inhibitors such as cyclophilin antagonists. The future of HCV therapy holds promise for significantly higher sustained virologic response rates with shorter treatment durations, as well as the intriguing potential to achieve virologic cure with interferon-free combination therapy regimens.
PMCID: PMC3317517  PMID: 22485076
Hepatitis C virus; genotype 1; boceprevir; telaprevir; direct-acting antiviral agents
2.  The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors 
PLoS Pathogens  2012;8(7):e1002832.
Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors – telaprevir, danoprevir, vaniprevir and MK-5172 – in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus.
Author Summary
Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. New classes of directly-acting antiviral agents that target various HCV enzymes are being developed. Two such drugs that target the essential HCV NS3/4A protease are approved by the FDA and several others are at various stages of clinical development. These drugs, when used in combination with pegylated interferon and ribavirin, significantly improve treatment outcomes. However HCV evolves very quickly and drug resistance develops against directly-acting antiviral agents. Thus, despite the therapeutic success of NS3/4A protease inhibitors, their long-term effectiveness is challenged by drug resistance. Our study explains in atomic detail how and why drug resistance occurs for four chemically representative protease inhibitors –telaprevir, danoprevir, vaniprevir and MK-5172. Potentially with this knowledge, new drugs could be developed that are less susceptible to drug resistance. More generally, understanding the underlying mechanisms by which drug resistance occurs can be incorporated in drug development to many quickly evolving diseases.
PMCID: PMC3406087  PMID: 22910833
3.  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-α and RBV combination therapy is less than 50% for genotype 1 HCV, 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 peg-IFN 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-α include 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 anti-HCV agents and assess the main factors affecting the efficacy of antiviral treatments.
PMCID: PMC3870549  PMID: 24379621
Hepatitis C virus; Treatment; Interferon; Protease inhibitors; IL28B protein; Polymorphisms; Viral load; Genotype; Hepatic steatosis
4.  Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives 
BioMed Research International  2013;2013:467869.
Currently, hepatitis C virus (HCV) infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs) against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir) have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin). The new therapy has significantly improved sustained virologic response (SVR); however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.
PMCID: PMC3825274  PMID: 24282816
5.  Pharmacogenetics of hepatitis C: transition from interferon-based therapies to direct-acting antiviral agents 
Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world’s population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.
PMCID: PMC4075960  PMID: 25114601
hepatitis C virus; interleukin-28B polymorphisms; PEGylated interferon and ribavirin; direct-acting antiviral agents; pharmacogenetics; rational therapeutics
6.  Hepatitis C virus resistance to new specifically-targeted antiviral therapy: A public health perspective 
World Journal of Virology  2013;2(1):6-15.
Until very recently, treatment for chronic hepatitis C virus (HCV) infection has been based on the combination of two non-viral specific drugs: pegylated interferon-α and ribavirin, which is effective in, overall, about 40%-50% of cases. To improve the response to treatment, novel drugs have been designed to specifically block viral proteins. Multiple compounds are under development, and the approval for clinical use of the first of such direct-acting antivirals in 2011 (Telaprevir and Boceprevir), represents a milestone in HCV treatment. HCV therapeutics is entering a new expanding era, and a highly-effective cure is envisioned for the first time since the discovery of the virus in 1989. However, any antiviral treatment may be limited by the capacity of the virus to overcome the selective pressure of new drugs, generating antiviral resistance. Here, we try to provide a basic overview of new treatments, HCV resistance to new antivirals and some considerations derived from a Public Health perspective, using HCV resistance to protease and polymerase inhibitors as examples.
PMCID: PMC3785043  PMID: 24175225
Specifically-targeted antiviral therapy; Direct-acting antiviral; Protease inhibitors; Polymerase inhibitors; Viral resistance
7.  Management of recurrent hepatitis C virus after liver transplantation 
World Journal of Gastroenterology : WJG  2014;20(44):16409-16417.
Chronic hepatitis C virus (HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation (LT) in the United States and Western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare (< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.
PMCID: PMC4248184  PMID: 25469009
Hepatitis C virus; Liver transplantation; Recurrence; Treatment
8.  New hepatitis C therapies in clinical development 
With the current standard of care for the treatment of chronic hepatitis C, a combination of pegylated interferon alfa and ribavirin, sustained virologic response rates can be achieved in approximately 50% of patients only.
Improved understanding of the viral life cycle has led to the identification of numerous potential targets for novel, direct-acting antiviral compounds. Inhibitors of the NS3/4A protease are currently the most advanced in clinical development. Recently completed phase 3 studies of the two protease inhibitors telaprevir and boceprevir, each given in combination with standard of care, yielded sustained virologic response rates in the range of 66-75% in treatment-naive patients and 59-66% in treatment-experienced patients with HCV genotype 1 infection. Studies of second-generation protease inhibitors, with the potential advantage of improved potency, drug metabolism and pharmacokinetics profile, are already underway.
Inhibitors of the HCV NS5A protein and NS5B polymerase are potentially active across different HCV genotypes and have shown promising antiviral efficacy in early clinical studies. Other emerging mechanisms include silymarin components and inhibitors of cell proteins required for HCV replication.
While improved formulations of current HCV therapies are also being developed, future hopes lie on the combination of direct-acting antivirals with the eventual possibility of interferon-free treatment regimens.
PMCID: PMC3352002  PMID: 21813371
chronic hepatitis C; direct-acting antivirals; protease inhibitor; polymerase inhibitor; NS5A inhibitor; cyclophilin inhibitor
9.  Hepatitis C virus NS5A inhibitors and drug resistance mutations 
Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for “difficult-to-treat” HCV-infected patients. “First generation” HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. “Second generation” NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.
PMCID: PMC3961994  PMID: 24659881
ACH-3102; Direct-acting antiviral agents; Daclatasvir; Hepatitis C virus; Ledipasvir
10.  Boceprevir: a novel nonstructural 3 (NS3) protease inhibitor for the treatment of chronic hepatitis C infection 
Chronic hepatitis C infection is a leading cause of morbidity and mortality worldwide, with hepatitis C related cirrhosis being the most common indication for transplant and a major cause for the increase in hepatocellular carcinoma worldwide. Treatment for hepatitis C has consisted of nonspecific immunomodulatory therapies that stimulate the immune system and inhibit hepatitis C replication. Pegylated (peg-)interferon and ribavirin have been the standard of care with an overall sustained response rate of 40–50% in patients with genotype 1 infection, and 80% in genotype 2 or 3. Recently, direct-acting antiviral agents, including boceprevir, have demonstrated improved sustained response rates in patients with genotype 1 infection when given in combination with interferon and ribavirin. Boceprevir is a structurally novel hepatitis C virus (HCV) nonstructural 3 (NS3) protease inhibitor that has demonstrated robust antiviral activity in HCV replicons. Clinically, in phase II and III trials, boceprevir 800 mg three times daily with peginterferon and ribavirin has led to improved sustained response rates in genotype 1 infection treatment-naive patients, relapsers, partial responders, and null responders. Phase II data have demonstrated that ribavirin is essential for optimal boceprevir response. Moreover, phase II data have suggested that a 4-week peginterferon or ribavirin lead-in strategy may reduce relapse rates and provide crucial on-treatment data for treatment response with boceprevir addition. Side effects of boceprevir when added to peginterferon and ribavirin are similar to peginterferon and ribavirin, though higher rates of anemia have been noted, with an incremental increase in erythropoietin use. The addition of boceprevir represents a major advance in patients with genotype 1 infection who are treatment naïve.
PMCID: PMC3342569  PMID: 22570678
hepatitis C; interferon; ribavirin; boceprevir; direct acting antiviral; resistance
11.  Profile of alisporivir and its potential in the treatment of hepatitis C 
Two classes of hepatitis C antiviral agents currently exist, ie, direct-acting antivirals and host-targeting antivirals. Direct-acting antivirals target viral proteins including NS3/NS4A protease, NS5B polymerase and NS5A protein, while host-targeting antivirals target various host proteins critical for replication of the hepatitis C virus (HCV). Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A. Due to its unique mechanism of antiviral action, alisporivir is pangenotypic, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting antivirals. Alisporivir has an excellent pharmacokinetic and safety profile. Phase I and II clinical studies have demonstrated that alisporivir causes a dramatic reduction in viral loads in HCV-infected patients. Alisporivir was shown to be highly potent in treatment-naïve and treatment-experienced patients with genotype 1 as well as in those with genotypes 2 or 3. Low viral breakthrough rates were observed and the most frequent clinical and laboratory adverse events associated with alisporivir in combination with pegylated interferon-alpha and ribavirin were similar to those associated with pegylated interferon-alpha and ribavirin used alone. A laboratory abnormality observed in some patients receiving alisporivir is hyperbilirubinemia, which is related to transporter inhibition and not to liver toxicity. The most recent clinical results suggest that alisporivir plus other direct-acting antivirals should provide a successful treatment option for difficult-to-treat populations, such as nonresponders to prior interferon-alpha therapy and patients with cirrhosis. In conclusion, alisporivir represents an attractive candidate component of future interferon-free regimens.
PMCID: PMC3578503  PMID: 23440335
alisporivir; cyclophilins; cyclophilin inhibitors; hepatitis C virus; treatment
12.  New agents for the treatment of hepatitis C in patients co-infected with HIV 
Pilot trials evaluating the efficacy and safety of the first licensed hepatitis C virus (HCV) protease inhibitors (PIs), boceprevir (BOC) and telaprevir (TVR), for the treatment of genotype 1 infection in HCV/HIV co-infected patients revealed similar results as in HCV mono-infected patients. HCV liver disease progresses more rapidly in co-infected patients, particularly with advanced immunodeficiency. Therefore, HCV treatment in HIV is of great importance. However, dual therapy with pegylated interferon (PegIFN) and ribavirin (RBV) has been associated with lower cure rates and increased toxicities in co-infected subjects, thereby limiting overall HCV therapy uptake. The availability of HCV PIs opens new perspectives for HCV cure in co-infected patients, with a 70% sustained virologic response (SVR) rate in HCV treatment-naïve patients. Despite these impressive advances, the use of the new treatment options has been low, reflecting the complex issues with modern triple HCV therapy. Indeed pill burden, adverse events (AEs), drug–drug interactions (DDIs) and high costs complicate HCV therapy in HIV. So far, studies have shown no tolerability differences in mono- and co-infected patients with the early stages of liver fibrosis. Regarding DDIs between HVC PIs and antiretroviral drugs, TVR can be safely administered with efavirenz (with dose adjustment of TVR), etravirine (ETR), rilpivirine, boosted atazanavir (ATV/r) and raltegravir (RAL), while BOC can be safely administered with ETR, RAL and potentially ATV/r for treatment-naïve patients under careful monitoring. Currently, the great number of HCV molecules under development is promising substantially improved treatment paradigms with shorter treatment durations, fewer AEs, less DDIs, once-daily administration and even interferon-free regimens. The decision to treat now with the available HCV PIs or defer therapy until the second generation of HCV direct acting antivirals become available should be based on liver fibrosis staging and fibrosis progression during follow up. More data are urgently needed regarding the efficacy of triple therapy in HIV/HCV co-infected patients who previously failed PegIFN/RBV therapy as well as in patients with more advanced fibrosis stages.
PMCID: PMC4040720  PMID: 25165545
HIV; hepatitis C; DAA; pegylated interferon; ribavirin
13.  A Viral Dynamic Model for Treatment Regimens with Direct-acting Antivirals for Chronic Hepatitis C Infection 
PLoS Computational Biology  2012;8(1):e1002339.
We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.
Author Summary
Hepatitis C virus chronically infects approximately 180 million people worldwide. The treatment aim for patients chronically infected with hepatitis C is viral eradication or sustained viral response (SVR). Historical standard of care for HCV treatment was peginterferon-alfa and ribavirin. Recently, approved HCV protease inhibitors, in combination with peginterferon-alfa and ribavirin, have demonstrated higher SVR rates compared to peginterferon-alfa and ribavirin alone. As members of a novel class of compounds directly targeting hepatitis C virus, HCV protease inhibitors have different mechanisms of actions and are affected by resistance and fitness of HCV variants. The significance of these different mechanisms of action, and the interplays between resistance and viral fitness to the treatment outcome has not been elucidated. Here, we developed and validated an integrative, mechanistic model of viral dynamics in response to a combination regimen including telaprevir, peginterferon-alfa, and ribavirin. The model was developed from early studies in 478 treatment-naïve patients and its SVR rate predictions were verified in 2380 patients in subsequent studies. These results provide an example of the use of mechanistic information to the development of viral dynamic model that has been useful in the design of optimal treatment regimens.
PMCID: PMC3252270  PMID: 22241977
14.  Finally sofosbuvir: an oral anti-HCV drug with wide performance capability 
Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance.
PMCID: PMC4270038  PMID: 25540594
Hepatitis C virus; sofosbuvir; polymerase inhibitors; interferon-free treatment
15.  Anti-HCV drugs in the pipeline 
Current opinion in virology  2011;1(6):607-616.
Several directly-acting and host-targeting antivirals that inhibit hepatitis C virus replication have entered clinical trials. Amongst the most advanced of these are RG7128, an inhibitor of the NS5B polymerase; BMS-790052, an inhibitor of NS5A; and alisporivir, an inhibitor of human cyclophilins. These agents have potent antiviral activity in chronic HCV patients, act additively or synergistically with inhibitors of the HCV NS3/4A protease, and improve the rate of virologic response produced by traditional pegylated interferon plus ribavirin therapy. No cross resistance has been observed; moreover, nucleoside NS5B and cyclophilin inhibitors appear to suppress resistance to non-nucleoside NS5B and NS3/4A inhibitors. Several recent reports of virologic responses produced by combinations of agents that inhibit HCV replication in the absence of interferon provide optimism that eradication of HCV will be possible without interferon in the future.
PMCID: PMC3775341  PMID: 22440918
16.  A Novel Small Molecule Inhibitor of Hepatitis C Virus Entry 
PLoS Pathogens  2010;6(9):e1001086.
Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.
Author Summary
Approximately 170 million people worldwide are chronically infected with hepatitis C virus (HCV), which is a leading cause of chronic liver disease. Current treatments are not optimal; however, several molecules that inhibit HCV replication are in development. However, resistance to individual antivirals is likely to develop, requiring therapy consisting of a combination of drugs targeting different stages of the viral life cycle. The entry of HCV into hepatocytes is a multistep process, involving at least four cellular receptors, leading to virion endocytosis and fusion of the viral and cellular membranes. Unlike the HCV replication process, these steps have not been thoroughly exploited as targets for antiviral intervention. Therefore, we screened a small molecule library for inhibitors of HCV entry and identified a compound, EI-1, that potently blocked genotype 1a and 1b HCV infection. Importantly, EI-1 also prevented direct cell-to-cell spread of HCV, a potentially significant route of transmission in infected livers. In addition, our studies suggest that EI-1 susceptibility is mediated by the viral E2 envelope glycoprotein, as resistance in E2 can overcome inhibition. The antiviral activity of EI-1 is potentiated by combinations with other HCV inhibitors, demonstrating the value of entry inhibitors in potential combination antiviral regimens.
PMCID: PMC2936744  PMID: 20838466
17.  Novel drugs in the management of difficult-to-treat hepatitis C genotypes 
Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States, with approximately 3.2 million Americans being chronically infected. Rates of HCV-related end-stage liver disease and its associated morbidity and mortality have yet to peak, so there is a pressing need for more effective and tolerable HCV treatment. HCV genotypes 1, 4, 5, and 6 are considered difficult to treat, and the need for improved therapies is especially great for persons infected with these genotypes.
Current strategies for HCV treatment
Current therapy for genotype 1 HCV infection includes triple therapy with pegylated interferon, ribavirin, and a NS3/4A protease inhibitor. Sustained virologic response (SVR) rates with triple therapy range from 42% to 75%, a vast improvement over pegylated interferon and ribavirin therapy alone. However, response rates remain suboptimal, and triple therapy is associated with significant adverse effects and is only indicated for genotype 1 HCV infection.
Novel drugs for HCV treatment
HCV drug development is proceeding at a rapid pace to meet this need. Novel direct acting antiviral agents in several classes, including new NS3/4A serine protease inhibitors, NS5A replication complex inhibitors, NS5B polymerase inhibitors, interferon lambda, and microRNAs, are in varying stages of development. These new therapeutic agents promise SVR rates of up to 100% with durations as short as 12 weeks and, often, fewer adverse effects.
New drug development in HCV is proceeding at an unprecedented pace. Novel agents promise higher SVR rates, shorter duration of therapy, and fewer adverse effects than have been possible with HCV therapy to date.
PMCID: PMC3953740  PMID: 24696624
hepatitis C; direct acting antivirals; genotype
18.  Emerging Therapies for Hepatitis C 
Gut and Liver  2014;8(5):471-479.
The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), the current therapy for hepatitis C virus (HCV) infection, has saved the lives of many HCV-infected patients. Direct-acting antivirals (DAAs) target several sites of HCV nonstructural proteins, resulting in the cessation of viral replication. The first NS3/4A protease inhibitors consisted of boceprevir and telaprevir, which have shown superior efficacy against genotype 1 HCV infection when combined with PEG-IFN/RBV compared with the standard therapy in both treatment-naive and -experienced patients. Simeprevir, faldaprevir, and asunaprevir are second-wave, first-generation NS3/4A inhibitors that have already been or will soon be approved. Second-generation protease inhibitors are in clinical trials. Daclatasvir is the first approved DAA belonging to the class of NS5A replication complex inhibitors. The potency of daclatasvir is very high, and this drug is an important and essential component of combination regimens for all genotypes. Sofosbuvir, the first approved NS5B polymerase inhibitor, is characterized by high potency and genetic barriers to resistance. Sofosbuvir combined with RBV achieved an interferon-free regimen in genotype 2 or 3 patients with a reduced treatment duration. It can also be used in combination with PEG-IFN/RBV in genotype 1 patients for 12 weeks. DAAs have provided new hope for curing HCV infections with a short treatment duration and acceptable adverse events.
PMCID: PMC4164256  PMID: 25228970
Hepatitis C; Direct acting antiviral; Pegylated interferon; Ribavirin
19.  New treatments for chronic hepatitis C: An overview for paediatricians 
World Journal of Gastroenterology : WJG  2014;20(43):15965-15974.
Pegylated interferon (IFN) α-2a or 2b in combination with ribavirin for children aged 3 years and older is the standard treatment for paediatric chronic hepatitis C. This treatment regimen was developed firstly in adults. In recent years, a number of direct-acting antiviral agents (DAAs) are under development for treatment of chronic hepatitis C virus (HCV) infection. These agents block viral replication inhibiting directly one of the several steps of HCV lifecycle. DAAs are classified into several categories based on their molecular target: HCV NS3/4A protease inhibitors, HCV NS5B polymerase inhibitors and HCV NS5A inhibitors. Other promising compounds are cyclophilin A inhibitors, mi-RNA122 and IFN-λ. Several new drugs associations will be developed in the near future starting from the actual standard of care. IFN-based and IFN-free regimens are being studied in adults. In this constantly evolving scenario new drug regimens targeted and suitable for children would be possible in the next future. Especially for children, it is crucial to identify the right combination of drugs with the highest potency, barrier to resistance and the best safety profile.
PMCID: PMC4239484  PMID: 25473150
Hepatitis C virus; Children; Treatment; Interferon; Ribavirin; Daclatasvir; Sofosbuvir; Efficacy; Safety
20.  Oral antiviral therapies for chronic hepatitis C infection 
The treatment of hepatitis C virus (HCV) infection with pegylated interferon alpha and ribavirin leads to a sustained virologic response in around 50% of patients with HCV genotype 1, 65% with HCV genotype 4, 75% with HCV genotype 3 and around 80% with HCV genotype 2. A better understanding of the HCV lifecycle has resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins [NS3/4A protease inhibitors, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase inhibitors, NS5A replication complex inhibitors]. This review summarizes the main clinical data for the combinations of oral DAAs. DAAs, either in combination with pegylated interferon alpha or in interferon-free regimens, have demonstrated a high level of antiviral efficacy and a generally well-tolerated safety profile in treatment-naïve patients and in prior nonresponders to pegylated interferon alpha/ribavirin. Oral combination of new DAAs is likely to become the standard of care for chronic HCV in treatment-naïve or treatment-experienced patients. However, most studies so far have included small numbers of ‘easy-to-treat’ patients with short post-treatment periods for defining the sustained virologic response. Extension of the number of treated patients (including ‘difficult-to-treat’ patients, i.e. patients infected with genotype 3, who failed to respond to first-generation protease inhibitors or with cirrhosis as well as immunocompromised patients) and of the post-treatment follow up in a real-life setting could significantly worsen the rate of recovery. In these ‘difficult-to-treat’ patients, the rate of virologic cure with new DAAs could be lower than expected and consequently interferons may be still necessary in combination with the new drugs.
PMCID: PMC4040722  PMID: 25165547
cirrhosis; combination therapy; direct-acting antiviral; hepatitis C virus; polymerase inhibitor; protease inhibitor; replication complex inhibitor
21.  Viral Determinants of Resistance to Treatment in Patients with Hepatitis C 
Clinical Microbiology Reviews  2007;20(1):23-38.
Chronic hepatitis C virus (HCV) infection affects more than 170 million persons worldwide and is responsible for the development of liver cirrhosis in many cases. Standard treatment with pegylated alpha interferon (IFN-α) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-α is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease/polymerase inhibitors) are being evaluated in phase 1/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-α-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. In turn, in vitro, several mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described for different HCV proteins. By the introduction of direct antiviral drugs, hepatitis C therapy now is entering a new era in which the development of resistance may become the most important parameter for treatment success or failure.
PMCID: PMC1797633  PMID: 17223621
22.  Hepatitis C: viral and host factors associated with non-response to pegylated interferon plus ribavirin 
Liver International  2010;30(9):1259-1269.
Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG-IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1-infected patients. Several viral and host factors have been associated with non-response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non-responders, some interferon-stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG-IFN plus ribavirin) to 70% (for patients treated with a combination of PEG-IFN plus ribavirin plus telaprevir). Different elements are associated with non-response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non-response, to overcome it and to identify factors that can help to predict the response to anti-HCV therapy.
PMCID: PMC3071938  PMID: 20633102
antiviral; boceprevir; immunity; interferon-stimulated genes; pegylated-interferon; polymerase inhibitors; protease inhibitors; STAT-C; sustained virological response; telaprevir
23.  Modeling Viral Evolutionary Dynamics after Telaprevir-Based Treatment 
PLoS Computational Biology  2014;10(8):e1003772.
For patients infected with hepatitis C virus (HCV), the combination of the direct-acting antiviral agent telaprevir, pegylated-interferon alfa (Peg-IFN), and ribavirin (RBV) significantly increases the chances of sustained virologic response (SVR) over treatment with Peg-IFN and RBV alone. If patients do not achieve SVR with telaprevir-based treatment, their viral population is often significantly enriched with telaprevir-resistant variants at the end of treatment. We sought to quantify the evolutionary dynamics of these post-treatment resistant variant populations. Previous estimates of these dynamics were limited by analyzing only population sequence data (20% sensitivity, qualitative resistance information) from 388 patients enrolled in Phase 3 clinical studies. Here we add clonal sequence analysis (5% sensitivity, quantitative) for a subset of these patients. We developed a computational model which integrates both the qualitative and quantitative sequence data, and which forms a framework for future analyses of drug resistance. The model was qualified by showing that deep-sequence data (1% sensitivity) from a subset of these patients are consistent with model predictions. When determining the median time for viral populations to revert to 20% resistance in these patients, the model predicts 8.3 (95% CI: 7.6, 8.4) months versus 10.7 (9.9, 12.8) months estimated using solely population sequence data for genotype 1a, and 1.0 (0.0, 1.4) months versus 0.9 (0.0, 2.7) months for genotype 1b. For each individual patient, the time to revert to 20% resistance predicted by the model was typically comparable to or faster than that estimated using solely population sequence data. Furthermore, the model predicts a median of 11.0 and 2.1 months after treatment failure for viral populations to revert to 99% wild-type in patients with HCV genotypes 1a or 1b, respectively. Our modeling approach provides a framework for projecting accurate, quantitative assessment of HCV resistance dynamics from a data set consisting of largely qualitative information.
Author Summary
Hepatitis C virus (HCV) chronically infects approximately 170 million people worldwide. The goal of HCV treatment is viral eradication (sustained virologic response; SVR). Telaprevir directly inhibits viral replication by inhibiting the HCV protease, leading to high SVR rates when combined with pegylated-interferon alfa and ribavirin. Telaprevir-resistant variants may be detected in the subset of patients who do not achieve SVR with telaprevir. While the clinical impact of viral resistance is unknown, typically the telaprevir-sensitive virus re-emerges after the end of treatment due to competition between the telaprevir-sensitive and resistant variants. Previous estimates of these competition dynamics were obtained from population sequence data, which are qualitative and have a limited sensitivity of ∼20%. We sought to improve these estimates by combining these data with clonal sequence data, which are quantitative and have a sensitivity of ∼5%, and using quantitative modeling. The resulting model, which was verified with an independent data set, predicted that the median time for telaprevir-resistant variants to decline to less than 1% of the viral population was ≤1 year. Our modeling approach provides a framework for accurately projecting HCV resistance dynamics from a dataset consisting of largely qualitative information.
PMCID: PMC4138032  PMID: 25101970
24.  Hepatitis C virus protease inhibitor-resistance mutations: Our experience and review 
Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection are one of the major advances in its medical treatment. The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States, Europe, and Japan. When combined with peginterferon plus ribavirin, these agents increase sustained virologic response rates to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection. Without peginterferon plus ribavirin, DAA mono-therapies increased DAA-resistance mutations. Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future. However, it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases. Furthermore, these mutations exhibit cross-resistance to multiple drugs. The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown, and it is as yet uncertain whether such variants are sensitive to DAAs. We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors. Here, we reviewed the literature on resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience.
PMCID: PMC3870547  PMID: 24379619
Direct-acting antiviral agent; Hepatitis C virus; Protease inhibitor; Resistance mutation; Sequence analysis
25.  Human Subtilase SKI-1/S1P Is a Master Regulator of the HCV Lifecycle and a Potential Host Cell Target for Developing Indirect-Acting Antiviral Agents 
PLoS Pathogens  2012;8(1):e1002468.
HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1) – or site-1 protease (S1P). SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI-1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP)/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF-429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow development of novel broad-spectrum biopharmaceuticals that could lead to novel indirect-acting antiviral options with the current standard of care.
Author Summary
Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver cancer and liver transplantation worldwide. No vaccine is available for preventing the spread of HCV, and the current therapeutic regimen is only moderately effective and causes serious side effects. New antiviral agents are required to treat HCV infection, but the high mutation rate of HCV hinders the effectiveness of virus-specific inhibitors. Targeting the host enzymes required for HCV to replicate offers a promising new direction for antiviral therapy. During infection, HCV promotes excessive fat accumulation in the liver, which benefits the virus as this promotes formation of lipid droplets, a cellular organelle essential for assembly of new HCV infectious viral particles. Here, we report the development of a specific inhibitor targeting SKI-1/S1P, a host enzyme required for lipid production in human cells. We show that inhibiting SKI-1/S1P activity in human liver cells effectively blocks lipid droplet formation and HCV infection. Many prevalent human viruses, such as dengue, rotavirus, and hepatitis B virus, hijack host lipid metabolic pathways similar to those targeted by HCV to complete their lifecycle. Thus, we propose that cellular SKI-1/S1P is a potential target for developing desperately needed novel broad-spectrum antiviral drugs.
PMCID: PMC3252376  PMID: 22241994

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