HCV Drug Resistance

A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (30 June 2015) | Viewed by 107231

Special Issue Editor


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Guest Editor
Institut National de la Santé et de la Recherche Médicale, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Pôle Hépato-digestif, Institut Hopitalo-Universitaire, Strasbourg, Université de Strasbourg, Strasbourg, France
Interests: hepatology; liver fibrosis; non-alcoholic fatty liver disease (NAFLD); hepatocellular carcinoma; chemoprevention; viral hepatitis
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Special Issue Information

Dear Collegues,

Chronic hepatitis C is a major cause of liver diseases world-wide. These include liver cirrhosis and hepatocellular carcinoma. More than 130 million persons, or about 3% of the world’s population, are chronically infected with the hepatitis C virus (HCV). In the United States, chronic hepatitis C, the most common cause of liver-related death and reason for liver transplantation, recently eclipsed HIV as a cause of mortality. The development of direct-acting antivirals (DAAs) has revolutionized HCV treatment by offering genuine prospects for the first comprehensive cure of a chronic viral infection in man (R. T. Chung and T. F. Baumert, New Engl. J. Med. 2014). While antiviral resistance is a significant challenge for interferon-based therapies, drug resistance in advanced DAA combination therapies appears to be limited to a small fraction of patients. However, distinct genotypes, patients with advanced liver disease and transplantation or patients with HIV-HCV co-infection may pose challenges. In this special issue of Viruses we review mechanisms of antiviral resistance for different class of antiviral drugs, the detection and monitoring of resistance in clinical practice, the clinical impact of resistance in different patient groups and strategies how to prevent and address resistance using complementary antiviral strategies.

Prof. Thomas F. Baumert, MD
Guest Editor

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Keywords

  • hepatitis C
  • direct-acting antivirals
  • interferon
  • co-infection
  • resistance
  • ribavirin
  • liver disease

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Published Papers (10 papers)

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Editorial

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155 KiB  
Editorial
Addressing the Challenges of Hepatitis C Virus Resistance and Treatment Failure
by Che C. Colpitts and Thomas F. Baumert
Viruses 2016, 8(8), 226; https://doi.org/10.3390/v8080226 - 16 Aug 2016
Cited by 11 | Viewed by 5343
Abstract
Chronic hepatitis C is a major cause of chronic liver disease, including liver cirrhosis and hepatocellular carcinoma. The development of direct-acting antivirals (DAAs) revolutionized hepatitis C virus (HCV) treatment by offering genuine prospects for the first comprehensive cure of a chronic viral infection [...] Read more.
Chronic hepatitis C is a major cause of chronic liver disease, including liver cirrhosis and hepatocellular carcinoma. The development of direct-acting antivirals (DAAs) revolutionized hepatitis C virus (HCV) treatment by offering genuine prospects for the first comprehensive cure of a chronic viral infection in humans. While antiviral resistance is a significant limitation for interferon-based therapies, resistance and treatment failure still appear to be present in a small fraction of patients even in state-of-the-art DAA combination therapies. Therefore, treatment failure and resistance still remain a clinical challenge for the management of patients not responding to DAAs. In this special issue of Viruses on HCV drug resistance, mechanisms of antiviral resistance for different classes of antiviral drugs are described. Furthermore, the detection and monitoring of resistance in clinical practice, the clinical impact of resistance in different patient groups and strategies to prevent and address resistance and treatment failure using complementary antiviral strategies are reviewed. Full article
(This article belongs to the Special Issue HCV Drug Resistance)

Review

Jump to: Editorial

614 KiB  
Review
Mouse Systems to Model Hepatitis C Virus Treatment and Associated Resistance
by Ahmed Atef Mesalam, Koen Vercauteren and Philip Meuleman
Viruses 2016, 8(6), 176; https://doi.org/10.3390/v8060176 - 22 Jun 2016
Cited by 15 | Viewed by 7507
Abstract
While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to [...] Read more.
While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to the emergence of resistant viral variants. Meanwhile, multiple direct acting antiviral agents (DAAs) targeting either the HCV NS3/4A protease, NS5A or NS5B polymerase have been approved and these have varying potencies and distinct propensities to provoke resistance. The pre-clinical in vivo assessment of drug efficacy and resistant variant emergence underwent a great evolution over the last decade. This field had long been hampered by the lack of suitable small animal models that robustly support the entire HCV life cycle. In particular, chimeric mice with humanized livers (humanized mice) and chimpanzees have been instrumental for studying HCV inhibitors and the evolution of drug resistance. In this review, we present the different in vivo HCV infection models and discuss their applicability to assess HCV therapy response and emergence of resistant variants. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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671 KiB  
Review
Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals
by Asma Ahmed and Daniel J. Felmlee
Viruses 2015, 7(12), 6716-6729; https://doi.org/10.3390/v7122968 - 18 Dec 2015
Cited by 72 | Viewed by 16693
Abstract
There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained [...] Read more.
There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained viral response (SVR) rates of more than 90% in phase 2 and phase 3 clinical trials; however, this is slightly lower in real-life cohorts. Hepatitis C virus resistant variants are seen in most patients who do not achieve SVR due to selection and outgrowth of resistant hepatitis C virus variants within a given host. These resistance associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes. The understanding of these mutations has a clear clinical implication in terms of choice and combination of drugs used. In this review, we describe mechanism of action of currently available drugs and summarize clinically relevant resistance data. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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Review
Virologic Tools for HCV Drug Resistance Testing
by Slim Fourati and Jean-Michel Pawlotsky
Viruses 2015, 7(12), 6346-6359; https://doi.org/10.3390/v7122941 - 4 Dec 2015
Cited by 43 | Viewed by 6647
Abstract
Recent advances in molecular biology have led to the development of new antiviral drugs that target specific steps of the Hepatitis C Virus (HCV) lifecycle. These drugs, collectively termed direct-acting antivirals (DAAs), include non-structural (NS) HCV protein inhibitors, NS3/4A protease inhibitors, NS5B RNA-dependent [...] Read more.
Recent advances in molecular biology have led to the development of new antiviral drugs that target specific steps of the Hepatitis C Virus (HCV) lifecycle. These drugs, collectively termed direct-acting antivirals (DAAs), include non-structural (NS) HCV protein inhibitors, NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors (nucleotide analogues and non-nucleoside inhibitors), and NS5A inhibitors. Due to the high genetic variability of HCV, the outcome of DAA-based therapies may be altered by the selection of amino-acid substitutions located within the targeted proteins, which affect viral susceptibility to the administered compounds. At the drug developmental stage, preclinical and clinical characterization of HCV resistance to new drugs in development is mandatory. In the clinical setting, accurate diagnostic tools have become available to monitor drug resistance in patients who receive treatment with DAAs. In this review, we describe tools available to investigate drug resistance in preclinical studies, clinical trials and clinical practice. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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Review
Natural Products as Tools for Defining How Cellular Metabolism Influences Cellular Immune and Inflammatory Function during Chronic Infection
by Erica S. Lovelace and Stephen J. Polyak
Viruses 2015, 7(12), 6218-6232; https://doi.org/10.3390/v7122933 - 30 Nov 2015
Cited by 19 | Viewed by 6919
Abstract
Chronic viral infections like those caused by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause disease that establishes an ongoing state of chronic inflammation. While there have been tremendous improvements towards curing HCV with directly acting antiviral agents (DAA) and keeping [...] Read more.
Chronic viral infections like those caused by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause disease that establishes an ongoing state of chronic inflammation. While there have been tremendous improvements towards curing HCV with directly acting antiviral agents (DAA) and keeping HIV viral loads below detection with antiretroviral therapy (ART), there is still a need to control inflammation in these diseases. Recent studies indicate that many natural products like curcumin, resveratrol and silymarin alter cellular metabolism and signal transduction pathways via enzymes such as adenosine monophosphate kinase (AMPK) and mechanistic target of rapamycin (mTOR), and these pathways directly influence cellular inflammatory status (such as NF-κB) and immune function. Natural products represent a vast toolkit to dissect and define how cellular metabolism controls cellular immune and inflammatory function. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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Review
Resistance of Hepatitis C Virus to Inhibitors: Complexity and Clinical Implications
by Celia Perales, Josep Quer, Josep Gregori, Juan Ignacio Esteban and Esteban Domingo
Viruses 2015, 7(11), 5746-5766; https://doi.org/10.3390/v7112902 - 6 Nov 2015
Cited by 39 | Viewed by 15275
Abstract
Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they [...] Read more.
Selection of inhibitor-resistant viral mutants is universal for viruses that display quasi-species dynamics, and hepatitis C virus (HCV) is no exception. Here we review recent results on drug resistance in HCV, with emphasis on resistance to the newly-developed, directly-acting antiviral agents, as they are increasingly employed in the clinic. We put the experimental observations in the context of quasi-species dynamics, in particular what the genetic and phenotypic barriers to resistance mean in terms of exploration of sequence space while HCV replicates in the liver of infected patients or in cell culture. Strategies to diminish the probability of viral breakthrough during treatment are briefly outlined. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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Review
Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection
by Mirjam B. Zeisel, Emilie Crouchet, Thomas F. Baumert and Catherine Schuster
Viruses 2015, 7(11), 5659-5685; https://doi.org/10.3390/v7112898 - 2 Nov 2015
Cited by 53 | Viewed by 17044
Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of [...] Read more.
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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Review
HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy
by Kazuaki Chayama and C. Nelson Hayes
Viruses 2015, 7(10), 5328-5342; https://doi.org/10.3390/v7102876 - 13 Oct 2015
Cited by 33 | Viewed by 9945
Abstract
Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, [...] Read more.
Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV) therapy in Asia have largely paralleled those in the United States, Japan’s July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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Review
Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance
by Auda A. Eltahla, Fabio Luciani, Peter A. White, Andrew R. Lloyd and Rowena A. Bull
Viruses 2015, 7(10), 5206-5224; https://doi.org/10.3390/v7102868 - 29 Sep 2015
Cited by 100 | Viewed by 13210
Abstract
The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The [...] Read more.
The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development, and direct-acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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Review
Interferon-Free Hepatitis C Treatment before and after Liver Transplantation: The Role of HCV Drug Resistance
by Bruno Roche, Audrey Coilly, Anne-Marie Roque-Afonso and Didier Samuel
Viruses 2015, 7(9), 5155-5168; https://doi.org/10.3390/v7092864 - 23 Sep 2015
Cited by 19 | Viewed by 6909
Abstract
Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within [...] Read more.
Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients. Full article
(This article belongs to the Special Issue HCV Drug Resistance)
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