ReviewStatus of Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection and Remaining Challenges
Section snippets
How Short Can Therapy Be?
Two oral DAA regimens have been approved for 8-week treatment duration in selected patients with chronic HCV infection: 1) sofosbuvir and ledipasvir and 2) glecaprevir and pibrentasvir. The combination of sofosbuvir and ledipasvir can be used in patients infected with HCV genotype 1 who are treatment naïve, without cirrhosis, nonblack, and HIV negative. In the phase 3 ION-3 protocol, 647 treatment-naïve patients without cirrhosis infected with HCV genotype 1 were randomly assigned to groups
How Effective Are Generic Agents?
The World Health Organization released a global strategy on viral hepatitis that calls for the elimination of HCV infection as a public health threat by 2030, defined by an 80% reduction in new HCV infections and a 65% reduction in HCV-associated mortality,25 which is estimated to result in an absolute decrease in annual global HCV-associated deaths from 1.4 million to fewer than 0.5 million.26 However, this will require diagnosing 90% of people living with HCV and treating 80% of diagnosed
Management of DAA Failure
Treatment with DAAs leads to selection for drug-resistant HCV variants. HCV infection is a master among viruses at acquisition of RASs, which arise in patients receiving suboptimal antiviral regimens. Risk of treatment failure is low in patients receiving 2 different classes of highly active DAAs.52, 53 However, even if we assume a low rate of treatment failure (less than 2% in previously untreated patients with compensated liver disease who adhered to an optimal first-line regimen), the number
Association of Failed DAA Regimens With RAS
In most patients for whom DAA therapy fails, strains of HCV emerge with variants that mediate resistance to the drug the patient received. The risk for selection of RASs is higher among patients with virologic breakthrough compared with patients with relapse. In 2 large multicenter studies (1 from European collaborators and 1 from Italy), the prevalence of drug-specific RASs after DAA failure ranged from 66% to 77% after a relapse and 86% to 97% after nonresponse or on-treatment virologic
Testing for Baseline RASs
A genotype (analysis of RAS)-to-phenotype (susceptibility to DAAs) personalized approach to treatment (selecting the optimal combination from the available 3 different DAA classes, based on baseline RAS) seems logical. Why then do guidelines not support baseline tests for resistance—especially when facing second-line treatments for patients failed by a previous all-oral DAA regimen?1, 68 The positive predictive value for treatment failure associated with certain pre-existing baseline RASs is
Treatment of Patients Failed by DAAs
Second-line treatment strategies should involve combinations of DAAs that target different viral proteins and have nonoverlapping resistance profiles. Sofosbuvir has become the backbone of most of the recommended regimens for patients failed by DAAs because of its pangenotypic activity and a high barrier to development of resistant virus.79 This nucleoside NS5B inhibitor is effective in nearly all patients, regardless of treatment history, except for patients with HCV strains that acquire the
Are New Drugs Needed?
Given the unprecedented revolution in the paradigm for the treatment of chronic HCV infection by the licensing of DAAs, are the licensed and next-generation DAAs sufficient to eradicate HCV, or will new drugs and new targets still be needed? Observational studies from the real world indicate that more than 90% of patients with chronic HCV infection are cured by DAA-based regimens. Nevertheless, several challenges remain.91 Probably the most important challenge is the limited access to DAA
What Are the Most Promising Targets?
In addition to developing DAAs, researchers have been developing strategies to stimulate the anti-HCV immune response. For example, therapeutic vaccines have been used to boost T-cell responses to the virus, or broadly neutralizing antiviral antibodies to prevent HCV infection of grafts. In clinical trials, therapeutic vaccines have had only limited success compared with DAAs—most likely because of their inability to restore functional T-cell responses in patients with chronic infection and
Future Directions
Thirty years after the discovery of HCV, the development of DAAs revolutionized the care of patients with chronic infection. Licensed DAAs achieve cure in more than 90% of patients in the real world. Combinations have reduced the duration of therapy, although there appears to be a minimum length of treatment, and truncated regimens are not optimal for all patient populations. Difficult-to-treat patients, such as those with advanced liver disease, renal failure, or HCV genotype 3 infection,
Acknowledgments
Thomas F. Baumert would like to thank Drs Emilie Crouchet, Gaetan Ligat, and Catherine Schuster (University of Strasbourg) for preparing Figure 1. We acknowledge Dr Gaetan Ligat for his assistance with formatting the reference section.
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Conflicts of interest Thomas F. Baumert is a coinventor on patent applications and a patent on claudin-1–specific antibodies for treatment of chronic hepatitis C virus infection filed by INSERM, the University of Strasbourg, and Genovac. He has received grant support from Biotest and served as an advisor for Gilead and Biotest. Joseph K. Lim has received research grant support from AbbVie, Allergan, Conatus, Genfit, Gilead, and Intercept and has served as consultant to Bristol-Myers Squibb and Gilead. David R. Nelson has received research grant support from AbbVie, Bristol-Myers Squibb, Gilead Janssen, and Merck. He is a stockholder of Target PharmaSolutions. Thomas Berg has received research support from AbbVie, Roche, Bristol-Myers Squibb, Gilead, Novartis, Merck/MSD, Intercept, Janssen, Novartis, Sequana Medical, and Pfizer; and has provided consultancy, been a member of speakers bureaus, and participated in advisory boards for AbbVie, Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GSK, Intercept, Janssen, MSD/Merck, Merz, Novartis, Sequana Medical, and Roche.
Funding Thomas F. Baumert acknowledges research support by the European Union (ERC-AdG-2014-671231-HEPCIR, EU H2020-667273-HEPCAR, FP7 HEPAMAB GAN 305600), The French National Research Agency (LABEX ANR-10-LABX-0028_HEPSYS), the National Institutes of Health (1U19AI123862-01, 1R21CA209940-01A1, R03AI131066), the US Department of Defense (W81XWH-16-1-0363), ARC Paris, and Institute Hopitalo-Universitaire Strasbourg (TheraHCC IHUARC IHU201301187) and the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (2017/1633). David R. Nelson acknowledges research support by the University of Florida Clinical and Translational Science Institute, which is supported in part by the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR001427.