ReviewChallenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection
Introduction
Hepatitis C virus (HCV) infection is a major global health concern, affecting approximately 70 million people or 1% of the world population according to recent estimates.1 Moreover, chronic HCV infection is associated with substantial morbidity and mortality, with liver-related complications including cirrhosis, liver failure and hepatocellular carcinoma (HCC).1 The goal of antiviral therapy is to prevent these complications by achieving viral eradication. This is defined as undetectable HCV RNA 12 weeks after treatment cessation, also called a sustained virologic response (SVR).[2], [3]
The recent introduction of direct-acting antivirals (DAAs) has revolutionised HCV therapy and made viral cure, which is associated with improved quality of life, a reality in the vast majority of patients.[4], [5] Even in patients in whom interferon-based treatment has traditionally been difficult or contraindicated, including those with decompensated cirrhosis or severe kidney disease, HCV can now be eradicated with minimal toxicity and good overall tolerability.[6], [7], [8] Moreover, large-scale post-marketing studies have shown that data from clinical trials can be replicated in the real-world setting with high overall efficacy and few safety concerns.[9], [10], [11]
Finally, there is increasing evidence that viral eradication following DAA therapy is associated with a significant decrease in liver-related morbidity and mortality, and the adverse extrahepatic sequelae of HCV infection, while being associated with an increase in health-related quality of life.[12], [13], [14], [15] Despite these overwhelming advances, there remain challenges to eliminating HCV in some patient subgroups, including those in whom previous DAA-based therapies have failed.
The recent approval of pangenotypic DAA regimens has addressed the remaining gaps in the HCV treatment portfolio (Fig. 1). These regimens include the NS3/4A protease inhibitor pibrentasvir plus the NS5A inhibitor glecaprevir (GLE/PIB; AbbVie, North Chicago, IL, USA) and the NS5B polymerase inhibitor sofosbuvir in combination with the NS5A inhibitor velpatasvir plus the NS3/4A protease inhibitor voxilaprevir (SOF/VEL/VOX; Gilead Sciences, Foster City, CA, USA).
In this review, we will discuss the limitations of previous DAA regimens and how these have been overcome with the advent of recently approved DAA regimens (Table 1, Table 2).
Section snippets
Genotype inclusivity of existing DAA regimens
There are eight major HCV genotypes and several dozens of subtypes that show a high degree of genetic variability.[16], [17] Worldwide, genotype 1 is the most prevalent HCV genotype, followed by genotypes 3, 2 and 4.18 Interestingly, some genotypes show a high degree of endemicity, particularly genotype 3 in India and Pakistan and genotype 4 in Egypt and the Middle East.[18], [19] The natural course of HCV infection may vary among genotypes. For example, genotype 3 is associated with increased
Glecaprevir/pibrentasvir clinical trials
Both glecaprevir and pibrentasvir (GLE/PIB) have very limited metabolic activity in the liver or kidney, and have potent antiviral activity in vitro against all major HCV genotypes. PIB has a high barrier to common RASs identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, and 93 of the NS5A gene.62
A number of phase III trials evaluated an 8–16-week treatment duration in non-cirrhotic patients across genotypes 1–6. In the ENDURANCE-1 study, 8 or 12 weeks
Sofosbuvir/velpatasvir/voxilaprevir clinical trials
The SOF/VEL/VOX regimen is approved in Europe, Canada and the United States for the treatment of patients with chronic HCV infection without cirrhosis or with compensated cirrhosis who have previously been treated with an NS5A inhibitor. The recommended treatment duration is 12 weeks. In Europe, 8–12 weeks of SOF/VEL/VOX is also approved for DAA-naïve patients, with and without compensated cirrhosis. As with the major GLE/PIB trials, the four POLARIS phase III trials, which evaluated the safety
Pangenotypic therapies
From a global perspective, HCV elimination can only be achieved with DAA regimens that are highly active in all known HCV genotypes, while having excellent tolerability profiles and few drug-drug interactions. The two direct-acting antiviral drug combinations GLE/PIB and SOF/VEL, with SOF/VEL/VOX as a backup, have the ability to address most, if not all, existing therapeutic challenges and limitations associated with HCV therapy. This is particularly true for the treatment of HCV genotypes 4,
Remaining challenges
As with all other regimens containing HCV NS3/4A protease inhibitors, GLE/PIB and SOF/VEL/VOX, which both contain an NS3/4A protease inhibitor, are not recommended in patients with decompensated cirrhosis (Child-Turcotte-Pugh stage B or C). Thus, patients with decompensated cirrhosis and prior DAA failure have no explicit treatment options at this time. For these patients, alternative treatment options, including off label DAA combinations without an NS3/4A inhibitor such as SOF/VEL ± ribavirin
Conflict of interest
J.V. reports personal fees from AbbVie, Gilead, Merck, outside the submitted work. I.J. reports personal fees from AbbVie, Bristol-Myers Squibb, Intercept; grants and personal fees from Gilead, Merck, Janssen, outside the submitted work. J.S.P. reports personal fees from Gilead, outside the submitted work. S.Z. reports personal fees from AbbVie, Gilead, Merck, Janssen, Falk, Intercept, outside the submitted work.
Please refer to the accompanying ICMJE disclosure forms for further details.
References (78)
- et al.
Patient-reported outcomes and fatigue in patients with chronic hepatitis C infection
Clin Liver Dis
(2017) - et al.
Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study
Lancet
(2015) - et al.
Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real-world cohort
J Hepatol
(2017) - et al.
Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C
J Hepatol
(2018) - et al.
Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation
J Hepatol
(2017) - et al.
Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis
J Hepatol
(2016) - et al.
Global epidemiology and genotype distribution of the hepatitis C virus infection
J Hepatol
(2014) - et al.
Treatment predictors of a sustained virologic response in hepatitis B and C
J Hepatol
(2008) - et al.
Clinical relevance of HCV antiviral drug resistance
Curr Opin Virol
(2012) - et al.
SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon α-2b for genotype 1 nonresponders
Gastroenterology
(2007)
Dynamic hepatitis c virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir
Gastroenterology
Origin, prevalence and response to therapy of hepatitis C virus genotype 2k/1b chimeras
J Hepatol
Efficacy of an eight-week regimen of grazoprevir plus elbasvir with and without ribavirin in treatment-naive, noncirrhotic HCV genotype 1B infection
J Hepatol
Ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis C virus genotype 1b infection without cirrhosis (GARNET): a single-arm, open-label, phase 3b trial
Lancet Gastroenterol Hepatol
Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS
Kidney Int
Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease
Gastroenterology
HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe
J Hepatol
The importance of resistance to direct antiviral drugs in HCV infection in clinical practice
J Hepatol
Long-term follow-up of treatment-emergent resistance-associated variants in NS3, NS5A and NS5B with paritaprevir/r-, ombitasvir- and dasabuvir-based regimens
J Hepatol
Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies
J Hepatol
Retreatment of patients who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks
J Hepatol
Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis
Clin Gastroenterol Hepatol
Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial
Lancet Infect Dis
Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials
Gastroenterology
Eliminating hepatitis C within low-income countries – The need to cure genotypes 4, 5, 6
J Hepatol
High SVR rates with eight and twelve weeks of pangenotypic glecaprevir/pibrentasvir: integrated efficacy and safety analysis of genotype 1–6 patients without cirrhosis
J Hepatol
Pooled resistance analysis in HCV genotype 1–6 infected patients treated with glecaprevir/pibrentasvir in phase 2 and 3 clinical trials
J Hepatol
EASL recommendations on treatment of hepatitis C 2018
J Hepatol
Hepatitis C virus infection
Nat Rev Dis Prim
Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment
N Engl J Med
Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis
N Engl J Med
Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients
Antivir Ther
Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment
Liver Int
Systematic review: patient-reported outcomes in chronic hepatitis C – the impact of liver disease and new treatment regimens
Aliment Pharmacol Ther
Identification of novel HCV genotype and subtypes in patients treated with sofosbuvir based regimens
Hepatology
Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource
Hepatology
A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt
Liver Int
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2022, Bioorganic and Medicinal ChemistryRedesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier
2022, European Journal of Medicinal ChemistryCitation Excerpt :Despite the fact that DAA therapy options continue to increase and develop, efficacy of DAAs varies against different genotypes, this is mainly a consequence of the fact that DAA drug development was initially focused on HCV genotype 1, partly because interferon showed the lowest efficacy in this genotype and partly because it is the most common genotype worldwide. On the other hand, genotype 3 appears to be more difficult to cure with DAAs than other genotypes [2]. HCV genotype 3 (GT3) is the second-most prevalent genotype, accounting for 25% of all infections.
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2022, Computational and Structural Biotechnology JournalCitation Excerpt :Use of these DAAs eliminated the side-effects of previous interferon therapy and improved the quality of life of HCV infected patients. Treatment using DAAs achieves sustained virologic response (SVR) in about 92–95% cases [8]. However, DAA therapy is quite costly and fails in about 5–10% cases due to pre-existing or new generation of resistance-associated substitutions (RAS) [9 10].