Oral Combination Therapies for Hepatitis C Virus Infection: Successes, Challenges, and Unmet Needs

Abstract

The current standard of care for the treatment of hepatitis C virus (HCV) consists of interferon-free direct-acting antiviral (DAA) regimens, including combinations of DAAs and fixed-dose combination pills. DAAs for HCV are likely to be heralded as one of medicine's greatest advancements. Viral eradication rates are pushing 100% for many HCV-infected populations, including patients with HIV/HCV coinfection, decompensated cirrhosis, liver and kidney transplants, and end-stage liver disease. We highlight the greatest successes of combination DAA therapies, discuss the ongoing challenges, and identify the remaining patient subgroups with unmet medical needs.

Exposure‐Response (Efficacy) Analysis of Daclatasvir and Asunaprevir in Japanese Patients With Hepatitis C Virus Infection

“…In the last 5 years, treatment of chronic hepatitis C virus (HCV) infection has been revolutionized by the development of all‐oral combination regimens of direct‐acting antivirals (DAAs) that have rapidly superseded pegylated interferons (pegIFNs) plus ribavirin (RBV) as the standard of care . These DAA regimens have proven to be better tolerated than pegIFN‐based therapies, with higher rates of posttreatment sustained virologic response (SVR; a surrogate of cure) and shorter treatment durations …”

“…1 These DAA regimens have proven to be better tolerated than pegIFN-based therapies, with higher rates of posttreatment sustained virologic response (SVR; a surrogate of cure) and shorter treatment durations. 2,3 Daclatasvir (DCV; tablets) is an orally available small molecule and pangenotypic nonstructural protein (NS) 5A inhibitor with picomolar in vitro activity against HCV genotypes (GT) 1-6 4 ; asunaprevir (ASV; capsules) is also an orally available small molecule and tripeptidic acylsulfonamide inhibitor of the HCV NS3/4A protease with vitro antiviral activity against GTs 1, 4, 5, and 6. 5 In early replicon studies, an additive to synergistic interaction between DCV and ASV was observed.…”

Sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin in direct‐acting antiviral–experienced patients with genotype 1 hepatitis C virus

“…Of the six major hepatitis C virus (HCV) genotypes, infection with genotype 1 is the most prevalent, accounting for nearly half of all HCV infections worldwide . A paradigm shift in the treatment of patients with chronic HCV genotype 1 infection occurred in 2011 with the introduction of direct‐acting antivirals (DAAs), which interfere with HCV replication by targeting viral proteins such as the nonstructural protein (NS) 3/4A serine protease, NS5A, and the polymerase, NS5B . For the few patients with genotype 1 infection who fail interferon (IFN)‐free DAA‐based therapies, retreatment strategies remain unclear.…”

Exposure‐Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV‐Infected Patients

“…In the last 5 years, treatment of chronic hepatitis C virus (HCV) infection has been revolutionized by the development of all‐oral combination regimens of direct‐acting antivirals (DAAs) that have rapidly superseded pegylated interferons (pegIFNs) plus ribavirin (RBV) as the standard of care . These DAA regimens have proven to be better tolerated than pegIFN‐based therapies, with higher rates of posttreatment sustained virologic response (SVR; a surrogate of cure) and shorter treatment durations . Although the all‐oral combination therapy of daclatasvir and asunaprevir had been approved as the first direct‐acting antiviral therapy (DUAL treatment) in Japan, not requiring injectable pegIFN or RBV, for treating genotype‐1 (GT 1), still there were difficult‐to‐treat patients including GT 1 patients especially who have NS5A mutation.…”

“…[1][2][3] These DAA regimens have proven to be better tolerated than pegIFN-based therapies, with higher rates of posttreatment sustained virologic response (SVR; a surrogate of cure) and shorter treatment durations. 4,5 Although the all-oral combination therapy of daclatasvir and asunaprevir had been approved as the first direct-acting antiviral therapy (DUAL treatment) in Japan, not requiring injectable pegIFN or RBV, for treating genotype-1 (GT 1), still there were difficult-to-treat patients including GT 1 patients especially who have NS5A mutation. NS5A amino acid polymorphisms L31M/V and Y93H have been identified as the major pretreatment HCV resistance-associated substitution to daclatasvir in GT 1b and have been observed to reduce the efficacy of DUAL treatment when present at baseline.…”