Direct-acting antivirals for the treatment of chronic hepatitis C: open issues and future perspectives

Abstract

Currently, two direct-acting antivirals (DAAs) show well-established efficacy against hepatitis C virus (HCV), namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC) regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN) not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR). But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%). Oral drug combinations will be standard of care in the near future.

Figure 1

Targets for direct-acting antivirals. Modified from [2].

Figure 2

Phase III trials of boceprevir in patients with hepatitis C genotype-1 infection. (a) SPRINT-2 trial in previously untreated patients. (b) RESPOND-2 trial for previously treated patients; patients were partial responders and relapsers and null-responders. PR: pegylated interferon-α-2b 1.5 μg/kg per week plus weight-based ribavirin 600–1400 mg per day. BOC: boceprevir 800 mg every 8 h. ^aHepatitis C RNA treatment weeks 8–24 undetectable. ^bHepatitis C RNA treatment week 8 detectable, treatment week 24 undetectable. ^cHepatitis C RNA treatment weeks 8–12 undetectable. ^dHepatitis C RNA treatment week 8 detectable, treatment week 12 undetectable. Excerpted from Pearlman [11].

Figure 3

Proposed algorithm for the use of protease inhibitors in treatment-naïve HCV genotype 1 infected patients. Pretreatment assessment should include careful consideration of lifestyle factors, comorbid conditions, potential drug interactions, and assessment for the presence of cirrhosis. In noncirrhotic patients, the presence of factors predictive of a poor response to therapy should be patients with no risk factors for a poor response to therapy; the decision to use a 4-week lead-in with peginterferon and ribavirin and to continue on SOC in those who achieve an RVR should only be taken following careful and balanced discussion with the patient. Excerpted from Ramachandrean et al. [35].

Figure 4

Proposed algorithm for the use of protease inhibitors in HCV genotype 1 infected patients who have had previous virological failure on treatment. Pretreatment assessment should include careful consideration of lifestyle factors, comorbid conditions, potential drug interactions, assessment for the presence of cirrhosis, and the presence of factors predictive of a poor response to therapy. Identification of the degree of previous response should be attempted. If this information is not available, patients should be considered as prior null responders to maximize cure rates. In cirrhotic prior null responders, the decision to watch and wait for novel therapies or to use a 4-week lead-in with peginterferon and ribavirin to identify patients more likely to achieve an SVR should only be taken following careful and balanced discussion with the patient. Excerpted from Ramachandrean et al. [35].