Only 20 years after the discovery of the hepatitis C virus, a cure is now likely for most people with chronic infection. The latest review in our Drug Therapy series considers current therapy and the present landscape of drug development for hepatitis C.
The hepatitis C virus (HCV) carries a substantial disease burden, not only in the United States but also worldwide. The recent approval of two direct-acting antiviral agents that specifically inhibit viral replication has dramatically increased the viral clearance rate, from less than 10% with the initial regimen of interferon monotherapy to more than 70% with current therapy.
• What are the current CDC recommendations for screening for HCV?
Because most infected persons are unaware of their diagnosis, the Centers for Disease Control and Prevention recently recommended screening for HCV all persons born between 1945 and 1965. It is anticipated that in the course of such a screening process, a large number of persons will be found to be infected with the virus; whether it will be possible to treat all these people is unclear.
• What is the endpoint of successful therapy for HCV infection?
The goal of therapy for chronic hepatitis C is eradication of the virus, which should limit or prevent the development of complications. The end point of successful therapy is a sustained virologic response, defined as undetectable HCV RNA in serum 24 weeks after treatment has been stopped. This outcome is predictive of long-term eradication of the virus and correlates with a reduction in symptoms and improvement in clinical outcomes.
Morning Report Questions
Q: How has the treatment of HCV infection changed over the past five years?
A: The combination of peginterferon and ribavirin has been the standard of care for patients with chronic hepatitis C, regardless of the strain of the virus (genotype 1, 2, 3, 4, 5, or 6). This regimen results in rates of sustained virologic response of 70 to 80% among patients with HCV genotype 2 or 3 infection and rates of 45 to 70% among patients with any of the other genotypes. The approval of boceprevir and telaprevir has led to triple therapy for HCV genotype 1 infection — one of these two protease inhibitors in combination with peginterferon and ribavirin. These two triple-therapy regimens result in similar response rates but differ greatly with respect to the timing of administration (both when they should be administered and for how long). The combination of peginterferon and ribavirin remains the recommended therapy for HCV genotypes 2, 3, 4, 5, and 6 infection. Preliminary results of a study of a polymerase inhibitor (sofosbuvir) in combination with ribavirin, administered for 12 weeks, showed a 100% rate of sustained virologic response among patients with HCV genotype 2 or 3 infection. As reported in this issue of the Journal, two phase 3 trials of the same oral combination showed similar response rates among patients with genotype 2 infection (93% and 97% in the two studies) but much lower response rates among patients with genotype 3 infection (56% and 61% in the two studies).
Q: What are the challenges of triple therapy regimens for HCV with protease inhibitors?
A: Although the approved triple-therapy regimens are more efficacious than a regimen of peginterferon and ribavirin without a protease inhibitor, they have additional side effects and are quite complex to adhere to because patients must take an increased number of pills and the schedule requires pills to be taken every 8 hours. The most common side effects with boceprevir are anemia, neutropenia, and dysgeusia (altered taste sensation), and the most common side effects with telaprevir are anemia, rash, and anorectal discomfort. Anemia (a hemoglobin level of <10 g per deciliter) occurs in 36 to 50% of cases and is the most challenging complication to manage. Drug-drug interactions are a major issue, and antiviral resistance is another major concern and may develop as early as 4 days after initiation of the drug when these agents are used as monotherapy.