The old adage, “The more things change, the more they stay the same,” simply does not apply when it comes to the treatment of hepatitis C virus (HCV). The mainstay of HCV treatment for many years has included interferon (peginterferon, since 2001) and ribavirin. While relatively effective for patients with HCV genotypes 2 and 3, this regimen achieves a sustained virologic response – undetectable serum HCV RNA after treatment – in only 40% of patients with HCV genotype 1, the cause of more than 70% of all cases of chronic HCV in the United States. Sequencing of the viral genome and characterization of HCV proteins led to development of the direct-acting HCV NS3/4A protease inhibitors telaprevir and boceprevir, which, when combined with peginterferon and ribavirin, improve response rates for patients with genotype 1. Yet patients who fail this regimen have historically had no treatment options. Now, however, a new generation of direct-acting antivirals is poised to take center stage, changing the outlook for this and other “difficult-to-treat” subgroups. Currently approved regimens – limited by formidable side effects, suboptimal treatment adherence, and viral resistance, and unavailable to those for whom interferon is contraindicated – will likely give way to safer, shorter duration, and easier-to-administer interferon- and ribavirin-free regimens. A multitude of clinical trials are underway, investigating these new therapies in a variety of clinical settings.
In this week’s NEJM, Afdhal et al. report the findings of a study involving patients with HCV genotype 1 who have failed treatment with prior interferon-based therapy. Building upon promising phase 2 trial results, they conducted a multicenter phase 3, randomized, open-label study of a fixed dose, once-daily oral combination pill containing sofosbuvir, a nucleotide analogue HCV NS5B polymerase inhibitor approved by the FDA in late 2013, and ledipasvir, a new experimental HCV NS5A protein inhibitor. Eligibility criteria included age 18 years or older, chronic HCV genotype 1 infection, and failure to achieve a sustained virologic response to prior peginterferon and ribavirin treatment, either with or without a protease inhibitor. Four hundred and forty patients, all of whom received the same daily dose of sofosbuvir and ledipasvir, were randomized 1:1:1:1 to one of four treatment groups, including ledipasvir-sofosbuvir for 12 weeks or 24 weeks, either with or without ribavirin. Randomization was stratified by genotype (1a or 1b), prior treatment response (no response versus relapse or virologic breakthrough) and presence or absence of cirrhosis. The primary endpoint was the rate of sustained virologic response at 12 weeks after the end of therapy (SVR 12); SVR 24 was a secondary endpoint.
The study results showed high SVR 12 rates in all four groups, reportedly among the highest to date for HCV genotype 1: 94% and 96% for the 12 week groups without and with ribavirin, respectively, and 99% for both 24 week groups. Virologic relapse after the end of treatment occurred in 11 of 440 patients (2%), all from the 12 week treatment groups. All sustained virologic responses achieved at 12 weeks persisted at 24 weeks after the end of treatment. Ribavirin did not affect response rates with either 12 or 24 weeks of treatment. In the 12-week group only, response rates were slightly lower in patients with cirrhosis, compared to those without cirrhosis, although the study was not powered to allow confident intergroup comparisons. Mild to moderate adverse events were seen in all groups, with serious adverse events limited to a small number of patients in the 24-week groups; no participant had to discontinue treatment due to an adverse event.
In an accompanying editorial, Drs. Jay Hoofnagle and Averell Sherker of the National Institutes of Health characterize the study results as “striking,” stating that the availability of safe and effective oral therapies will remove most of the limitations and barriers to treatment. Their enthusiasm is tempered, however, by concerns about the high price tag for these therapies, saying, “Costs alone cast a pall over the stunning success in achieving the long-hoped-for goal of a well-tolerated and successful therapy for hepatitis C.”
NEJM Deputy Editor Dr. Mary Beth Hamel adds, “The recent development of several novel direct-acting antivirals represents a major advance in hepatitis C therapy, and offers the potential to save many lives.”