What's New in Hepatology: Triple Therapy for Hepatitis C
■ The first oral medications specifically for HCV, telaprevir and boceprevir, have received FDA approval.
■ These oral agents must be combined with traditional interferon and ribavirin therapy to prevent development of resistance.
■ Attention to drug-drug interactions with these medications is extremely important. Both telaprevir and boceprevir interact extensively with other commonly prescribed and OTC medications.
The hepatitis C virus (HCV) is a single-stranded RNA virus that acts on the liver and results in chronic disease in 50% to 90% of those infected. HCV infection creates a large burden of disease, affecting 170 million people worldwide, and is the primary indication for liver transplantation. The most common risk factors for infection include IV drug use, needlesticks in health care workers, blood transfusions performed prior to 1990 or outside the United States, and hemodialysis. Most cases manifest with chronic infection and are asymptomatic, with only mild elevations in serum aminotransferase levels. On average, cirrhosis develops within 20 years of the original infection and may lead to hepatocellular carcinoma and/or require transplantation.1
Two new treatments emerged during the past year, receiving FDA approval in May 2011: telaprevir (Incivek) and boceprevir (Victrelis). HCV infects and replicates mainly in the hepatocytes. Replication occurs rapidly and with a high rate of mutations, which makes creation of a vaccine and treatment very difficult. HCV replication involves production of a polyprotein that is then processed by two proteases, NS2 cysteine autoprotease and NS3-4A serine protease, into 10 new proteins.2 These new proteins are responsible for directing the HCV RNA into the RNA replication complex in order to replicate the virus.3 Telaprevir and boceprevir are protease inhibitors and specifically act to prevent NS3-4A from creating new proteins.4,5 Either medication must be combined with the traditional therapy of interferon (Copegus, Rebetol, generics) and ribavirin to prevent development of resistance.
The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial studied the efficacy of boceprevir in treatment-naive HCV genotype 1 patients. This double-blind study compared three different groups, all of which had a 4-week lead-in with ribavirin and interferon. The control group received a placebo, while the other two groups received either 24 weeks of triple therapy (boceprevir and pegylated interferon alfa-2b [PEG-INF]/ribavirin) or 44 weeks of triple therapy. The goal of any HCV therapy is a sustained viral response (SVR) or undetectable HCV RNA 6 months after the completion of therapy. (Table 1 defines responses to therapy.) SVR was achieved in 67% of patients in the group that received boceprevir with PEG-INF/ribavirin for only 24 weeks after the 4-week lead-in (total treatment duration: 28 weeks). This was similar to the results seen in the group receiving 44 weeks of triple therapy (total treatment duration: 48 weeks). This means that patients can take triple therapy for only 28 weeks, with similar rates of success.4
Telaprevir was evaluated in three studies of HCV genotype 1 patients: ADVANCE, which studied its use in treatment-naive patients; ILLUMINATE, which looked at the effects of extended therapy, also in treatment-naive patients; and REALIZE, which examined retreatment in patients who had failed standard therapy. The ADVANCE and ILLUMINATE studies found that the 24-week and the 48-week regimens produced similar SVR rates (92% versus 88%).5,6 The REALIZE study, which compared a lead-in (as described for boceprevir) and a simultaneous-start arm, demonstrated similar SVR in all groups (88% versus 83% in prior relapsers and 33% versus 29% in prior null responders).7