- Category: Experimental HCV Drugs
- Published on Tuesday, 04 March 2014 16:11
- Written by Keith Alcorn
The next-generation hepatitis C protease inhibitor simeprevir (Olysio) cured nearly 80% of previously untreated people with hepatitis C and HIV coinfection when used in combination with pegylated interferon and ribavirin, Douglas Dieterich of Mt. Sinai Medical Center reported on Tuesday at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) in Boston.
Simeprevir received U.S. marketing approval for treatment of hepatitis C monoinfection in November 2013, and is currently awaiting approval in the European Union. Simeprevir is a second-generation HCV protease inhibitor that is better tolerated than telaprevir (Incivek) and boceprevir (Victrelis), the first protease inhibitors approved for hepatitis C treatment. It is dosed once-daily in combination with pegylated interferon and ribavirin. It is currently licensed for treatment of HCV genotype 1 infection, but is active against all genotypes with the exception of 3.
Product developer Janssen designed the Phase 3 C212 study in order to establish the efficacy of simeprevir in patients with HIV and hepatitis C coinfection. The study recruited 106 non-cirrhotic patients with HCV genotype 1a (n=88) or 1b (n=18), stratified according to previous treatment history. Half of participants (n=53) were previously untreated. The remainder were relapsers (15), partial responders (n=15), or null responders (n=28). Null responders are least likely to respond to a subsequent interferon-based regimen because, by definition, they did not respond to previous interferon-based treatment and are therefore likely to have poor ability to either tolerate or respond to interferon.
The trial evaluated a once-daily dose of simeprevir in combination with pegylated interferon and ribavirin according to a response-guided treatment protocol. Treatment-naive participants and prior relapsers received 12 weeks of treatment with simeprevir and 24 or 48 weeks of pegylated interferon and ribavirin, according to virologic response at weeks 4 and 12. Partial or null responders all received 48 weeks of interferon treatment, as did cirrhotic patients.
The study population was 85% male and 14% African-American with an average age of 48 years. 82% of participants had HCV genotype 1a infection. 88% of participants were taking antiretroviral therapy (ART) during the study. The baseline CD4 count of participants was high: 561 cells/mm3 in those on ART and 677 cells/mm3 in those not taking ART.
The primary endpoint of the study was the proportion of patients with a sustained virological response 12 weeks after completing treatment (SVR12), which was compared to a historical control derived from the APRICOT study of pegylated interferon and ribavirin in coinfected patients.
Overall, 74% of study participants achieved SVR12. Among previously untreated patients 79% achieved SVR 12, compared to 29% treated with pegylated interferon and ribavirin in the historical control group.
The total number of relapsers, partial responders, and null responders was too small to allow statistical comparison between arms. 87% of relapsers, 70% of partial responders, and 57% of null responders achieved SVR12. In comparison, only 5% of null responders in the historical control group achieved SVR12.
Most patients (89%) met the criteria for response-guided therapy and achieved SVR12 after a 24-week treatment course, and there was no difference between previously untreated patients and prior relapsers in this respect.
A number of sub-group analyses were carried out in order to tease out where differences might exist in responses to treatment. In particular, the investigators looked at differences between genotypes 1a and 1b, and between patients with and without the Q80K hepatitis C mutation. This naturally occurring mutation, or polymorphism, is present in approximately half of all people with HCV genotype 1a, but is not present in genotype 1b virus.
By subtype, 89% of all patients with genotype 1b infection achieved SVR12 compared to 71% of genotype 1a patients. No difference was found in treatment response in genotype 1a patients according to the presence of the Q80K mutation (67% with vs 72% without). This lack of difference, suggested Dieterich, may be a consequence of higher adherence among HIV positive patients, which may be enough to overcome the presence of this mutation.
The investigators also analyzed responses according to the degree of liver damage, although the proportion of patients with advanced liver fibrois or cirrhosis (fibrosis stages F3 and F4) was 21%. In previously untreated patients, 89% of those with less advanced liver disease (stages F0-F2) achieved SVR12 compared to 57% of those with F3-F4 disease. In other study arms the numbers treated are too small for meaningful comparison. Overall, 80% of F0-F2 patients and 64% of F3-F4 patients achieved SVR12.
Treatment with simeprevir and pegylated interferon/ribavirin was fairly well-tolerated. 4 patients discontinued treatment due to adverse events. Throughout the entire study 46 patients experienced grade 3 or 4 adverse events, of which 10 were categorized as serious. Grade 3 and 4 adverse events were largely attributable to pegylated interferon and ribavirin (neutropenia, pruritus). Rash occurred in 16 patients during the first 12 weeks of treatment, but none were serious cases. There were 2 cases of grade 3 or 4 photosensitivity, a known side effect of simeprevir. The most frequent side effects (each experienced by at least 25% of patients) were headache, rash, and nausea. Grade 3 or 4 hemoglobin reductions or bilirubin elevations were rare, occurring in only 1.3% of patients.
Participants with the favorable IL28 CC genotype, which confers a better response to interferon-based treatment, were more likely to achieve SVR12 (96% vs 68% and 61% of CT and TT genotypes, respectively). All previously untreated patients, prior relapsers, and partial responders with the CC genotype achieved SVR12, suggesting that IL28 genotype will continue to be an important consideration when determining whether to embark on a course of treatment with simeprevir.
A similar difference was apparent in the faldaprevir study also presented during the conference session. Jurgen Rockstroh, session chair, questioned whether triple regimens combining a HCV protease inhibitor with pegylated interferon and ribavirin are sufficiently potent to cure patients with a non-CC IL28 genotype, whether or not they are HIV coinfected.
D Dieterich, JK Rockstroh, C Orkin, et al. et al. Simeprevir (TMC435) plus PegIFN/ribavirin in HCV genotype-1/HIV-1 coinfection (Study C212). 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 24.