Merck combination suppresses HCV in mono-infected and co-infected patients

An all-oral combination of the hepatitis C virus (HCV) protease inhibitor MK-5172 and NS5A inhibitor MK-8742, with or without ribavirin, demonstrated promising end-of-treatment viral suppression in people with HIV and HCV co-infection and high cure rates for people with hepatitis C alone, according to findings from the C-WORTHY study presented at recent conferences.

Merck's C-WORTHY trial started by testing 12-week oral regimens of MK-5172 plus MK-8742, with or without ribavirin, in 65 HIV-negative people with hepatitis C alone (Part A). Part B then enrolled 59 people with HIV and HCV co-infection.

Findings for mono-infected patients in Part A were presented at the AASLD Liver Meeting last November and at the Asian Pacific Association for the Study of the Liver (APASL) conference last week in Brisbane, with researchers reporting sustained virological response rates at 12 weeks post-treatment (SVR12). Findings for people with HIV and HCV co-infection in Part B were presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) this month in Boston. This part started later, so data were available through the end of the 12-week treatment period.

All participants in both parts were treatment-naive and did not have liver cirrhosis. About half of the participants with HCV alone, but nearly 80% of the participants with HIV and HCV co-infection, were men, about 80% in both parts were white and the average age was in the mid-forties. About 25% overall had the favourable IL28B CC gene variant associated with good interferon responsiveness.

In Part A about 75% of mono-infected participants treated with the triple regimen of MK-5172, MK-8742 and ribavirin had harder-to-treat HCV subtype 1a, but only people with subtype 1b were assigned to take MK-5172 and MK-8742 alone. After both regimens were shown to work well, the people with HIV and HCV co-infection – again about three-quarters with subtype 1a – were randomly assigned to either the dual or triple regimen. Also, Part A compared 20mg vs 50mg doses of MK-8742; after no significant difference was seen, all participants with HIV and HCV co-infection in Part B took the 50mg dose.

HCV protease inhibitors have the potential to interact with certain antiretroviral drugs, especially HIV protease inhibitors metabolised by the same enzymes in the liver. In this study, participants with HIV and HCV were all on a stable antiretroviral regimen consisting of the HIV integrase inhibitor raltegravir (Isentress) plus two nucleoside/nucleotide reverse transcriptase inhibitors and had undetectable HIV viral load and a CD4 cell count above 300 cells/mm³.

MK-5172 plus MK-8742, with or without ribavirin, was highly effective. In Part A SVR12 rates were 100% and 89% for genotype 1a/1b mono-infected participants taking the 20mg and 50mg doses of MK-8742 plus ribavirin respectively. The cure rate was also 100% for participants with HCV genotype 1b taking MK-5172 plus 50mg MK-8742 without ribavirin. One participant with genotype 1a taking triple therapy relapsed at week 4 of post-treatment follow-up and was found to have low drug levels suggesting poor adherence.

In Part B, 100% of participants with HIV and HCV genotype 1a/1b taking the triple regimen had undetectable HCV RNA at the end of 12 weeks of treatment, as did 90% of those taking MK-5172 plus MK-8742 alone. Two participants, both with genotype 1a, experienced viral breakthrough and were found to have low drug levels.

The end of treatment is too soon to declare hepatitis C cured – as relapse can still happen after therapy is completed – but these rates compare favourably to the 94% and 100% end-of-treatment response rates for triple and dual therapy, respectively, among the HCV mono-infected participants in Part A.

In both parts of the study, treatment was generally safe and well-tolerated. In Part A, there was a single serious adverse event in one of the ribavirin-containing arms. In Part B, there were three serious adverse events, of which two were in the ribavirin-containing arm. None of the participants with HIV and HCV co-infection experienced HIV viral breakthrough.

In Part A and Part B, respectively, 2% and 3% of people taking ribavirin – but no one taking MK-5172 plus MK-8742 alone – developed anaemia. The most common side-effects were fatigue, headache, nausea and diarrhoea. Most side-effects did not show a clear association with either MK-8742 dose or inclusion of ribavirin, though more ribavirin recipients reported headaches. While the researchers concluded that safety profiles were "comparable" for mono-infected and co-infected patients, all these symptoms were actually reported less often in Part B.

These findings support the trend in HCV direct-acting antiviral studies showing that response rates are equally good and side-effects are no worse for people with HIV and HCV co-infection compared to those with HCV alone – in contrast to interferon, which is both less effective and associated with more adverse events in people living with HIV.