CROI 2014/APASL 2014: Merck Combo Suppresses HCV in Monoinfected and Coinfected Patients

An all-oral combination of the HCV protease inhibitor MK-5172 and the NS5A inhibitor MK-8742, with or without ribavirin, demonstrated promising end-of-treatment viral suppression in HIV/HCV coinfected patients and high cure rates in 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 HIV/HCV coinfected patients.

Findings for monoinfected 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 coinfected patients in Part B were presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) 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 HCV monoinfected participants, but nearly 80% of the coinfected patients, were men, about 80% in both parts were white, and the average age was in the mid-40s. About 25% overall had the favorable IL28B CC gene variant associated with good interferon responsiveness.

In Part A, about 75% of monoinfected patients 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 coinfected patients -- again about three-quarters with subtype 1a -- were randomly assigned to either the dual or triple regimen. Also, Part A compared 20 mg vs 50 mg doses of MK-8742; after no significant difference was seen, all coinfected people in Part B took the 50 mg dose.

HCV protease inhibitors have the potential to interact with certain antiretroviral drugs, especially HIV protease inhibitors metabolized by the same enzymes in the liver. In this study, coinfected participants were all on a stable antiretroviral regimen consisting of the HIV integrase inhibitor raltegravir (Isentress) plus 2 nucleoside/nucleotide reverse transcriptase inhibitors and had undetectable HIV viral load and a CD4 T-cell count above 300 cells/mm³.

Results

• MK-5172 plus MK-8742, with or without ribavirin, was highly effective.
• In Part A, SVR12 rates were 100% and 89%, respectively, for genotype 1a/1b monoinfected patients treated with the 20 mg and 50 mg doses of MK-8742 plus ribavirin.
• The cure rate was also 100% for genotype 1b patients treated with MK-5172 plus 50 mg MK-8742 without ribavirin.
• 1 patient with genotype 1a assigned to 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 genotype 1a/1b coinfected participants 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.
• 2 patients , both with genotype 1a, experienced viral breakthrough and were found to have low drug levels.
• 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 3 serious adverse events, of which 2 were in the ribavirin-containing arm.
• None of the coinfected patients 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 anemia.
• The most common side effects were fatigue, headache, nausea, and diarrhea; 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 monoinfected and coinfected patients, all these symptoms were actually reported less often in Part B.

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

The end of treatment is too soon to declare a cure -- as relapse can still happen after therapy is completed -- but the rates reported for coinfected patients at CROI compare favorably to the 94% and 100% end-of-treatment response rates for triple and dual therapy, respectively, among the HCV monoinfected patients in Part A.

3/21/14

References

M Sulkowski, Josep Mallolas, Marc Bourliere, et al. On-Treatment Viral Response to MK-5172/MK-8742 ± RBV for 12 Weeks in HCV/HIV Coinfected Patients. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 654LB.

E Lawitz, J Vierling, A Murillo, et al. High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172/MK-8742 ± RBV  for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study. 23rd Conference of the Asian Pacific Association for the Study of the Liver (APASL 2014). Brisbane, March 12-15, 2014.

Other Source

Merck. Merck’s Investigational Hepatitis C Treatment Regimen MK-5172/MK-8742 Shows Robust Anti-HCV Activity in HIV/HCV Co-Infected Patients with HCV Genotype 1 Infection. Press release. March 5, 2014.