EASL 2012: Boceprevir Improves Cure Rates for HIV/HCV Coinfection but Beware of Drug Interactions

Adding boceprevir (Victrelis) to pegylated interferon and ribavirin for treatment of chronic hepatitis C in people with HIV substantially increased the likelihood of end-of-treatment response and sustained response 12 weeks after completing therapy, researchers reported at the 47th International Liver Congress (EASL 2012) last week in Barcelona.

Drug-drug interaction studies recently revealed that boceprevir can lower levels of some boosted HIV protease inhibitors, and vice versa; the U.S. Food and Drug Administration (FDA) just updated the Victrelis product label to reflect this new information. But in this Phase 2 trial, coinfected participants taking boceprevir did not show a higher rate of HIV or hepatitis C virus (HCV) breakthrough -- a potential consequence of inadequate drug concentrations -- than those taking pegylated interferon/ribavirin with placebo.

Josep Mallolas form the University of Barcelona presented data from an ongoing Phase 2 trial that included 100 previously untreated HIV/HCV coinfected participants with HCV genotype 1. Co-investigator Mark Sulkowski presented 12-week sustained virological response (SVR12) findings from this study at this year's Conference on Retroviruses and Opportunistic Infections (CROI 2012) in March.

Participants started with a 4-week lead-in period taking 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus weight-adjusted ribavirin, then were randomly assigned to add 800 mg 3-times-daily boceprevir or placebo for 44 more weeks. Although many hepatitis C monoinfected patients are eligible for shorter treatment using response-guide therapy, all HIV positive people in this trial were assigned to 48 weeks of therapy; 2 people dropped out before receiving study drugs.

Most participants (about 70%) were men, about 80% were white, and the median age was 43 years. About two-thirds had HCV genotype 1a, the rest 1b; most had high baseline HCV RNA and about 5% had cirrhosis. The group overall had well-controlled HIV disease with a median CD4 T-cell count of nearly 600 cells/mm³ and stable undetectable HIV viral load.

All participants were also on combination antiretroviral therapy (ART). Based on pharmacokinetic data, they were limited to regimens containing a ritonavir- boosted HIV protease inhibitor plus 2 selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). As noted above, further studies in healthy volunteers later revealed interactions between these drugs and boceprevir.

Results

• At the end of treatment at 48 weeks, 64% of participants in the boceprevir triple therapy arm had suppressed HCV viral load, compared with 29% in the placebo arm.
• 12 months after completion of treatment, 61% of participants in the boceprevir arm achieved SVR12, or continued HCV suppression, compared with 27% in the placebo arm.
• 9% of boceprevir recipients and 53% of placebo recipients experienced treatment failure while on HCV therapy.
• 2 people taking boceprevir and 3 taking placebo experienced HIV viral load rebound by the end of treatment, and an additional 1 person did so in each arm by post-treatment week 12.
• Approximately one-fifth of participants in both arms experienced serious adverse events, but boceprevir recipients were about twice as likely to discontinue therapy due to adverse events (20% vs 9%, respectively).
• Boceprevir recipients were more likely than placebo recipients to report several symptoms including fever, loss of appetite, vomiting, dysgeusia (unusual taste sensations), anemia, and neutropenia.
• Absolute CD4 T-cell counts decreased in both groups -- a known side effect of interferon -- but CD4 cell percentages remained stable.

"The addition of boceprevir to [pegylated interferon/ribavirin] was associated with higher rates of undetectable HCV RNA at all time points," the researchers concluded. "The safety and tolerability profile was consistent with that observed in HCV monoinfected patients."

The similarity of HIV breakthrough rates in this study raises questions about the clinical significance of the recent drug interaction findings. In this trial it appears that changes in drug levels were not sufficient to cause more HIV treatment failure than placebo. However, a Phase 2 trial of the other approved HCV protease inhibitor, telaprevir (Incivek/Incivo), with pegylated interferon/ribavirin in coinfected patients did not see any cases of HIV breakthrough.

The latest U.S. DHHS antiretroviral therapy guidelines and revised boceprevir product information from the FDA recommend against combining boceprevir with commonly used boosted HIV protease inhibitors. Based on outcomes in clinical trials, though, some experts think these drugs can be used together safely if HIV and HCV viral load are carefully monitored. Further study is needed to reconcile these conflicting findings.

FDA Label Update

On April 20, 2012, the FDA announced an update to the Victrelis product label describing drug-drug interactions between boceprevir and certain boosted HIV protease inhibitors. Key changes to the Drug Interaction section in the revised package insert include:

• Atazanavir/ritonavir [boosted Reyataz]: Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended.
• Darunavir/ritonavir [boosted Prezista]: Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir, and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended.
• Lopinavir/ritonavir [Kaletra]: Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended.
• Ritonavir: When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased.

According to the FDA announcement, the complete, revised label will be posted soon at Drugs@FDA.

4/24/12

Reference

J Mallolas, S Pol, A Rivero, et al. Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients: End of Treatment (Week 48) Interim Results [SVR12 data in oral presentation]. 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012). Barcelona, April 18-22, 2012. Abstract 50.

Other Sources

R Klein and K Struble. Victrelis (Boceprevir) Label Change Reflects Drug-Drug Interaction Information with HIV Protease Inhibitors. FDA Hepatitis Update. April 21, 2012.

EASL. New Studies Show Drug Interactions Won’t Exclude HCV Transplant or HIV Co-Infected Patients from Treatment. Press release. April 19, 2012.

M Sulkowski, S Pol, C Cooper, et al. Boceprevir + Pegylated Interferon + Ribavirin for the Treatment of HCV/HIV-coinfected Patients: End of Treatment (Week 48) Interim Results. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 47.

E Hulskotte, H-P Feng, F Xuan, et al. Pharmacokinetic Interaction Between the HCV Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Lopinavir, and Darunavir. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 771LB