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IDSA 2011: Boceprevir Increases Hepatitis C Treatment Response for HIV/HCV Coinfected People

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The recently approved hepatitis C virus (HCV) protease inhibitor boceprevir (Victrelis) added to pegylated interferon/ribavirin significantly improved the likelihood of virological response at week 24 in HIV/HCV coinfected patients, according to a late-breaker presentation at the 49th Annual Meeting of the Infectious Diseases Society of America (IDSA 2011) in Boston.

The advent of direct-acting antiviral drugs (DAAs) that target steps of the viral lifecycle has begun to revolutionize hepatitis C treatment for HCV monoinfected individuals with hard-to-treat HCV genotype 1. Studies have shown that the first 2 DAAs -- boceprevir and telaprevir (Incivek), both approved this past May -- significantly increase sustained virological response (SVR) or cure rates.

HIV/HCV coinfected people -- an estimated one-third of people with HIV -- tend to experience faster liver disease progression and respond less well to interferon-based therapy than patients with HCV alone. This population therefore urgently needs better treatment, and patients, clinicians, and advocates have eagerly awaited data showing whether the benefits of DAAs seen for HCV monoinfected people will also hold for coinfected individuals.

Mark Sulkowski and colleagues conducted a Phase 2b trial in which 100 previously untreated HIV/HCV coinfected patients with HCV genotype 1 were randomly assigned (2:1) to receive 800 mg 3-times-daily boceprevir plus 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) and 600-1400 mg/day weight-adjusted ribavirin, or else standard therapy alone; 2 dropped out before receiving any treatment.

A majority of participants (69%) were men, 82% were white, and the median age was 43 years; 65% had HCV genotype 1a, the rest 1b. Most (88%) had high HCV RNA levels (> 800,000 IU/mL), but only 5% had liver cirrhosis at baseline -- both predictors of poorer treatment response.

All patients started with a 4-week lead-in period of pegylated interferon/ribavirin. While HCV monoinfected patients may be eligible for shorter duration response-guided therapy if they show good early response, all coinfected people in this study were assigned to 48 total weeks of therapy, as HIV positive people tend to respond more slowly to interferon; Sulkowski presented interim 24 week results at the IDSA meeting. Patients with detectable HCV RNA and less than a 2 log decline at week 12, or detectable HCV RNA at week 24, stopped treatment due to expected futility of continuing.

Participants were also taking optimized antiretroviral therapy (ART) and had stable undetectable HIV viral load (< 50 copies/mL) and CD4 T-cell counts of at least 200 cells/mm3. Based on prior drug-drug interaction studies and expected additive side effects, they were limited to regimens containing a boosted protease inhibitor plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), excluding zidovudine (AZT; Retrovir), didanosine (ddI; Videx), or stavudine (d4; Zerit).

"Victrelis is a strong inhibitor of CYP3A4/5 and is partly metabolized by VYP3A4/5," cautions manufacturer Merck. "The potential for drug-drug interactions must be considered prior to and during therapy."

Results

  • In an interim analysis at 24 weeks, 70.5% of patients receiving boceprevir triple therapy had undetectable HCV RNA, compared to 34.4% of those receiving pegylated interferon/ribavirin alone (a difference of 36.1%).
  • Rates of complete early virological response (cEVR) at week 12 were 59.3% vs 25.8%, respectively (a difference of 33.5%).
  • Rates of rapid virological response (RVR) at week 8 -- 4 weeks of randomized treatment after the lead-in period -- were 37.5% vs 14.7%, respectively (a difference of 22.8%).
  • Boceprevir was generally well-tolerated, with no new or unexpected side effects not seen in HCV monoinfected patients.
  • Patients taking boceprevir triple therapy were more likely than standard therapy recipients to experience the following side effects:
    • Fever: 34% vs 21%;
    • Anorexia (loss of appetite): 30% vs 18%;
    • Headache: 28% vs 12%;
    • Vomiting: 25% vs 15%;
    • Dysgeusia (unusual unpleasant taste sensations): 25% vs 15%;
    • Neutropenia (low white blood cells): 13% vs 3%.
  • However, rates of anemia -- the greatest concern with boceprevir -- were similar in both treatment groups.
  • 8% of boceprevir recipients and 21% of standard therapy recipients experienced serious clinical adverse events.
  • 19% and 21%, respectively, required dose modification of any study drug due to adverse events.
  • 14% in the boceprevir arm and 9% in the standard therapy arm discontinued therapy due to adverse events.
  • About 5% taking boceprevir and 32% taking standard therapy discontinued due to futility.
  • Absolute CD4 cell counts and CD4 percentages did not differ in the 2 arms during treatment, and similar proportions maintained undetectable HIV viral load.

Based on these findings, the researchers concluded, "The addition of boceprevir to pegylated interferon/ribavirin was associated with higher rates of undetectable HCV RNA" at treatment week 8, 12, and 24.

"[T]he safety and tolerability profile was similar to that observed in HCV monoinfected patients," they continued. "These preliminary data support further studies of boceprevir plus pegylated interferon/ribavirin for the treatment of HCV in HIV-infected patients.

"We are encouraged by these interim results with Victrelis in combination therapy in this difficult-to-treat patient population,” said Roger Pomerantz, MD, FACP, Merck Research Laboratories Senior Vice President for Infectious Diseases, in a company press release.

In addition to this ongoing Phase 2b study -- which will follow patients to determine sustained virological response (SVR), or continued undetectable HCV RNA 24 weeks after completion of treatment -- Merck is collaborating with the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) on an ongoing Phase 2 study for coinfected patients who did not achieve SVR with previous hepatitis C treatment. A Phase 3 boceprevir coinfection study conducted by the AIDS Clinical Trials Group (ACTG) will start later this year.

Data from a study of the other newly approved HCV protease inhibitor -- telaprevir -- for HIV/HCV coinfected patients were previously reported at this year's Conference on Retroviruses and Opportunistic Infections (CROI), also showing a significant advantage over standard therapy alone.

Investigator affiliations: John Hopkins University School of Medicine, Baltimore, MD; Hopital Cochin, Paris, France; Ottawa Hospital, Ottawa, Ontario, Canada; Hospital De Infecciosas, Buenos Aires, Argentina; Saint Michael's Medical Center, Newark, NJ; Hospital Universitario Reina Sofia, Córdoba, Spain; Merck Sharp & Dohme, Whitehouse Station, NJ; ; Hospital Clinic i Provincial, Barcelona, Spain.

10/25/11

Reference

M Sulkowski, S Pol, C Cooper, et al. Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-infected Patients: Interim On-Treatment Results. 49th Annual Meeting of the Infectious Diseases Society of America (IDSA 2011). Boston, October 20-23, 2011. Abstract LB-37.

Other Source

Merck/MSD. Interim Phase IIb Data for Merck's Victrelis in Patients Coinfected with Chronic Hepatitis C and HIV-1 Presented. Press release. October 20, 2011.