Coinfection

AASLD 2012: Final Study Results Show Telaprevir Is Safe and Effective for HIV/HCV Coinfected Patients

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HIV/HCV coinfected people treated with telaprevir (Incivek) triple therapy are significantly more likely to achieve sustained virological response, or a cure, than people treated with pegylated interferon/ribavirin alone, according to final results from Study 110 presented at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this week in Boston.

Last year's approval of the first direct-acting agents that target the hepatitis C virus (HCV) lifecycle -- Vertex' telaprevir and Merck's boceprevir (Victrelis) -- ushered in a new treatment paradigm for chronic hepatitis C. These 2 HCV protease inhibitors were initially licensed only for HCV monoinfected patients, but HIV positive people with HCV coinfection also have a pressing need for better treatment, especially since liver disease tends to progress faster in this population.

Mark Sulkowski from Johns Hopkins University School of Medicine presented final 24-week sustained virological response results (SVR24) from a randomized, controlled Phase 2 trial evaluating triple therapy using telaprevir plus pegylated interferon and ribavirin in previously untreated coinfected patients with difficult-to-treat HCV genotype 1. Earlier results (SVR12) were presented at the 2012 Conference on Retroviruses and Opportunistic Infections this past March.

The study had 2 parts. Part A included 13 HIV/HCV coinfected participants who had CD4 T-cell counts of at least 500 cells/mm3 and were not yet taking antiretroviral therapy (ART), as was recommended by antiretroviral treatment guidelines in effect at the time (the latest DHHS guidelines recommend that everyone with HIV should be offered ART regardless of CD4 count).

Part B included 47 coinfected participants on ART with stable HIV suppression (HIV RNA < 50 copies/mL). On the basis of prior drug-drug interaction studies, they could be taking either efavirenz (Sustiva) plus tenofovir/emtricitabine (the drugs in Truvada, or all 3 together in the Atripla single-tablet regimen) or ritonavir-boosted atazanavir (Reyataz) plus either lamivudine (Epivir) or emtricitabine.

Most participants (nearly 90%) were men and the average age was about 45 years. Part A included a higher proportion of black patients (a group that does not respond as well to interferon-based therapy). Overall, about 70% had the more challenging HCV genotype 1a (the rest had 1b) and just over 10% had advanced liver fibrosis or cirrhosis at baseline, though these factors varied widely across treatment arms. Median CD4 cell counts in Part A and B were approximately 600 and 500 cells/mm3, respectively.

Participants in both parts of the study were randomly assigned to receive either telaprevir or placebo in combination with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus ribavirin (mostly 800 mg/day fixed dose). People using atazanavir took the usual 750 mg 3-times-daily telaprevir dose; to compensate for a known drug-drug interaction that lowers telaprevir levels, patients taking efavirenz increased their telaprevir dose to 1125 mg 3-times-daily.

Although HCV monoinfected people use telaprevir for variable lengths of time according to a response-guided therapy algorithm, all coinfected participants in this study received triple therapy for 12 weeks, followed by pegylated interferon/ribavirin alone for 36 more weeks (total treatment duration 48 weeks).

Patients stopped treatment based on futility rules if they had HCV RNA > 1000 IU/mL or < 2 log decrease from baseline at week 12, or detectable HCV viral load at week 24 or 36, or if they experienced HCV breakthrough.

Results

  • Overall, 74% of participants (28 out of 38) taking telaprevir triple therapy achieved SVR24 -- or continued undetectable HCV RNA at 24 weeks after completing treatment -- compared with just 45% (10 out of 22) of those taking pegylated interferon/ribavirin alone.
  • Among participants not taking ART in Part A, SVR24 rates were 71% and 33%, respectively.
  • By ART regimen, 69% of patients using efavirenz and 80% using boosted atazanavir achieved SVR24 with telaprevir, compared with 50% for both ART regimens with pegylated interferon/ribavirin alone.
  • All these SVR24 rates were the same as the SVR12 rates reported earlier at CROI, confirming that SVR12 is an accurate indicator of a cure.
  • Among the 10 telaprevir recipients who did not achieve SVR:
    • 2 (5%) discontinued due to stopping rules;
    • 1 (3%) experienced post-treatment HCV relapse;
    • 3 (8%) had detectable HCV RNA at the end of treatment;
    • 4 (11%) were lost to follow-up.
  • Overall, people taking telaprevir experienced more side effects than those on pegylated interferon/ribavirin alone.
  • 8 people taking telaprevir, but none in the placebo group, discontinued treatment early due to adverse events.
  • Adverse events that occurred at least 10% more often among telaprevir recipients than among placebo recipients during the 12 weeks of triple therapy included:
    • Pruritis, or itching (34% vs 5%);
    • Headache (34% vs 23%);
    • Nausea (32% vs 18%);
    • Skin rash (29% vs 18%);
    • Dizziness (21% vs 9%);
  • Myalgia, or muscle aches, were more common in the placebo arm (13% vs 23%).
  • No participants in either arm experienced severe rash.
  • Anemia was equally common in both groups, at 18%.
  • Although fewer telaprevir recipients had severe anemia (3% vs 5%), they were more likely to receive blood transfusions (11% vs 5%) and erythropoietin-stimulating agents (8% vs 5%).
  • No patients in either arm experienced HIV breakthrough.
  • Absolute CD4 counts fell in both arms -- a known side effect of interferon -- but CD4 cell percentages remained stable.
  • Measured telaprevir concentrations were similar among patients on ART and those not being treated for HIV.

Based on these findings, the Study 110 researchers concluded, "Higher SVR24 rates were observed in chronic genotype 1 HCV/HIV coinfected patients treated with telaprevir combination treatment."

"Drug interactions with telaprevir and select ART were not clinically meaningful," they added. "Overall safety and tolerability profile of [telaprevir/pegylated interferon/ribavirin] was comparable to that previously observed in HCV monoinfected patients."

"People who are coinfected with hepatitis C and HIV are among those who are most in need of effective new medicines, and these new data showed that 3 out of 4 people were able to clear the hepatitis C virus with telaprevir combination treatment," co-investigator Kenneth Sherman said in a Vertex press release. "We look forward to the results of the ongoing Phase 3 study."

11/12/12

Reference

MS Sulkowski, KE Sherman, V Soriano, et al. Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR24 Final Study Results. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 54.

Other Source

Vertex Pharmaceuticals. Vertex Presents New Phase 3 Data that Showed People with Hepatitis C Treated with Twice-Daily Telaprevir Achieved Viral Cure (SVR12) Rates Similar to Those Treated Three Times Daily. Press release. November 11, 2012.