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CROI 2012: Telaprevir and Boceprevir Improve Sustained Response Rates in HIV/HCV Coinfected Patients

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Adding a first-generation HCV protease inhibitor to pegylated interferon/ribavirin dramatically increases the likelihood of 12-week sustained virological response among HIV/HCV coinfected people, researchers reported Tuesday at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) in Seattle.

Last year's approval of the first direct-acting hepatitis C drugs has ushered in a new era of treatment. The HCV protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are licensed only for HCV monoinfected patients in combination with pegylated interferon and ribavirin. However, studies are ongoing for the HIV/HCV coinfected population, a group that urgently needs better treatment options.

Telaprevir

Douglas Dieterich from Mount Sinai School of Medicine presented the latest findings from Study 110, a Phase 2 trial testing telaprevir in combination with pegylated interferon/ribavirin in previously untreated coinfected patients with difficult-to-treat HCV genotype 1. Initial data were presented at last year's CROI, with further follow-up at the AASLD Liver Meeting last fall.

The study consisted of 2 parts. Part A included 13 coinfected participants who had CD4 T-cell counts of at least 500 cells/mm3 and were not yet taking antiretroviral therapy (ART). Part B included 47 people on ART; 24 took efavirenz (Sustiva) plus tenofovir (Viread) and emtricitabine (Emtriva), while 23 took ritonavir-boosted atazanavir (Reyataz) with either lamivudine (Epivir) or emtricitabine.

Most participants were men, with an average age of about 45 years. Part A included a higher proportion of black patients (a group that does not respond as well to interferon-based therapy). About half in Part A and 75% in Part B had HCV genotype 1a, the rest 1b. Most had high baseline HCV viral load about 10% had advanced liver fibrosis or cirrhosis. Median CD4 counts in Part A and B were approximately 600 and 500 cells/mm3, respectively; patients on ART had suppressed HIV RNA below 50 copies/mL.

In both parts of the study participants were randomly assigned to receive either telaprevir or placebo in combination with 180 mcg/week pegyalted interferon alfa-2a (Pegasys) plus ribavirin. Triple therapy continued for 12 weeks, followed by pegyalted interferon/ribavirin alone through week 48.

Patients taking atazanavir received the usual telaprevir dose of 750 mg 3-times-daily; to compensate for a known drug-drug interaction than lowers telaprevir levels, those taking efavirenz increased their dose to 1125 mg 3-times-daily.

Dieterich reported rates of sustained virological response, or continued undetectable viral load, at 12 weeks after completion of treatment, known as SVR12. This has been shown to be a good predictor of 24-week SVR, generally considered a cure.

Results

  • 2 patients (5%) in the triple therapy arm and 7 (32%) taking pegyalted interferon/ribavirin alone stopped treatment prematurely due to poor early response according to predefined "futility" rules.
  • Overall, 74% of patients taking telaprevir achieved SVR12, compared with just 45% of those taking pegylated interferon/ribavirin alone.
  • Among participants not taking ART in Part A, SVR12 rates were 71% and 33%, respectively.
  • By ART regimen, 69% using the efavirenz combination and 80% using boosted atazanavir achieved SVR12 with telaprevir, compared with 50% for both regimens with pegylated interferon/ribavirin alone.
  • 1 telaprevir recipient (3%) and 2 placebo recipients (15%) experienced HCV relapse after competing therapy.
  • 3 people on the telaprevir combination experienced HCV RNA breakthrough while on treatment.
  • No participants showed evidence of HIV viral load rebound.
  • Absolute CD4 cell counts fell in both arms -- a known effect of interferon -- but CD4 cell percentages did not change.
  • People taking telaprevir experienced more side effects overall than those on pegylated interferon/ribavirin alone.
  • 3 people on telaprevir, but none in the control group, discontinued treatment early due to adverse events.
  • Adverse events that occurred at least 10% more often among telaprevir recipients compared with placebo recipients included:
    • Pruritis, or itching (39% vs 9%);
    • Headache (37% vs 27%);
    • Nausea (34% vs 23%);
    • Skin rash (34% vs 23%);
    • Fever (21% vs 9%);
    • Depression (21% vs 9%).
  • Insomnia and weight loss were more common in the control group.
  • No patients in either arm experienced severe rash.
  • Anemia was equally common in both groups (18%).

"Higher SVR12 rates were observed in chronic genotype 1 patients treated with telaprevir combination treatment," the researchers concluded. "Overall safety and tolerability profile was comparable to that previously observed in chronic genotype 1 HCV monoinfected patients."

Boceprevir

Mark Sulkowski from Johns Hopkins presented data on boceprevir triple therapy in HIV/HCV coinfected patients. Earlier findings were presented at last year's Infectious Diseases Society of America (IDSA) meeting.

In this Phase 2 trial, 100 previously untreated coinfected participants with HCV genotype 1 were randomly assigned to receive 800 mg 3-times-daily boceprevir or placebo plus 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) and weight-adjusted ribavirin; 2 people dropped out before receiving study drugs.

All participants started with a 4-week lead-in period of pegylated interferon/ribavirin alone, followed by triple therapy for 44 more weeks. Here too, people with poor early response discontinued treatment according to predefined futility rules.

All patients in this trial were taking ART and had stable undetectable HIV viral load. Based on prior drug-drug interaction studies, they were limited to regimens containing a boosted HIV protease inhibitor plus 2 nucleoside/nucleotide reverse transcriptase inhibitors. Further analysis recently revealed that combining boceprevir with boosted HIV protease inhibitors can lower drug levels, potentially allowing HIV or HCV rebound.

Again, most participants (about 70%) were men and the median age was 44 years; 65% had HCV genotype 1a, the rest 1b. Most had high baseline HCV RNA and about 5% had cirrhosis. The median CD4 count was about 580 cells/mm3.

Results

  • 3 months after completion of treatment, 61% of participants in the boceprevir arm achieved SVR12, compared with only 27% in the placebo arm -- a difference of 34%.
  • There were 2 relapses after completing treatment in the triple therapy group and 1 in the control group.
  • 3 patients taking boceprevir and 4 taking pegylated interferon/ribavirin alone experienced HIV viral load rebound.
  • Again, absolute CD4 cell counts -- but not CD4 percentages -- fell in both groups.
  • 7 people (21%) taking boceprevir and 11 people (17%) taking pegylated interferon/ribavirin alone experienced serious adverse events.
  • Boceprevir recipients were at least 10% more likely than placebo recipients to report the following adverse events:
    • Anemia (41% vs 26%);
    • Fever (36% vs 21%);
    • Weakness (34% vs 24%);
    • Loss of appetite (34% vs 18%);
    • Diarrhea (28% vs 18%);
    • Vomiting (28% vs 15%);
    • Dysgeusia, or unusual taste sensations (28% vs 15%);
    • Neutropenia (19% vs 6%).
  • Flu-like symptoms were more common in the control group.

"HCV-HIV coinfected patients who were previously untreated had higher rates of HCV response on boceprevir," the investigators concluded. "Preliminary safety data of boceprevir/pegylated interferon/ribavirin in coinfected patients is consistent with that observed in [HCV] monoinfected patients."

At a press conference to discuss the findings Sulkowski said the latest data, taken together, are "really very encouraging," suggesting that triple therapy with an HCV protease inhibitor may be an important option for coinfected patients.

The similarity in rates of HIV breakthrough in the boceprevir and placebo arms raises a question about the clinical significance of the recently announced drug-drug interaction findings. But in a press release describing the SVR12 findings, Merck said it "does not recommend the co-administration of [boceprevir] and ritonavir-boosted HIV protease inhibitors."

[Mark Sulkowski discusses the implications of boceprevir-antiretroviral drug interactions at CROI press conference, Seattle, March 6, 2012]

3/7/12

References

D Dieterich, V Soriano, K Sherman, et al. Telaprevir in Combination with Pegylated Interferon-alfa-2a + Ribavirin in HCV/HIV-coinfected Patients: A 24-Week Treatment Interim Analysis. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 46.

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.

Other Sources

Vertex Pharmaceuticals. Data from Phase 2 Study of an Incivek Combination Regimen Showed 74% of People Co-Infected with Hepatitis C and HIV Had Undetectable Hepatitis C Virus 12 Weeks After Treatment Ended (SVR12). Press release. March 6, 2012.

Merck. Results from Investigational Studies with Victrelis (boceprevir) Presented at the Conference on Retroviruses and Opportunistic Infections to Understand Potential Use in Patients Coinfected with Chronic Hepatitis C and HIV-1. Press release. March 6, 2012.