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ICAAC 2014: AbbVie 3D Combination Works Well for People with HIV/HCV Coinfection

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An all-oral regimen of 3 direct-acting antivirals plus ribavirin taken for 12 weeks led to sustained virological response in 94% of HIV positive people with mostly genotype 1a hepatitis C coinfection in the TURQUOISE-I study, according to data presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy this week in Washington, DC.

Direct-acting antiviral agents that target different steps of the hepatitis C virus (HCV) lifecycle have brought about a revolution in treatment, especially with the advent of interferon-free regimens. People with HIV/HCV coinfection experience more rapid liver disease progression than people with HCV alone and do not respond as well to interferon-based therapy, but several studies suggest that having HIV is no longer a predictor of poorer response when using interferon-free regimens.

Joseph Eron from the University of North Carolina at Chapel Hill presented findings from the Phase 3 TURQUOISE-I trial, which evaluated the safety and efficacy of AbbVie's 3D regimen for HIV/HCV coinfected patients.

This regimen contains the HCV protease inhibitor ABT-450 (150 mg), a boosting dose of ritonavir (100 mg), and the NS5A inhibitor ombitasvir (formerly ABT-267; 25 mg), all in a once-daily coformulation, taken with the twice-daily non-nucleoside HCV polymerase inhibitor dasabuvir (formerly ABT-333; 250 mg). Because coinfected people are considered harder to treat, all participants in this open-label trial also received weight-based ribavirin and they were randomly assigned to 12 or 24 weeks of therapy. (In the PEARL trials of HCV genotype 1b monoinfected patients, in contrast, everyone was treated for 12 weeks and only half were randomized to receive ribavirin.)

TURQUOISE-I is being conducted in 2 parts. Part 1 included 63 genotype 1 HIV/HCV coinfected patients. More than 90% were men, 76% were white, and the mean age was 51 years. The study enrolled both previously untreated people (67%) and treatment-experienced patients (33%), about half of whom were prior null responders. Most participants (nearly 90%) had harder-to-treat HCV genotype 1a, about 80% had unfavorable IL28B non-CC gene variants, and 19% had compensated liver cirrhosis. With regard to HIV status, they were on stable antiretroviral therapy (ART) with undetectable HIV viral load and a CD4 T-cell count of at least 200 cells/mm3 (median 630 cells/mm3).

Prior to testing in coinfected people, researchers performed extensive drug-drug interaction studies in healthy volunteers, which showed that the AbbVie drugs have no clinically meaningful interactions with tenofovir or emtricitabine (the drugs in Truvada), atazanavir (Reyataz), or raltegravir (Isentress). In Part 1 of TURQUOISE-I, participants were on ART containing atazanavir or raltegravir. Part 2 will look at coinfected patients taking darunavir (Prezista). The ritonavir in the ABT-450 coformulation will also act as a booster for atazanavir or darunavir.

The primary endpoint was sustained virological response, or undetectable HCV RNA at 12 weeks after completing treatment (SVR12). All patients in the 12-week arm had reached this endpoint at the time of the data analysis. SVR4, or 4-week post-treatment sustained response, was reported for people in the 24-week arm. SVR4 is too early to consider a cure, as relapse may still occur after this point.

Results

  • SVR4 rates at 4-weeks post-treatment were 94% in the 12-week arm and 97% in the 24-week arm.
  • With no further relapses, the SVR12 rate in the 12-week arm remained at 94%.
  • 1 person experienced HCV relapse at 2 weeks post-treatment and 1 experienced viral breakthrough at week 16 while on treatment.
  • Both of these patients were prior null responders with cirrhosis who had HCV subtype 1a and the least favorable IL28B TT gene variant.
  • The 3D regimen plus ribavirin was generally safe and well-tolerated.
  • The most common side effects were fatigue, insomnia, nausea, and headache, mostly mild or moderate.
  • No participants experienced serious adverse events or discontinued treatment for this reason.
  • Looking at laboratory abnormalities, 35% of participants in the 12-week experienced bilirubin elevation, a known side effect of atazanavir.
  • 4 people in the 12-week arm and 3 in the 24-week arm developed low hemoglobin, but no one progressed to severe anemia.
  • 6 patients reduced their ribavirin dose due to anemia, but all went on to achieve SVR.
  • Participants maintained good HIV control, with none having confirmed HIV RNA >200 copies/mL and no notable changes in CD4 count.

"The high virologic response and low rate of discontinuation with 3D + ribavirin in genotype 1 HCV/HIV-1 coinfected patients are consistent with HCV genotype 1-monoinfected patients, despite multiple unfavorable predictors of response," the researchers concluded.

Presenting similar findings at the recent 20th International AIDS Conference in Melbourne, co-investigator Mark Sulkowski suggested that people with HCV genotype 1b probably do not need to include ribavirin and most patients probably need only 12 weeks of treatment. The biggest concern is the subgroup of hard-to-treat prior non-responders with HCV 1a and cirrhosis.

The AbbVie 3D regimen is currently under regulatory review in the U.S. and Europe, with an FDA approval decision expected by the end of the year. While the first-generation HCV direct-acting antivirals boceprevir (Victrelis) and telaprevir (Incivek or Incivo) were approved first for HIV negative people, the initial indication for the next-generation agent sofosbuvir (Sovaldi) is the same for both HCV monoinfected and HIV/HCV coinfected people.

9/7/14

Reference

J Eron, D Wyles, M Sulkowski, et al. TURQUOISE-I: Safety and Efficacy of ABT-450/r/Ombitasvir, Dasabuvir, and Ribavirin in Patients Co-infected with HCV and HIV-1.54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract V-673.