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Three-DAA Regimen (Abbvie) Achieves 99% SVR12 Rates in HCV Genotype 1b Naives
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CROI 2014, March 3-6, 2014, Boston
CROI: PEARL III: SVR ≥99% AFTER 12 WKS OF ABT-450/R/267 + ABT-333 ± RBV IN TREATMENT-NAIVE HCV GT1B INFECTION - (03/04/14)
Mark Mascolini
Almost everyone treated for 12 weeks with three direct-acting antiretrovirals (DAAs) for HCV genotype 1b infection had a sustained virologic response 12 weeks after treatment ended (SVR12), regardless of whether they added ribavirin to the three DAAs [1]. Side effects proved more common and more serious among people randomized to ribavirin in this study of people without cirrhosis.
With new DAAs for HCV infection proliferating, the race is on to identify effective, easy-to-take, and safe combinations that do not include either of the older toxic anti-HCV drugs, ribavirin and interferon. One candidate for this crown emerged in the PEARL III trial, which combined three DAAs made by the same company, AbbVie: (1) ABT-450, a ritonavir-boosted HCV protease inhibitor, (2) ABT-267, an NS5A inhibitor, and (3) ABT-333, a nonnucleoside polymerase inhibitor. The first two agents (and ritonavir) are combined in a once-daily fixed-dose formulation and, when combined with twice-daily ABT-333, are informally called 3D.
PEARL III randomized 419 treatment-naïve, adults with genotype 1b HCV and without cirrhosis to 3D with weight-based ribavirin or ribavirin placebo. (Genotype 1b is the most prevalent HCV subgenotype worldwide.) The study excluded anyone with HBV infection, any HCV genotype other than 1b, and anyone with liver disease not caused by chronic HCV infection.
Half of participants in the ribavirin arm (50.5%) and 41.1% in the no-ribavirin arm were men; 94% in each group were white. Age averaged 48.4 in the ribavirin group and 49.2 in the no-ribavirin group. The same proportion in each group, 21%, had the IL28B CC haplotype, which favors a good response to interferon/ribavirin. Pretreatment HCV RNA averaged 6.29 log10 IU/mL in the ribavirin group and 6.33 in the other arm.
Twelve weeks after the 12-week treatment ended, 99.5% in the ribavirin group (209 of 210) and 99% in the no-ribavirin group (207 of 209) had a sustained virologic response (SVR12). The ribavirin-free regimen proved noninferior to the ribavirin-containing regimen (95% confidence interval for SVR12 -2.1% to 1.1%).
Two people in the no-ribavirin group were lost to follow-up, one after treatment ended and one after achieving SVR for 4 weeks after treatment ended. PEARL III investigators recorded one on-treatment virologic failure in the ribavirin group and none in the no-ribavirin group. No one had a virologic relapse after completing 12 weeks of therapy. Virologic efficacy did not differ by gender, race (black versus nonblack), or IL28B genotype.
Four people in each study arm had a serious adverse event. Researchers judged only one of these adverse events--arthritis in the no-ribavirin arm--as possibly related to study drug. Nineteen people randomized to ribavirin and none randomized to 3D alone had a hemoglobin drop to below 10 g/dL, a highly significant difference (P < 0.001). Everyone with low hemoglobin had a ribavirin dose reduction, and all achieved SVR12.
Pruritus, nausea, insomnia, and cough also affected significantly more people randomized to ribavirin. Headache and fatigue affected about one quarter of participants in each study arm. No one dropped out of the trial because of adverse events or lab abnormalities.
Reference
1. Ferenci P, Nyberg A, Bernstein D, et al. PEARL III: SVR ≥99% after 12 wks of ABT-450/r/267 + ABT-333 ± RBV in treatment naive HCV GT1b infection. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 29LB.
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