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Abstract Details
Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C in the SPRINT-1 Trial
Ogert RA, Howe JA, Vierling JM, Kwo PY, Lawitz EJ, McCone J, Schiff ER, Pound D, Davis MN, Gordon SC, Ravendhran N, Rossaro L, Jacobson IM, Ralston R, Chaudhri E, Qiu P, Pedicone LD, Brass CA, Albrecht JK, Barnard RJ, Hazuda DJ, Howe AY. Antivir Ther. 2013 Feb 12. doi: 10.3851/IMP2549. [Epub ahead of print]
Source
Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. robert.ogert@merck.com.
Abstract
BACKGROUND:
Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C.
METHODS:
SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (N=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to peginterferon alfa 2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analyzed by population sequencing for detection of BOC associated resistance-associated variants (RAVs).
RESULTS:
17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virologic response (SVR). V55A/I (n=13), Q41H (n=11), and T54S (n=9) were the most frequently detected polymorphisms at baseline. 7 Non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and nonresponse, n=1) and/or R155K (nonresponse, n=2). In total, 63/144 (44%) patients having postbaseline samples sequenced (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%], and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%], and V170A [2/11; 18%]. RAV frequency varied according to the virologic response: 90%, 67%, 27%, and 37% of breakthrough, incomplete virologic response, relapse, and nonresponder patients, respectively had postbaseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of postbaseline RAVs was highest in the low-dose ribavirin arm.
CONCLUSIONS:
SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of postbaseline RAVs.