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

Robert A. Ogert, John A. Howe, John M. Vierling, Paul Y. Kwo, Eric J. Lawitz, Jonathan McCone, Eugene R. Schiff, David Pound, Mitchell N. Davis, Stuart C. Gordon, Natarajan Ravendhran, Lorenzo Rossaro, Ira M. Jacobson, Robert Ralston, Eirum Chaudhri, Ping Qiu, Lisa D. Pedicone, Clifford A. Brass, Janice K. Albrecht, Richard J.O. BarnardDaria J. Hazuda, Anita Y.M. Howe

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs). Results: A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (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 virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline 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 post-baseline RAVs.

Original languageEnglish (US)
Pages (from-to)387-397
Number of pages11
JournalAntiviral Therapy
Volume18
Issue number3
DOIs
StatePublished - May 28 2013

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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