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

Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. 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...

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Published in:Antiviral therapy 2013, Vol.18 (3), p.387-397
Main Authors: OGERT, Robert A, HOWE, John A, RAVENDHRAN, Natarajan, ROSSARO, Lorenzo, JACOBSON, Ira M, RALSTON, Robert, CHAUDHRI, Eirum, PING QIU, PEDICONE, Lisa D, BRASS, Clifford A, ALBRECHT, Janice K, BARNARD, Richard Jo, VIERLING, John M, HAZUDA, Daria J, HOWE, Anita Ym, KWO, Paul Y, LAWITZ, Eric J, MCCONE, Jonathan, SCHIFF, Eugene R, POUND, David, DAVIS, Mitchell N, GORDON, Stuart C
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Drug Resistance, Viral - genetics
Drug Therapy, Combination
Genotype
Hepacivirus - genetics
Hepatitis C, Chronic - drug therapy
Human viral diseases
Humans
Infectious diseases
Interferon-alpha - administration & dosage
Interferon-alpha - therapeutic use
Medical sciences
Pharmacology. Drug treatments
Polyethylene Glycols - administration & dosage
Polyethylene Glycols - therapeutic use
Proline - administration & dosage
Proline - analogs & derivatives
Proline - therapeutic use
Recombinant Proteins - administration & dosage
Recombinant Proteins - therapeutic use
Recurrence
Ribavirin - administration & dosage
Ribavirin - therapeutic use
RNA, Viral
Treatment Outcome
Viral diseases
Viral hepatitis
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Summary:Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. 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). 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. 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.
ISSN:1359-6535
2040-2058
DOI:10.3851/IMP2549