Journal
GASTROENTEROLOGY
Volume 143, Issue 3, Pages 608-U95Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2012.05.011
Keywords
Clinical Trial; Response to Therapy; Prognostic Factors; Genetic
Categories
Funding
- Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ
- Merck
- Vertex
- Abbott
- Gilead
- Achillion
- Genentech
- Tibotec
- Salix
- Roche
- Bristol Myers Squibb
- Janssen
- Bayer
- Boehringer Ingelheim
- Novartis
- Anadys
- Exalenz
- GlaxoSmithKline
- CVS-Caremark
- HGS
- Pharmasset
- Pfizer
- GlobeImmune
- Roche/Genentech
- Human Genome Sciences
- BIPI
- Three Rivers Pharmaceuticals
- Valeant
- Wyeth
- Romark Laboratories
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BACKGROUND & AIMS: Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors. METHODS: Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28-48 wk). A good response to interferon was defined as a >= 1 log(10) decrease in HCV RNA at week 4; a poor response was defined as a >= 1 log(10) decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [IL]-28B rs12979860) associated with response. The polymorphism IL-28B rs8099917 also was assessed. RESULTS: In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%-89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a >= 1 log10 decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR. CONCLUSIONS: The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A >= 1 log(10) decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B. ClinicalTrials.gov; numbers NCT00705432 and NCT00708500.
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