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
Free accessResearch articleFirst published online April, 2013
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.
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.
References
1.
BaconB.R., GordonS.C., LawitzE.Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med2011; 364: 1207–1217.
2.
PoordadF., McConeJ., BaconB.R.Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med2011; 364: 1195–1206.
3.
ChaseR., SkeltonA., XiaE.A novel HCV NS3 protease mutation selected by combination treatment of the protease inhibitor boceprevir and NS5B polymerase inhibitors. Antiviral Res2009; 84: 178–184.
4.
TongX., BogenS., ChaseR.Characterization of resistance mutations against HCV ketoamide protease inhibitors. Antiviral Res2008; 77: 177–185.
5.
TongX., ChaseR., SkeltonA.Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res2006; 70: 28–38.
6.
TongX., GuoZ., Wright-MinogueJ.Impact of naturally occurring variants of HCV protease on the binding of different classes of protease inhibitors. Biochemistry2006; 45: 1353–1361.
7.
LinC., LinK., LuongY.P.In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J Biol Chem2004; 279: 17508–17514.
8.
WelschC., DominguesF.S., SusserS.Molecular basis of telaprevir resistance due to V36 and T54 mutations in the NS3-4A protease of the hepatitis C virus. Genome Biol2008; 9: R16.
9.
ZhouY., BartelsD.J., HanzelkaB.L.Phenotypic characterization of resistant Val36 variants of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother2008; 52: 110–120.
10.
ZhouY., MuhU., HanzelkaB.L.Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon alpha. J Biol Chem2007; 282: 22619–22628.
11.
RomanoK.P., AliA., RoyerW.E.Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding. Proc Natl Acad Sci U S A2010; 107: 20986–20991.
12.
RomanoK.P., LaineJ.M., DeveauL.M.Molecular mechanisms of viral and host cell substrate recognition by hepatitis C virus NS3/4A protease. J Virol2011; 85: 6106–6116.
13.
RongL., DahariH., RibeiroR.M.Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med2010; 2: 30–32.
14.
KwoP.Y., LawitzE.J., McConeJ.Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre Phase 2 trial. Lancet2010; 376: 705–716.
15.
QiuP., SanforenzoV., CurryS.Identification of HCV protease inhibitor resistance mutations by selection pressure-based method. Nucleic Acids Res2009; 37: e74.
16.
SusserS., WelschC., WangY.Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology2009; 50: 1709–1718.
17.
CrottyS., MaagD., ArnoldJ.J.The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med2000; 6: 1375–1379.
18.
SulkowskiM.S., PoordadF., MannsM.P.Anemia during treatment with peginterferon alfa-2B/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previous-treatment-failure patients.46th Annual Meeting of the European Association for the Study of the Liver. 30 March–3 April, 2011, Berlin, Germany. Abstract 476.
19.
PoordadF., SulkowskiM., ReddyR.Anemia had no effect on efficacy outcomes in treatment-naive patients who received telaprevir-based regimen in the ADVANCE and ILLUMINATE Phase 3 studies.Digestive Disease Week. 7–10 May 2011, Chicago, IL, USA. Abstract 626.
20.
PoordadF., LawitzE., ReddyR.A randomized trial comparing ribavirin dose reduction versus erythropoietin for anemia management in previously untreated patients with chronic hepatitis C receiving boceprevir plus peginterferon/ribavirin. J Hepatol2012; 56Suppl 2: S559.
21.
ChayamaK., HayesC.N., AbeH.IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis2011; 204: 84–93.
22.
GeD., FellayJ., ThompsonA.J.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature2009; 461: 399–401.
23.
LokA.S., GardinerD.F., LawitzE.Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med2012; 366: 216–224.
24.
SulkowskiM., GardinerD., LawitzE.Potent viral suppression with all oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (NS5B inhibitor), +/-ribavirin, in treatment-naive patients with chronic HCV GT1, 2 or 3. J Hepatol2012; 56Suppl 2: S560.
25.
PoordadF., LawitzE., KowdleyK.V.12-Week interferon-free regimen of ABT-450/R +ABT-333 +ribavirin achieved SVR12 in more than 90% of treatment-naive HCV genotype 1 infected subjects and 47% of previous non-responders. Hepatology2012; 56Suppl 2: S549–S550.
26.
GaneE.J., RobertsS.K., StedmanC.A.Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet2010; 376: 1467–1475.
