Pharmacogenetics of efficacy and safety of HCV treatment in HCV-HIV coinfected patients: significant associations with IL28B and SOCS3 gene variants

PLoS One. 2012;7(11):e47725. doi: 10.1371/journal.pone.0047725. Epub 2012 Nov 2.

Abstract

Background and aims: This was a safety and efficacy pharmacogenetic study of a previously performed randomized trial which compared the effectiveness of treatment of hepatitis C virus infection with pegylated interferon alpha (pegIFNα) 2a vs. 2b, both with ribavirin, for 48 weeks, in HCV-HIV coinfected patients.

Methods: The study groups were made of 99 patients (efficacy pharmacogenetic substudy) and of 114 patients (safety pharmacogenetic substudy). Polymorphisms in the following candidate genes IL28B, IL6, IL10, TNFα, IFNγ, CCL5, MxA, OAS1, SOCS3, CTLA4 and ITPA were assessed. Genotyping was carried out using Sequenom iPLEX-Gold, a single-base extension polymerase chain reaction. Efficacy end-points assessed were: rapid, early and sustained virological response (RVR, EVR and SVR, respectively). Safety end-points assessed were: anemia, neutropenia, thrombocytopenia, flu-like syndrome, gastrointestinal disturbances and depression. Chi square test, Student's T test, Mann-Whitney U test and logistic regression were used for statistic analyses.

Results: As efficacy is concerned, IL28B and CTLA4 gene polymorphisms were associated with RVR (p<0.05 for both comparisons). Nevertheless, only polymorphism in the IL28B gene was associated with SVR (p = 0.004). In the multivariate analysis, the only gene independently associated with SVR was IL28B (OR 2.61, 95%CI 1.2-5.6, p = 0.01). With respect to safety, there were no significant associations between flu-like syndrome or depression and the genetic variants studied. Gastrointestinal disturbances were associated with ITPA gene polymorphism (p = 0.04). Anemia was associated with OAS1 and CTLA4 gene polymorphisms (p = 0.049 and p = 0.045, respectively), neutropenia and thromobocytopenia were associated with SOCS3 gene polymorphism (p = 0.02 and p = 0.002, respectively). In the multivariate analysis, the associations of the SOCS3 gene polymorphism with neutropenia (OR 0.26, 95%CI 0.09-0.75, p = 0.01) and thrombocytopenia (OR 0.07, 95%CI 0.008-0.57, p = 0.01) remained significant.

Conclusions: In HCV-HIV coinfected patients treated with PegIFNα and ribavirin, SVR is associated with IL28B rs8099917 polymorphism. HCV treatment-induced neutropenia and thrombocytopenia are associated with SOCS3 rs4969170 polymorphism.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Gene Expression Regulation, Viral*
  • Genetic Variation*
  • Genotype
  • HIV Infections / complications
  • HIV Infections / drug therapy*
  • HIV Infections / genetics*
  • Hepatitis C / complications
  • Hepatitis C / drug therapy*
  • Hepatitis C / genetics*
  • Humans
  • Interferon-alpha / metabolism
  • Interferons
  • Interleukins / biosynthesis*
  • Male
  • Models, Genetic
  • Models, Statistical
  • Pharmacogenetics / methods*
  • Phenotype
  • Polymorphism, Genetic
  • Ribavirin / pharmacology
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / biosynthesis*

Substances

  • IFNL3 protein, human
  • Interferon-alpha
  • Interleukins
  • SOCS3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Ribavirin
  • Interferons

Grant support

This work was partially financed by a grant from the Red de Investigación de Sida (RIS, RD06/0006/0000, RD06/0006/1004, RD06/0006/1017); Instituto de Salud Carlos III (ISCIII); Fondo de Investigación Sanitaria (PI09/01778, PI09/1778 and PI10/2635); Ministerio de Economia y Conocimiento (SAF 2008 22870 and SAF2012-35198; Ministerio de Sanidad, Servicios Sociales e Igualdad (EC11-293); Programa de Suport als Grups de Recerca AGAUR (L'Agència de Gestió d'Ajuts Universitaris i de Recerca) (2009SGR1061 and 2009SGR1159). Montserrat Laguno is funded by a grant from the Spanish Ministry of Health (FIS 2007). Francesc Vidal is funded by the Programa de Intensificación de la Actividad Investigadora (ISCIII, I3SNS, INT11/240). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.