title: Variation in both IL28B and KIR2DS3 genes influence pegylated interferon and ribavirin hepatitis C treatment outcome in HIV-1 co-infection.
abstract: Pegylated-IFN and ribavirin remains the current treatment for chronic HCV infection in patients co-infected with HIV-1, but this regimen has low efficacy rates, particularly for HCV genotype 1/4 infection, has severe side effects and is extremely costly. Therefore, accurate prediction of treatment response is urgently required. We have recently shown that the NK cell gene, KIR2DS3 and a SNP associated with the IL28B gene synergise to increase the risk of chronic infection in primary HCV mono-infected patients. Identification of SNPs associated with the IL28B gene has also proven very powerful for predicting patient response to treatment. Patients co-infected with HIV-1 are of particular concern given they respond less well to HCV treatment, have more side effects and suffer a more rapid liver disease progression. In this study, we examined both IL28B and KIR2DS3 for their ability to predict treatment response in a cohort of HIV-1/HCV co-infected patients attending two treatment centres in Europe. We found that variation in both host genetic risk factors, IL28B and KIR2DS3, was strongly associated with sustained virological response (SVR) to treatment in our co-infected cohort (n = 149). The majority of patients who achieved a rapid virological response (RVR) achieved a SVR. However, it is currently impossible to predict treatment outcome in patients who fail to achieve an RVR. In our cohort, the presence of host genetic risk factors, IL28B-T and KIR2DS3 alleles, resulted in increased odds of treatment failure in these RVR negative patients (n = 88). Our data suggests that testing for host genetic factors will improve predicting treatment responsiveness in the clinical management of co-infected patients, and provides further evidence of the importance of the innate immune system in the immune response to HCV.
authors.affiliation: Natural Killer Cell Group, School of Biochemistry & Immunology, Trinity College, Dublin, Ireland.
authors.forename: Ciara
authors.initials: C
authors.lastname: Keane
authors.forename: Daire
authors.initials: D
authors.lastname: O'Shea
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiberger
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.forename: Gillian
authors.initials: G
authors.lastname: Farrell
authors.forename: Colm
authors.initials: C
authors.lastname: Bergin
authors.forename: Clair M
authors.initials: CM
authors.lastname: Gardiner
mesh_terms: D000328:Adult; D000483:Alleles; D015331:Cohort Studies; D060085:Coinfection / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054340:Receptors, KIR / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D016896:Treatment Outcome; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D054340:Receptors, KIR; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C541358:KIR2DS3 protein, human; C100416:peginterferon alfa-2a