Variants in the ITPA Gene Protect Against Ribavirin-Induced Hemolytic Anemia in HIV/HCV-Coinfected Patients With All HCV Genotypes

Hepatitis C virus (HCV) chronically infects approximately 170 million people worldwide [1]. In resource-rich countries, HCV is the leading cause of end-stage liver disease and hepatocellular carcinoma, as well as the main indication of the need for liver transplantation [1]. In the United States and Europe, HCV affects 15%–30% of individuals infected with human immunodeficiency virus (HIV) and currently represents a major cause of morbidity and mortality in the coinfected population [2, 3]. Therapy for chronic hepatitis C with pegylated interferon alfa (pegIFN) plus ribavirin (RBV) is poorly tolerated, and only half of patients who receive therapy achieve a sustained virological response (SVR) [4]. This figure is lower in HIV/HCV-coinfected patients, who are at greater risk of hematologic adverse effects [5, 6]. Increased RBV dose has been shown to improve SVR rates in difficult to treat patient groups, and serum ribavirin levels have, in some studies, been shown to correlate with on-treatment response; however, higher ribavirin exposure may also increase adverse events, particularly RBV-induced hemolytic anemia [7–9]. A genomewide association study (GWAS) of a subset of HCV genotype-1 monoinfected patients from the IDEAL study recently reported a strong association between a single-nucleotide polymorphism (SNP) rs6051702 on chromosome 20 and treatment-related anemia in individuals with genotype 1 infection [10]. The responsible gene locus is in the inosine triphosphatase (ITPA) gene, which encodes inosine triphosphatase (ITPase), a protein that hydrolyses inosine triphosphase [10]. Previous reports of loss of function gene mutations have been described that lead to ITPase deficiency: a benign red cell enzymopathy characterized by accumulation of ITP in erythrocytes and increased toxicity of purine analog drugs [11, 12]. Genotyping of these variants demonstrated that the association signal was entirely explained by 2 functional variants in the ITPA gene: a missense variant in exon 2 (rs1127354) and a splice-altering SNP in intron 2 (rs7270101) [13–16]. The mechanism by which these mutations result in protection from treatment-induced anemia is in part related to the ability of ITP to substitute for erythrocyte guanosine triphosphate (GTP), which is depleted by RBV during biosynthesis of adenosine triphosphate (ATP) [17]. Recent data also suggest that ITPA variants may remain predictive in the setting of triple combination therapy with telaprevir plus pegIFN/RBV [18]. We sought to extend our understanding of this genetic association in an HIV/HCV-coinfected cohort of patients and in other HCV genotypes. Specifically, we investigate the association between the functional ITPA variants and the development of anemia at week 4, and the impact on hemoglobin levels over the course of therapy. We also explore whether these genetic variants are associated with serum RBV levels, RBV dose reductions, rapid virological response (RVR), and SVR.