Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort.

Department of Infectious Diseases, Medical Division, Akershus University Hospital, Lørenskog, Norway.
European journal of gastroenterology & hepatology (Impact Factor: 2.15). 05/2012; 24(8):890-6. DOI: 10.1097/MEG.0b013e3283546efd
Source: PubMed

ABSTRACT Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response.
Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4.
Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22).
We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Single-nucleotide polymorphisms (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene correlate with ribavirin (RBV)-induced anemia in patients with chronic hepatitis C (CHC) receiving combination therapy. Managing anemia is an early priority in the treatment process. The aim was to develop a predictive index based on ITPA SNP status to identify CHC patients at risk of anemia. A total of 418 eligible East Asian patients diagnosed with CHC genotype 1 (G1) received combination therapy in this study. Participant DNA was genotyped for a functional ITPA SNP (C/C, A/A or C/A) on chromosome 20 at rs1127354. A predictive index was constructed by incorporating independent factors identified for severe anemia events (hemoglobin < 10 g/dL). Areas under the receiver-operating characteristic curves (AUCs) represented the diagnostic accuracies of the predictive index in randomly assigned development and validation cohorts. Multiple logistic regressions identified age (≥ 50 y: OR = 9.7, 95% CI = 5.0 - 18.6), ITPA rs1127354 (C/C: OR = 3.3, 95% CI = 1.8 - 5.8) and baseline hemoglobin (< 14.0 g/dL: OR 6.4, 95% CI = 3.3 - 12.1; 14.0 - 14.9: OR = 2.4, 95% CI = 1.2 - 4.6) as predictors of severe anemia throughout the treatment. For severe anemia, the predictive index incorporating age, ITPA SNP status and baseline hemoglobin yielded diagnostic accuracies (AUCs) of 0.830 (95% CI = 0.783 - 0.871) in the development (n = 324) and 0.902 (0.826 - 0.925) in the validation (n = 81) cohorts. In patients with CHC G1 and receiving combination therapy, ITPA SNP-based index was an accurate and practical solution for prediction of severe anemia.
    Hepatitis Monthly 03/2015; 15(3):e27148. DOI:10.5812/hepatmon.27148 · 1.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: EDITORIAL Do variations in the ITPA gene determine the risk of hepatitis C virus relapse? KEYWORDS • hepatitis C virus • inosine triphosphatase • inosine triphosphate pyrophosphatase • ITPA ITPA polymorphisms & ribavirin-induced anemia A recent genome-wide association study demonstrated that two genetic variants, a missense variant in exon 2 (rs1127354, P32T) and a splice-altering single-nucleo-tide polymorphism in intron 2 (rs7270101, IVS2) of the ITPA gene, entailing reduced ITPase activity, protecting against ribavi-rin-induced hemolytic anemia during inter-feron and ribavirin therapy for hepatitis C virus (HCV) genotype 1 [1]. This protec-tion against anemia has been subsequently confirmed in numerous studies [2–8], but divergent results regarding the association with outcome have been reported. ITPA polymorphisms & sustained virological response Several, but far from all studies have reported associations between homo-or hetero-zygosity at A rs1127354 or C rs7270101 , which are present in 37% of HCV patients [2], and a higher likelihood of achieving sustained virological response (sustained virological response [SVR]; i.e., undetect-able HCV RNA 24 weeks after termina-tion of therapy), mediated by reduced relapse rates [2–5]. This reduction in relapse resembles that reported when ribavirin was added to interferon, thus markedly improving outcomes as compared with prior interferon monotherapy [9]. In con-trast to the aforementioned studies, oth-ers have not been able to demonstrate any significant association between ITPA vari-ants and outcome [1,6–8]. These discordant results may potentially be explained by differences in adherence monitoring and ribavirin dosing. When evaluating the impact of potential response predictors, monitoring of adher-ence to medication is essential in order to minimize the dilution effect caused by the inclusion in the analysis of patients not achieving SVR due to premature treatment termination secondary to neuropsychiat-ric side effects of interferon. Furthermore, the well-established relationship between reduced ITPase activity and protection against anemia may act as a confounding factor, as the latter subsequently improves ribavirin adherence [8], which consequently impacts on outcome. When evaluating a cohort of northern European treatment-naive patients with
    Future Microbiology 09/2014; 969(9(9)):1009–1012. DOI:10.2217/FMB.14.69 · 3.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) infection is a global health problem that affects more than 170 million people worldwide. It is a major cause of cirrhosis and hepatocellular carcinoma, making the virus the most common cause of liver failure and transplantation. The standard-of-care treatment for chronic hepatitis C (CHC) has been changed during the last decade and direct acting antiviral drugs have already been used. Besides, understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment. Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection. The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
    World Journal of Gastroenterology 03/2014; 20(11):2839-2853. DOI:10.3748/wjg.v20.i11.2839 · 2.43 Impact Factor