inosine-triphosphate and Hepatitis-C--Chronic

Topics: Adenosine Triphosphate; Anemia, Hemolytic; Female; Guanosine Triphosphate; Hepatitis C, Chronic; Humans; Inosine Triphosphatase; Inosine Triphosphate; Male; Middle Aged; Nucleotides; Phenotype; Polymorphism, Single Nucleotide; Purines; Pyrophosphatases; Retrospective Studies; Ribavirin; Sofosbuvir

It is not yet clear which factors are associated with the outcome of 72-week treatment with pegylated-interferon and ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection.. In 66 patients with HCV genotype 1 who had a late viral response (LVR) to 72-week treatment of pegylated-interferon and RBV, we examined the factors that determined the outcome, including single nucleotide polymorphisms of interleukin-28B and inosine triphosphatase (ITPA) genes.. Thirty seven of 66 (56%) patients with LVR achieved a sustained viral response (SVR). The mean age of these 37 SVR patients was 55, compared with 61 in 29 relapsed patients (P = 0.009). Twenty six of 54 (48%) patients with the CC genotype and 11 of 12 (92%) with the CA/AA genotype of ITPA rs1127354 achieved SVR (P = 0.006). The SVR rates were 79%, 40%, 60%, and 33% in patients with undetectable HCV RNA on weeks 16, 20, 24, and 28 or later, respectively (P = 0.014). Finally, serum RBV concentration at week 44 of treatment was significantly higher in the SVR group (2651 ng/mL) than in the relapse group (1989 ng/mL, P = 0.002). In contrast, the rate of the interleukin-28B genotype was not different between the groups. Multiple regression analysis showed that age < 60 years, ITPA CA/AA genotype, and serum RBV concentration were significant independent predictive factors for SVR.. Our findings elucidated the association of four factors, including ITPA genotype, with the outcome of 72-week treatment in LVR patients.

Topics: Adult; Aged; Antiviral Agents; Drug Therapy, Combination; Female; Genotype; Hepatitis C, Chronic; Humans; Inosine Triphosphatase; Inosine Triphosphate; Interferon alpha-2; Interferon-alpha; Interferons; Interleukins; Male; Middle Aged; Polyethylene Glycols; Polymorphism, Single Nucleotide; Pyrophosphatases; Recombinant Proteins; Regression Analysis; Ribavirin; Time Factors; Treatment Outcome; Young Adult

Genetic variation of inosine triphosphatase (ITPA) causing an accumulation of inosine triphosphate (ITP) has been shown to protect patients against ribavirin (RBV)-induced anemia during treatment for chronic hepatitis C infection by genome-wide association study (GWAS). However, the biologic mechanism by which this occurs is unknown.. We examined whether ITP can be used by adenosine triphosphatase (ATPase) in human erythrocytes or recombinant human adenylosuccinate synthase (ADSS). RBV-induced adenosine triphosphate (ATP) reduction in erythrocytes was compared with the genetically determined low or normal activity of ITPA, leading respectively to high or normal ITP levels.. Although ITP is not used directly by human erythrocyte ATPase, it can be used for ATP biosynthesis via ADSS in place of guanosine triphosphate (GTP). With RBV challenge, erythrocyte ATP reduction was more severe in the wild-type ITPA genotype than in the hemolysis protective ITPA genotype. This difference also remains after inhibiting adenosine uptake using nitrobenzylmercaptopurine riboside (NBMPR). Interestingly, the alleviation of ATP reduction by the hemolysis protective ITPA genotype was canceled by the ADSS inhibitor 6-mercaptoethanol (6-MP).. ITP confers protection against RBV-induced ATP reduction by substituting for erythrocyte GTP, which is depleted by RBV, in the biosynthesis of ATP. Because patients with excess ITP appear largely protected against anemia, these results confirm that RBV-induced anemia is due primarily to the effect of the drug on GTP and consequently ATP levels in erythrocytes.

Topics: Adenosine Triphosphate; Adenylosuccinate Synthase; Adolescent; Adult; Anemia; Antiviral Agents; Enzyme Activation; Erythrocytes; Genetic Variation; Genotype; Guanosine Triphosphate; Hepatitis C, Chronic; Humans; In Vitro Techniques; Inosine Triphosphatase; Inosine Triphosphate; Pyrophosphatases; Ribavirin; Young Adult