Impact of Genetic Variants in Inosine Triphosphate Pyrophosphatase and Interferon-λ4 on Natural History, Treatment Response and Ribavirin Pharmacology in Hepatitis C Virus Infection
Hepatitis C virus (HCV) impacts on global health with around 70 million chronically infected worldwide. The infection increases the risk of cirrhosis and primary liver cancer. The treatment until 2013 has been based on interferon-α and ribavirin, but is now replaced by direct acting antivirals. Ribavirin is still used in the most difficult-to cure patients. This thesis evaluates host genetic variations in inosine triphosphate pyrophosphatase (ITPA) and interferon-λ4 (IFNL4) in relation to cure rates in patient treated with interferon-α and ribavirin as well as ribavirin pharmacology in the setting of chronic HCV infection, and spontaneous resolution of acute HCV infection. In a post-hoc analysis of 354 HCV genotype 2/3 infected patients receiving interferon-α and ribavirin, genetic variation in ITPA entailing reduced ITPase activity was associated with increased cure rates (paper I). Small inhibiting RNA aimed at ITPA reduced ITPase levels and increased the antiviral effect of ribavirin, ribavirin associated viral mutations and concentrations of ribavirin triphosphate intracellularly, in vitro. ITPase was also shown to be able to dephosphorylate ribavirin triphosphate (paper III). In a randomized trial, standard interferon-α and ribavirin treatment was compared to four weeks ribavirin monotherapy prior to combination treatment and to two weeks of ribavirin double dosage alongside with interferon-α. Both experimental strategies succeeded in reaching high ribavirin concentrations at earlier timepoints in dual therapy. Ribavirin monotherapy resulted in a viral decline associated with IFNL4 genotype (paper II). IFNL4 genotype was associated with clearance in acute HCV genotype 1 as well as in genotype 2/3 infection. ITPA genotype showed significant associations with age at seroconversion and spontaneous resolution in males with favorable IFNL4 genotype (paper IV).
Parts of work
I. Rembeck K, Waldenstrom J, Hellstrand K, Nilsson S, Nystrom K, Martner A, et al. Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3. Hepatology. 2014;59(6):2131-9. ::doi::10.1002/hep.27009II. Waldenstrom J, Westin J, Nystrom K, Christensen P, Dalgard O, Farkkila M, et al. Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection. PLoS One. 2016;11(5):e0155142. ::doi::10.1371/journal.pone.0155142III. Nystrom K, Wanrooij PH, Waldenstrom J, Adamek L, Brunet S, Said J, et al. Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus. J Virol. 2018;92(19). ::doi::10.1128/JVI.01087-18IV. Waldenstrom J, Kåberg M, Alanko-Blomé M, Widell A, Björkman P, Nilsson S, et al. I. Interferon-λ 4 Genetic Variants are Independently Associated with Spontaneous Clearance of Acute Hepatitis C Virus Genotype 1-3 Infection, and Inosine Triphosphate Pyrophosphatase Polymorphisms Impact on Immune Responses in Men. In Manuscript.
Doctor of Philosophy (Medicine)
University of Gothenburg. Sahlgrenska Academy
Institute of Biomedicine. Department of Infectious Diseases
Fredagen den 15 maj 2020, kl 9.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg, https://gu-se.zoom.us/webinar/register/WN_B5-j3E6iSBeGzPU_r78puw
Date of defence
Hepatitis C virus
Inosine triphosphate pyrophosphatase