Absence of interferon-lambda 4 enhances spontaneous clearance of acute hepatitis C virus genotypes 1-3 infection
Journal article, 2021

Objectives Absence of a functional interferon-lambda 4 (IFN-lambda 4) gene (IFNL4) predicts spontaneous resolution of acute hepatitis C virus (HCV) infections in regions with a predominance of genotype 1, whereas variants of the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) entailing reduced activity associate with increased sustained virologic response rates following some therapeutic regimens. This study aimed at investigating the impact of IFNL4 on acute HCV genotype 2 or 3 infections, and whether ITPase activity influenced outcome. Materials and Methods Two hundred and seven people who injected drugs (PWID) with documented anti-HCV seroconversion, and 57 PWID with reinfection with HCV were analyzed regarding IFNL4 (rs368234815 and rs12979860) and ITPA (rs1127354 and rs7270101), and longitudinally followed regarding HCV RNA. Results The spontaneous clearance of HCV infection in anti-HCV seronegative PWID was enhanced when IFN-lambda 4 was absent (44% vs. 20% for IFNL4 TT/TTrs1368234815 and Delta G(rs1368234815) respectively, p < .001; OR 3.2) across genotypes 1-3. The proportion lacking IFN-lambda 4 was further increased following resolution of repeated re-exposure to HCV (74% among re-infected participants who had cleared at least two documented HCV infections). ITPA genetic variants did not independently impact on the outcome, but among males lacking IFN-lambda 4, reduced ITPase activity markedly augmented the likelihood of resolution (65% vs. 29% for <100% and 100% ITPase activity, p = .006). Conclusions Absence of IFN-lambda 4 entails an enhanced likelihood of spontaneous resolution both following primary acute infection and repeated re-exposure to HCV across genotypes 1-3. Among men lacking IFN-lambda 4, reduced ITPase activity improved outcome.


spontaneous resolution

Interferon-λ 4

spontaneous clearance

hepatitis C virus

incident infection

inosine triphosphate pyrophosphatase

acute infection




Jesper Waldenstrom

University of Gothenburg

Sahlgrenska University Hospital

Martin Kaberg

Karolinska Institutet

Marianne Alanko Blome

Lund University

Anders Widell

Lund University

Per Bjorkman

Lund University

Staffan Nilsson

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

University of Gothenburg

Anders Hammarberg

Karolinska Institutet

Stockholm County Council

Ola Weiland

Karolinska Institutet

Kristina Nystrom

Sahlgrenska University Hospital

University of Gothenburg

Martin Lagging

Sahlgrenska University Hospital

University of Gothenburg

Scandinavian Journal of Gastroenterology

0036-5521 (ISSN) 1502-7708 (eISSN)

Vol. In Press

Subject Categories

Infectious Medicine

Gastroenterology and Hepatology

Microbiology in the medical area





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Latest update

6/7/2021 1