Is hepatitis C subtyping still relevant in the era of direct-acting antiviral therapy?

Abstract

Hepatitis C virus (HCV) infects *3 % of the world population and an estimated 3–4 million new infections occur each year [1]. Not only is the virus a leading cause of chronic liver disease, but it is also associated with extrahepatic complications including type 2 diabetes and cardiovascular disease [2, 3]. The HCV is a member of the Flaviviridae family of RNA viruses and is classified into seven recognized genotypes (1–7) [4]; these are further classified into 67 confirmed and 20 provisional subtypes [4]. Each genotype differs from the others by 30–35 % in its nucleotide sequence, while subtypes within each genotype differ by 20–25 % [4]. This remarkable genetic diversity creates a challenge for the development of both HCV vaccines and pan-genotypic drug therapies [4]. Apart from nucleotide sequence variability, HCV genotypes differ in their geographic distribution, rates of viral clearance, risk of progression of liver fibrosis, predilection to hepatic steatosis, the risk of development of hepatocellular carcinoma and in the response to therapy [4– 10]. HCV genotype 1 is the most prevalent genotype and the major subtypes, 1a and 1b, are common in North America, Europe and Australia. Genotype 1a is more common than 1b in the United States, while the converse is true in Western Europe [5]. Genotype 2 is dominant in West Africa and south Asia and genotype 3 in south Asia, parts of Europe, the United States and Australia. Genotype 4 frequencies are highest from central Africa to the Middle East, particularly in Egypt, while genotype 5 has higher frequencies in southern Africa and genotype 6 is common in East and Southeast Asia. As regards the difference in other clinical characteristics, we recently reported that HCV genotype 1 is associated with greater spontaneous clearance compared to genotype non-1 [8]. HCV genotype 3 has also been shown to be associated with virus-induced hepatic steatosis and accelerated fibrosis progression compared to the other HCV genotypes [6, 10]. HCV genotype 1b has been suggested to be a risk factor for hepatocellular carcinoma development, a finding supported by a recent meta-analysis [7]. In spite of the quantum improvements in HCV therapies, the duration and regimen for treatment, types of resistance mutations, cure rates and the need for adjuvant interferon and ribavirin with the new direct antiviral drug (DAA) therapies will remain dependent in part on HCV genotype and subtype, as well as on the cost of treatment in less privileged parts of the world. Thus, more detailed knowledge of the epidemiology and characteristics of HCV genotypes and subtypes is invaluable from a clinical and research perspective and for helping in the development of national treatment policies using the new and old agents. In this issue of Hepatology International, Andriulli et al. [11] present the results of a large Italian multi-center cohort study (n = 1,233) of the differences between HCV 1a and 1b subtypes in response to pegylated interferon and ribavirin combination therapy, including a meta-analysis of studies of treatment outcome between patients with HCV subtype 1a and 1b. As expected from the known geographic distribution of HCV subtypes, the majority of subjects in this Italian cohort were infected with HCV 1b (87 %). Subjects with HCV 1a were more likely to be M. Eslam J. George Storr Liver Unit, Westmead Millennium Institute, Westmead Hospital and University of Sydney, Sydney, NSW, Australia