Current opinion Investigating the endemic transmission of the hepatitis C virus Oliver G. Pybus a, * ,1 , Peter V. Markov a,1 , Anna Wu a , Andrew J. Tatem a,b a Department of Zoology, University of Oxford, South Parks Road, OX1 3PS, UK b Malaria Public Health and Epidemiology Group, Centre for Geographic Medicine, KEMRI/Wellcome Trust Research Laboratories, P.O. Box 43640, 00100 Nairobi, Kenya Received 5 February 2007; received in revised form 16 April 2007; accepted 20 April 2007 Abstract The hepatitis C virus (HCV) infects at least 3% of people worldwide and is a leading global cause of liver disease. Although HCV spread epidemically during the 20th century, particularly by blood transfusion, it has clearly been present in human populations for several centuries. Here we attempt to redress the paucity of investigation into how long-term endemic transmission of HCV has been maintained. Such transmission not only represents the ‘natural’ route of infection but also contributes to new infections today. As a first step, we investigate the hypothesis that HCV can be mechanically transmitted by biting arthropods. Firstly, we use a combined bioin- formatic and geographic approach to build a spatial database of endemic HCV infection and demonstrate that this can be used to geo- graphically compare endemic HCV with the range distributions of potential vector species. Second, we use models from mathematical epidemiology to investigate if the parameters that describe the biting behaviour of vectors are consistent with a proposed basic repro- duction number (R 0 ) for HCV, and with the sustained transmission of the virus by mechanical transmission. Our analyses indicate that the mechanical transmission of HCV is plausible and that much further research into endemic HCV is needed. Ó 2007 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. Keywords: Hepatitis C virus: Transmission; Vector; Arthropod; Basic reproduction number; Phylogeny 1. Introduction The hepatitis C virus (HCV) is an important viral path- ogen of humans, infecting an estimated 120–180 million people globally (CDC, 1998) and causing 3–4 million new infections each year. HCV causes substantial morbidity and mortality worldwide – chronic infection can lead to liver damage (cirrhosis) and hepatocellular carcinoma, resulting in 8000–10,000 deaths per year in the United States alone. HCV is a positive-sense single-stranded RNA virus, taxonomically classified as the sole member of the genus Hepacivirus in the family Flaviviridae. It there- fore shares genomic similarities with the flaviviruses, a genus of about 70 species that contains several important human pathogens, including Dengue virus and West Nile virus (Table 1). The vast majority of flaviviruses are trans- mitted by arthropod vectors, either mosquitoes or ticks, within which they are able to replicate (Gaunt et al., 2001). HCV is a genetically diverse virus that is classified by phylogenetic analysis into six major genotypes (denoted 1–6), each of which contains many different subtypes (denoted alphabetically, 1a, 2c, 3d, etc.; Simmonds et al., 2005). The majority of HCV infections worldwide are caused by a subset of subtypes, notably subtypes 1a, 1b, 2a, 2b, 2c and 3a (Simmonds, 2004). These strains are both highly prevalent and globally distributed and consequently have been termed ‘epidemic’ subtypes (Smith et al., 1997; Pybus et al., 2001). Their existence stems from the recent transmission history of HCV, a blood-borne infection that remained unidentified until 1989. During the 20th century, the ‘epidemic’ strains rode a rising tide of human behav- iours that inadvertently promoted the rapid global trans- mission of HCV: blood transfusion, use of blood products, haemodialysis, non-sterile administration of medicines by injection and intravenous drug use. Unsur- prisingly, most research interest has been directed towards 0020-7519/$30.00 Ó 2007 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijpara.2007.04.009 * Corresponding author. Tel.: +44 1865 271274; fax: +44 1865 271249. E-mail address: oliver.pybus@zoo.ox.ac.uk (O.G. Pybus). 1 These authors contributed equally. www.elsevier.com/locate/ijpara International Journal for Parasitology 37 (2007) 839–849