The role of re-infection in determining rates of spontaneous clearance after hepatitis C exposure
Authors: Gail V. Matthews, Jason Grebely, Gregory J. Dore
Journal: Journal of Hepatology (2008)

Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patientsJournal of HepatologyVol. 49Issue 3PreviewThere are conflicting data regarding the incidence and factors implicated in the spontaneous clearance of hepatitis C virus (HCV) after acute infection. The aim of this study was to determine the epidemiological factors that predict the resolution of acute HCV infection without therapy in patients with human immunodeficiency virus (HIV) infection. Full-Text PDF In this issue of the Journal, Shores and colleagues report that sexual transmission may be associated with higher rates of spontaneous hepatitis C virus (HCV) clearance in HIV infected patients. In an international cross-sectional study of 769 HIV/HCV coinfected patients (positive for HIV and HCV antibodies), HCV RNA status was assessed at an undetermined timepoint following initial HCV infection. Evidence of spontaneous HCV clearance (as determined by a single negative HCV RNA test in the absence of any HCV-specific treatment) was found in 13% of patients overall, a lower rate than the 20–30% rate generally found in HCV monoinfected populations [[1]Micallef J.M. Kaldor J.M. Dore G.J. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.J Viral Hepat. 2006; 13: 34-41Crossref PubMed Scopus (646) Google Scholar]. In multivariate analysis, the only factors predicting negative HCV RNA were HBV coinfection and the risk factor for HIV and/or HCV transmission. Rates of spontaneous clearance were 11.6% in those presumed to be infected through injecting drug use (IDU) and 21.9% in those infected through sexual contact. Further, although the number of patients reporting homosexual contact as a risk factor was small, these patients had a similar rate of negative HCV RNA as the IDU group (13.5% vs 11.6%). Differences in spontaneous clearance rates appeared to be driven by the group with heterosexual contact as the major risk factor for viral transmission (26% of whom were HCV RNA negative). In the multivariate model, heterosexual transmission was independently associated with negative HCV RNA with an odds ratio of 2.81 (95% CI 1.55–5.09, p = 0.001). The authors declare that the reasons for this are unclear but postulate that the observed differences may be linked to smaller viral inoculums or differing genital immune responses in the group infected through heterosexual contact. However, a more likely explanation for their findings would appear to be differential risk of re-exposure and subsequent HCV re-infection across the study groups.HCV re-infection following spontaneous HCV clearance has been demonstrated in both chimpanzees [2Farci P. Alter H.J. Govindarajan S. Wong D.C. Engle R. Lesniewski R.R. et al.Lack of protective immunity against reinfection with hepatitis C virus.Science. 1992; 258: 135-140Crossref PubMed Scopus (693) Google Scholar, 3Nascimbeni M. Mizukoshi E. Bosmann M. Major M.E. Mihalik K. Rice C.M. et al.Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.J Virol. 2003; 77: 4781-4793Crossref PubMed Scopus (169) Google Scholar, 4Lanford R.E. Guerra B. Chavez D. Bigger C. Brasky K.M. Wang X.H. et al.Cross-genotype immunity to hepatitis C virus.J Virol. 2004; 78: 1575-1581Crossref PubMed Scopus (161) Google Scholar, 5Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar, 6Bassett S.E. Guerra B. Brasky K. Miskovsky E. Houghton M. Klimpel G.R. et al.Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.Hepatology. 2001; 33: 1479-1487Crossref PubMed Scopus (203) Google Scholar, 7Major M.E. Mihalik K. Puig M. Rehermann B. Nascimbeni M. Rice C.M. et al.Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge.J Virol. 2002; 76: 6586-6595Crossref PubMed Scopus (158) Google Scholar] and humans [8Lai M.E. Mazzoleni A.P. Argiolu F. De Virgilis S. Balestrieri A. Purcell R.H. et al.Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children.Lancet. 1994; 343: 388-390Abstract PubMed Scopus (275) Google Scholar, 9Tisone G. Baiocchi L. Orlando G. Palmieri G.P. Pisani F. Rapicetta M. et al.Hepatitis C reinfection after liver transplantation in relation to virus genotype.Transplant Proc. 1999; 31: 490-491Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 10Proust B. Dubois F. Bacq Y. Le Pogam S. Rogez S. Levillain R. et al.Two successive hepatitis C virus infections in an intravenous drug user.J Clin Microbiol. 2000; 38: 3125-3127PubMed Google Scholar, 11Payen J.L. Izopet J. Barange K. Puel J. Selves J. Pascal J.P. Hepatitis C virus reinfection after an intravenous drug injection.Gastroenterol Clin Biol. 1998; 22: 469-470PubMed Google Scholar, 12Vispo E. Martinez-Alarcon J. Poveda E. Toro C. Soriano V. Initial spontaneous clearance and re-infection with a distinct hepatitis C virus genotype leading to chronic hepatitis C in an HIV+ intravenous drug user.AIDS. 2008; 22: 318Crossref PubMed Scopus (4) Google Scholar]. In chimpanzees with clearance of primary infection, HCV rechallenge with both homologous or heterologous virus can lead to HCV re-infection, despite the presence of persistent humoral immunity [2Farci P. Alter H.J. Govindarajan S. Wong D.C. Engle R. Lesniewski R.R. et al.Lack of protective immunity against reinfection with hepatitis C virus.Science. 1992; 258: 135-140Crossref PubMed Scopus (693) Google Scholar, 3Nascimbeni M. Mizukoshi E. Bosmann M. Major M.E. Mihalik K. Rice C.M. et al.Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.J Virol. 2003; 77: 4781-4793Crossref PubMed Scopus (169) Google Scholar, 4Lanford R.E. Guerra B. Chavez D. Bigger C. Brasky K.M. Wang X.H. et al.Cross-genotype immunity to hepatitis C virus.J Virol. 2004; 78: 1575-1581Crossref PubMed Scopus (161) Google Scholar, 5Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar, 6Bassett S.E. Guerra B. Brasky K. Miskovsky E. Houghton M. Klimpel G.R. et al.Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.Hepatology. 2001; 33: 1479-1487Crossref PubMed Scopus (203) Google Scholar, 7Major M.E. Mihalik K. Puig M. Rehermann B. Nascimbeni M. Rice C.M. et al.Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge.J Virol. 2002; 76: 6586-6595Crossref PubMed Scopus (158) Google Scholar]. There is often rapid control of viral replication, accelerated clearance of viraemia and greater likelihood of spontaneous resolution of secondary infection, suggestive of partial protective immunity [4Lanford R.E. Guerra B. Chavez D. Bigger C. Brasky K.M. Wang X.H. et al.Cross-genotype immunity to hepatitis C virus.J Virol. 2004; 78: 1575-1581Crossref PubMed Scopus (161) Google Scholar, 6Bassett S.E. Guerra B. Brasky K. Miskovsky E. Houghton M. Klimpel G.R. et al.Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.Hepatology. 2001; 33: 1479-1487Crossref PubMed Scopus (203) Google Scholar, 7Major M.E. Mihalik K. Puig M. Rehermann B. Nascimbeni M. Rice C.M. et al.Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge.J Virol. 2002; 76: 6586-6595Crossref PubMed Scopus (158) Google Scholar]. However, some chimpanzees rechallenged with HCV develop viral persistence [[2]Farci P. Alter H.J. Govindarajan S. Wong D.C. Engle R. Lesniewski R.R. et al.Lack of protective immunity against reinfection with hepatitis C virus.Science. 1992; 258: 135-140Crossref PubMed Scopus (693) Google Scholar]. A number of studies have now demonstrated that control of re-infection is likely associated with HCV-specific T-cell responses [3Nascimbeni M. Mizukoshi E. Bosmann M. Major M.E. Mihalik K. Rice C.M. et al.Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.J Virol. 2003; 77: 4781-4793Crossref PubMed Scopus (169) Google Scholar, 5Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar, 13Grakoui A. Shoukry N.H. Woollard D.J. Han J.H. Hanson H.L. Ghrayeb J. et al.HCV persistence and immune evasion in the absence of memory T cell help.Science. 2003; 302: 659-662Crossref PubMed Scopus (689) Google Scholar].In human studies, similar findings have been observed. HCV re-infection following spontaneous HCV clearance has been described in children receiving multiple transfusions for thalassemia [[8]Lai M.E. Mazzoleni A.P. Argiolu F. De Virgilis S. Balestrieri A. Purcell R.H. et al.Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children.Lancet. 1994; 343: 388-390Abstract PubMed Scopus (275) Google Scholar] and among IDU [10Proust B. Dubois F. Bacq Y. Le Pogam S. Rogez S. Levillain R. et al.Two successive hepatitis C virus infections in an intravenous drug user.J Clin Microbiol. 2000; 38: 3125-3127PubMed Google Scholar, 11Payen J.L. Izopet J. Barange K. Puel J. Selves J. Pascal J.P. Hepatitis C virus reinfection after an intravenous drug injection.Gastroenterol Clin Biol. 1998; 22: 469-470PubMed Google Scholar, 12Vispo E. Martinez-Alarcon J. Poveda E. Toro C. Soriano V. Initial spontaneous clearance and re-infection with a distinct hepatitis C virus genotype leading to chronic hepatitis C in an HIV+ intravenous drug user.AIDS. 2008; 22: 318Crossref PubMed Scopus (4) Google Scholar] and MSM [[14]Jones R, Brown D, Nelson M, Bhagani S, Atkins M, Danta M, et al. Hepatitis C viremia following sustained virological response to pegylated interferon and ribavarin in HIV+ men who have sex with men – re-infection or late relapse? In: Programs and abstracts of the 15th conference on retroviruses and opportunistic infections [Abstract 61LB]; 2008; Boston, MA; 2008.Google Scholar] who were subsequently re-exposed to the virus. One study of acute infection and re-infection following spontaneous HCV clearance demonstrated that HCV viremia in the setting of HCV re-infection was at a lower level, generally transient and of shorter duration than compared to initial infection [[15]Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.C. Ulsenheimer A. et al.Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar]. In addition, some cohort studies suggest that IDU with previous clearance of HCV have a lower risk of developing de novo infection [16Mehta S.H. Cox A. Hoover D.R. Wang X.H. Mao Q. Ray S. et al.Protection against persistence of hepatitis C.Lancet. 2002; 359: 1478-1483Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 17Dove L. Phung Y. Bzowej N. Kim M. Monto A. Wright T.L. Viral evolution of hepatitis C in injection drug users.J Viral Hepat. 2005; 12: 574-583Crossref PubMed Scopus (13) Google Scholar, 18Grebely J. Conway B. Raffa J.D. Lai C. Krajden M. Tyndall M.W. Hepatitis C virus reinfection in injection drug users.Hepatology. 2006; 44: 1139-1145Crossref PubMed Scopus (127) Google Scholar, 19Currie S.L. Ryan J.C. Tracy D. Wright T.L. George S. McQuaid R. et al.A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus.Drug Alcohol Depend. 2008; 93: 148-154Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. Moreover, in some of these studies, individuals that had spontaneously cleared HCV infection and subsequently acquired HIV infection during the follow-up period lost this apparent immune protection, implicating a role for CD4+ T-cells in HCV-specific immunity [16Mehta S.H. Cox A. Hoover D.R. Wang X.H. Mao Q. Ray S. et al.Protection against persistence of hepatitis C.Lancet. 2002; 359: 1478-1483Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 18Grebely J. Conway B. Raffa J.D. Lai C. Krajden M. Tyndall M.W. Hepatitis C virus reinfection in injection drug users.Hepatology. 2006; 44: 1139-1145Crossref PubMed Scopus (127) Google Scholar]. Despite these findings, the true extent to which protective immunity exists is confounded by demographic, behavioural and genetic differences in the populations studied, and difficulties in performing adequate interval sampling in longitudinal studies in IDUs. A further cohort study from a young, high-risk injecting cohort from Sydney with more frequent testing found no difference in the rate of HCV infection in uninfected individuals as compared to those with previously HCV clearance, suggesting limited protective immunity [[20]Micallef J.M. Macdonald V. Jauncey M. Amin J. Rawlinson W. van Beek I. et al.High incidence of hepatitis C virus reinfection within a cohort of injecting drug users.J Viral Hepat. 2007; 14: 413-418Crossref PubMed Scopus (97) Google Scholar]. The level of protective immunity following spontaneous HCV clearance may remain a topic of debate and further research. However, it is clear that HCV re-infection does occur and is particularly common among some population groups.These data have relevance to the study by Shores et al. suggesting that mode of acquisition may be associated with spontaneous HCV clearance. Whilst the authors propose various mechanisms for their findings, a more likely explanation may be a simpler one of risk behaviour and re-exposure resulting in re-infection and a higher cross-sectional prevalence of chronic HCV infection among individuals with injecting drug use and homosexual contact as their risk factor for HCV acquisition. This study gives no details of the duration from first HCV exposure or information on risk behaviour patterns in the various groups. The median age of 41 years indicates that the majority of subjects, particularly in the IDU group, would be many years from initial HCV exposure. Further, the cross-sectional study design means that spontaneous HCV clearance rates are in fact rates of negative viraemia at a single time point. High levels of ongoing risk behaviour in IDU, after spontaneous [16Mehta S.H. Cox A. Hoover D.R. Wang X.H. Mao Q. Ray S. et al.Protection against persistence of hepatitis C.Lancet. 2002; 359: 1478-1483Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 18Grebely J. Conway B. Raffa J.D. Lai C. Krajden M. Tyndall M.W. Hepatitis C virus reinfection in injection drug users.Hepatology. 2006; 44: 1139-1145Crossref PubMed Scopus (127) Google Scholar] and even treatment-induced HCV clearance [21Backmund M. Meyer K. Edlin B.R. Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users.Clin Infect Dis. 2004; 39: 1540-1543Crossref PubMed Scopus (90) Google Scholar, 22Dalgard O. Follow-up studies of treatment for hepatitis C virus infection among injection drug users.Clin Infect Dis. 2005; 40: S336-S338Crossref PubMed Scopus (83) Google Scholar], are well documented. Thus, repeated exposures to HCV, particularly with different genotypes, may have resulted in establishment of chronic HCV infection in many IDU subjects who initially cleared primary HCV infection. Primary sexual transmission of HCV via the heterosexual route on the other hand is relatively uncommon even in the setting of longstanding discordant relationships [[23]Vandelli C. Renzo F. Romano L. Tisminetzky S. De Palma M. Stroffolini T. et al.Lack of evidence of sexual transmission of hepatitis C among monogamous couples: results of a 10-year prospective follow-up study.Am J Gastroenterol. 2004; 99: 855-859Crossref PubMed Scopus (232) Google Scholar], thus subsequent re-infection may be less likely, even in the setting of ongoing re-exposure.The finding that the rate of negative HCV viraemia in those with homosexual contact was lower than rates observed in heterosexually acquired infection is intriguing. In recent years, a significant increase in sexually acquired acute HCV infection among HIV positive men who have sex with men (MSM) has been observed in many countries [24Gambotti L. Batisse D. Colin-de-Verdiere N. Delaroque-Astagneau E. Desenclos J.C. Dominguez S. et al.Acute hepatitis C infection in HIV positive men who have sex with men in Paris, France, 2001–2004.Euro Surveill. 2005; 10: 115-117PubMed Google Scholar, 25Ghosn J. Deveau C. Goujard C. Garrigue I. Saichi N. Galimand J. et al.Increase in hepatitis C virus incidence in HIV-1-infected patients followed up since primary infection.Sex Transm Infect. 2006; 82: 458-460Crossref PubMed Scopus (49) Google Scholar, 26van de Laar T.J. van der Bij A.K. Prins M. Bruisten S.M. Brinkman K. Ruys T.A. et al.Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission.J Infect Dis. 2007; 196: 230-238Crossref PubMed Scopus (231) Google Scholar, 27Rauch A. Rickenbach M. Weber R. Hirschel B. Tarr P.E. Bucher H.C. et al.Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study.Clin Infect Dis. 2005; 41: 395-402Crossref PubMed Scopus (181) Google Scholar, 28Danta M. Brown D. Bhagani S. Pybus O.G. Sabin C.A. Nelson M. et al.Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours.AIDS. 2007; 21: 983-991Crossref PubMed Scopus (340) Google Scholar, 29Matthews G.V. Hellard M. Kaldor J. Lloyd A. Dore G.J. Further evidence of HCV sexual transmission among HIV-positive men who have sex with men: response to Danta et al.AIDS. 2007; 21: 2112-2113Crossref PubMed Scopus (52) Google Scholar]. A case control study performed in London demonstrated that acquisition in this setting was associated with a particular set of high-risk behaviours including group sex, use of non parenteral recreational (‘party’) drugs, traumatic sexual practices and the co-existence of other sexually transmitted infections [[28]Danta M. Brown D. Bhagani S. Pybus O.G. Sabin C.A. Nelson M. et al.Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours.AIDS. 2007; 21: 983-991Crossref PubMed Scopus (340) Google Scholar]. Re-infection following spontaneous clearance of sexually acquired HCV in an HIV positive MSM has recently been described [[12]Vispo E. Martinez-Alarcon J. Poveda E. Toro C. Soriano V. Initial spontaneous clearance and re-infection with a distinct hepatitis C virus genotype leading to chronic hepatitis C in an HIV+ intravenous drug user.AIDS. 2008; 22: 318Crossref PubMed Scopus (4) Google Scholar] and there is further preliminary data to suggest that rates of re-infection in this setting may be high [[14]Jones R, Brown D, Nelson M, Bhagani S, Atkins M, Danta M, et al. Hepatitis C viremia following sustained virological response to pegylated interferon and ribavarin in HIV+ men who have sex with men – re-infection or late relapse? In: Programs and abstracts of the 15th conference on retroviruses and opportunistic infections [Abstract 61LB]; 2008; Boston, MA; 2008.Google Scholar], presumably due to repeated exposures and lack of modification of ongoing high-risk behaviours. Again, no further details on risk factor behaviour in the homosexual group were provided in the study by Shores et al. [[30]Shores N.J. Maida I. Soriano V. Núňez M. Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients.J Hepatol. 2008; 49: 323-328Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] so any conclusions must be speculative, but the perceived ‘low rate of spontaneous clearance’ in the homosexually acquired cases may in fact represent instead a high rate of HCV re-exposure through ongoing high-risk sexual behaviour, similar to that observed in IDUs.In summary, the true rate of spontaneous viral clearance after primary HCV infection cannot be adequately determined through a cross-sectional study performed at an indeterminate time following initial infection. Whilst the rate of clearance in subjects with low or absent ongoing risk behaviour may be relatively accurate (the estimated rate of clearance of 25% in the heterosexually infected group was consistent with that of other reported studies [[1]Micallef J.M. Kaldor J.M. Dore G.J. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.J Viral Hepat. 2006; 13: 34-41Crossref PubMed Scopus (646) Google Scholar]), the rate of spontaneous clearance may be falsely estimated in groups with ongoing high-risk behaviour due to recurrent HCV re-exposure. Re-infection incidence, and the contribution of any degree of protective immunity, can only be truly assessed in well-designed longitudinal prospective cohorts of high-risk individuals. The collection of appropriate virological, immunological and behavioural data in such studies will not only contribute significantly to future understanding of this complex area but also help inform crucial public health messages. In this issue of the Journal, Shores and colleagues report that sexual transmission may be associated with higher rates of spontaneous hepatitis C virus (HCV) clearance in HIV infected patients. In an international cross-sectional study of 769 HIV/HCV coinfected patients (positive for HIV and HCV antibodies), HCV RNA status was assessed at an undetermined timepoint following initial HCV infection. Evidence of spontaneous HCV clearance (as determined by a single negative HCV RNA test in the absence of any HCV-specific treatment) was found in 13% of patients overall, a lower rate than the 20–30% rate generally found in HCV monoinfected populations [[1]Micallef J.M. Kaldor J.M. Dore G.J. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.J Viral Hepat. 2006; 13: 34-41Crossref PubMed Scopus (646) Google Scholar]. In multivariate analysis, the only factors predicting negative HCV RNA were HBV coinfection and the risk factor for HIV and/or HCV transmission. Rates of spontaneous clearance were 11.6% in those presumed to be infected through injecting drug use (IDU) and 21.9% in those infected through sexual contact. Further, although the number of patients reporting homosexual contact as a risk factor was small, these patients had a similar rate of negative HCV RNA as the IDU group (13.5% vs 11.6%). Differences in spontaneous clearance rates appeared to be driven by the group with heterosexual contact as the major risk factor for viral transmission (26% of whom were HCV RNA negative). In the multivariate model, heterosexual transmission was independently associated with negative HCV RNA with an odds ratio of 2.81 (95% CI 1.55–5.09, p = 0.001). The authors declare that the reasons for this are unclear but postulate that the observed differences may be linked to smaller viral inoculums or differing genital immune responses in the group infected through heterosexual contact. However, a more likely explanation for their findings would appear to be differential risk of re-exposure and subsequent HCV re-infection across the study groups. HCV re-infection following spontaneous HCV clearance has been demonstrated in both chimpanzees [2Farci P. Alter H.J. Govindarajan S. Wong D.C. Engle R. Lesniewski R.R. et al.Lack of protective immunity against reinfection with hepatitis C virus.Science. 1992; 258: 135-140Crossref PubMed Scopus (693) Google Scholar, 3Nascimbeni M. Mizukoshi E. Bosmann M. Major M.E. Mihalik K. Rice C.M. et al.Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.J Virol. 2003; 77: 4781-4793Crossref PubMed Scopus (169) Google Scholar, 4Lanford R.E. Guerra B. Chavez D. Bigger C. Brasky K.M. Wang X.H. et al.Cross-genotype immunity to hepatitis C virus.J Virol. 2004; 78: 1575-1581Crossref PubMed Scopus (161) Google Scholar, 5Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar, 6Bassett S.E. Guerra B. Brasky K. Miskovsky E. Houghton M. Klimpel G.R. et al.Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.Hepatology. 2001; 33: 1479-1487Crossref PubMed Scopus (203) Google Scholar, 7Major M.E. Mihalik K. Puig M. Rehermann B. Nascimbeni M. Rice C.M. et al.Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge.J Virol. 2002; 76: 6586-6595Crossref PubMed Scopus (158) Google Scholar] and humans [8Lai M.E. Mazzoleni A.P. Argiolu F. De Virgilis S. Balestrieri A. Purcell R.H. et al.Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children.Lancet. 1994; 343: 388-390Abstract PubMed Scopus (275) Google Scholar, 9Tisone G. Baiocchi L. Orlando G. Palmieri G.P. Pisani F. Rapicetta M. et al.Hepatitis C reinfection after liver transplantation in relation to virus genotype.Transplant Proc. 1999; 31: 490-491Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 10Proust B. Dubois F. Bacq Y. Le Pogam S. Rogez S. Levillain R. et al.Two successive hepatitis C virus infections in an intravenous drug user.J Clin Microbiol. 2000; 38: 3125-3127PubMed Google Scholar, 11Payen J.L. Izopet J. Barange K. Puel J. Selves J. Pascal J.P. Hepatitis C virus reinfection after an intravenous drug injection.Gastroenterol Clin Biol. 1998; 22: 469-470PubMed Google Scholar, 12Vispo E. Martinez-Alarcon J. Poveda E. Toro C. Soriano V. Initial spontaneous clearance and re-infection with a distinct hepatitis C virus genotype leading to chronic hepatitis C in an HIV+ intravenous drug user.AIDS. 2008; 22: 318Crossref PubMed Scopus (4) Google Scholar]. In chimpanzees with clearance of primary infection, HCV rechallenge with both homologous or heterologous virus can lead to HCV re-infection, despite the presence of persistent humoral immunity [2Farci P. Alter H.J. Govindarajan S. Wong D.C. Engle R. Lesniewski R.R. et al.Lack of protective immunity against reinfection with hepatitis C virus.Science. 1992; 258: 135-140Crossref PubMed Scopus (693) Google Scholar, 3Nascimbeni M. Mizukoshi E. Bosmann M. Major M.E. Mihalik K. Rice C.M. et al.Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.J Virol. 2003; 77: 4781-4793Crossref PubMed Scopus (169) Google Scholar, 4Lanford R.E. Guerra B. Chavez D. Bigger C. Brasky K.M. Wang X.H. et al.Cross-genotype immunity to hepatitis C virus.J Virol. 2004; 78: 1575-1581Crossref PubMed Scopus (161) Google Scholar, 5Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar, 6Bassett S.E. Guerra B. Brasky K. Miskovsky E. Houghton M. Klimpel G.R. et al.Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.Hepatology. 2001; 33: 1479-1487Crossref PubMed Scopus (203) Google Scholar, 7Major M.E. Mihalik K. Puig M. Rehermann B. Nascimbeni M. Rice C.M. et al.Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge.J Virol. 2002; 76: 6586-6595Crossref PubMed Scopus (158) Google Scholar]. There is often rapid control of viral replication, accelerated clearance of viraemia and greater likelihood of spontaneous resolution of secondary infection, suggestive of partial protective immunity [4Lanford R.E. Guerra B. Chavez D. Bigger C. Brasky K.M. Wang X.H. et al.Cross-genotype immunity to hepatitis C virus.J Virol. 2004; 78: 1575-1581Crossref PubMed Scopus (161) Google Scholar, 6Bassett S.E. Guerra B. Brasky K. Miskovsky E. Houghton M. Klimpel G.R. et al.Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection.Hepatology. 2001; 33: 1479-1487Crossref PubMed Scopus (203) Google Scholar, 7Major M.E. Mihalik K. Puig M. Rehermann B. Nascimbeni M. Rice C.M. et al.Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge.J Virol. 2002; 76: 6586-6595Crossref PubMed Scopus (158) Google Scholar]. However, some chimpanzees rechallenged with HCV develop viral persistence [[2]Farci P. Alter H.J. Govindarajan S. Wong D.C. Engle R. Lesniewski R.R. et al.Lack of protective immunity against reinfection with hepatitis C virus.Science. 1992; 258: 135-140Crossref PubMed Scopus (693) Google Scholar]. A number of studies have now demonstrated that control of re-infection is likely associated with HCV-specific T-cell responses [3Nascimbeni M. Mizukoshi E. Bosmann M. Major M.E. Mihalik K. Rice C.M. et al.Kinetics of CD4+ and CD8+ memory T-cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.J Virol. 2003; 77: 4781-4793Crossref PubMed Scopus (169) Google Scholar, 5Shoukry N.H. Grakoui A. Houghton M. Chien D.Y. Ghrayeb J. Reimann K.A. et al.Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection.J Exp Med. 2003; 197: 1645-1655Crossref PubMed Scopus (523) Google Scholar, 13Grakoui A. Shoukry N.H. Woollard D.J. Han J.H. Hanson H.L. Ghrayeb J. et al.HCV persistence and immune evasion in the absence of memory T cell help.Science. 2003; 302: 659-662Crossref PubMed Scopus (689) Google Scholar]. In human studies, similar findings have been observed. HCV re-infection following spontaneous HCV clearance has been described in children receiving multiple transfusions for thalassemia [[8]Lai M.E. Mazzoleni A.P. Argiolu F. De Virgilis S. Balestrieri A. Purcell R.H. et al.Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children.Lancet. 1994; 343: 388-390Abstract PubMed Scopus (275) Google Scholar] and among IDU [10Proust B. Dubois F. Bacq Y. Le Pogam S. Rogez S. Levillain R. et al.Two successive hepatitis C virus infections in an intravenous drug user.J Clin Microbiol. 2000; 38: 3125-3127PubMed Google Scholar, 11Payen J.L. Izopet J. Barange K. Puel J. Selves J. Pascal J.P. Hepatitis C virus reinfection after an intravenous drug injection.Gastroenterol Clin Biol. 1998; 22: 469-470PubMed Google Scholar, 12Vispo E. Martinez-Alarcon J. Poveda E. Toro C. Soriano V. Initial spontaneous clearance and re-infection with a distinct hepatitis C virus genotype leading to chronic hepatitis C in an HIV+ intravenous drug user.AIDS. 2008; 22: 318Crossref PubMed Scopus (4) Google Scholar] and MSM [[14]Jones R, Brown D, Nelson M, Bhagani S, Atkins M, Danta M, et al. Hepatitis C viremia following sustained virological response to pegylated interferon and ribavarin in HIV+ men who have sex with men – re-infection or late relapse? In: Programs and abstracts of the 15th conference on retroviruses and opportunistic infections [Abstract 61LB]; 2008; Boston, MA; 2008.Google Scholar] who were subsequently re-exposed to the virus. One study of acute infection and re-infection following spontaneous HCV clearance demonstrated that HCV viremia in the setting of HCV re-infection was at a lower level, generally transient and of shorter duration than compared to initial infection [[15]Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.C. Ulsenheimer A. et al.Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar]. In addition, some cohort studies suggest that IDU with previous clearance of HCV have a lower risk of developing de novo infection [16Mehta S.H. Cox A. Hoover D.R. Wang X.H. Mao Q. Ray S. et al.Protection against persistence of hepatitis C.Lancet. 2002; 359: 1478-1483Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 17Dove L. Phung Y. Bzowej N. Kim M. Monto A. Wright T.L. Viral evolution of hepatitis C in injection drug users.J Viral Hepat. 2005; 12: 574-583Crossref PubMed Scopus (13) Google Scholar, 18Grebely J. Conway B. Raffa J.D. Lai C. Krajden M. Tyndall M.W. Hepatitis C virus reinfection in injection drug users.Hepatology. 2006; 44: 1139-1145Crossref PubMed Scopus (127) Google Scholar, 19Currie S.L. Ryan J.C. Tracy D. Wright T.L. George S. McQuaid R. et al.A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus.Drug Alcohol Depend. 2008; 93: 148-154Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. Moreover, in some of these studies, individuals that had spontaneously cleared HCV infection and subsequently acquired HIV infection during the follow-up period lost this apparent immune protection, implicating a role for CD4+ T-cells in HCV-specific immunity [16Mehta S.H. Cox A. Hoover D.R. Wang X.H. Mao Q. Ray S. et al.Protection against persistence of hepatitis C.Lancet. 2002; 359: 1478-1483Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 18Grebely J. Conway B. Raffa J.D. Lai C. Krajden M. Tyndall M.W. Hepatitis C virus reinfection in injection drug users.Hepatology. 2006; 44: 1139-1145Crossref PubMed Scopus (127) Google Scholar]. Despite these findings, the true extent to which protective immunity exists is confounded by demographic, behavioural and genetic differences in the populations studied, and difficulties in performing adequate interval sampling in longitudinal studies in IDUs. A further cohort study from a young, high-risk injecting cohort from Sydney with more frequent testing found no difference in the rate of HCV infection in uninfected individuals as compared to those with previously HCV clearance, suggesting limited protective immunity [[20]Micallef J.M. Macdonald V. Jauncey M. Amin J. Rawlinson W. van Beek I. et al.High incidence of hepatitis C virus reinfection within a cohort of injecting drug users.J Viral Hepat. 2007; 14: 413-418Crossref PubMed Scopus (97) Google Scholar]. The level of protective immunity following spontaneous HCV clearance may remain a topic of debate and further research. However, it is clear that HCV re-infection does occur and is particularly common among some population groups. These data have relevance to the study by Shores et al. suggesting that mode of acquisition may be associated with spontaneous HCV clearance. Whilst the authors propose various mechanisms for their findings, a more likely explanation may be a simpler one of risk behaviour and re-exposure resulting in re-infection and a higher cross-sectional prevalence of chronic HCV infection among individuals with injecting drug use and homosexual contact as their risk factor for HCV acquisition. This study gives no details of the duration from first HCV exposure or information on risk behaviour patterns in the various groups. The median age of 41 years indicates that the majority of subjects, particularly in the IDU group, would be many years from initial HCV exposure. Further, the cross-sectional study design means that spontaneous HCV clearance rates are in fact rates of negative viraemia at a single time point. High levels of ongoing risk behaviour in IDU, after spontaneous [16Mehta S.H. Cox A. Hoover D.R. Wang X.H. Mao Q. Ray S. et al.Protection against persistence of hepatitis C.Lancet. 2002; 359: 1478-1483Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 18Grebely J. Conway B. Raffa J.D. Lai C. Krajden M. Tyndall M.W. Hepatitis C virus reinfection in injection drug users.Hepatology. 2006; 44: 1139-1145Crossref PubMed Scopus (127) Google Scholar] and even treatment-induced HCV clearance [21Backmund M. Meyer K. Edlin B.R. Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users.Clin Infect Dis. 2004; 39: 1540-1543Crossref PubMed Scopus (90) Google Scholar, 22Dalgard O. Follow-up studies of treatment for hepatitis C virus infection among injection drug users.Clin Infect Dis. 2005; 40: S336-S338Crossref PubMed Scopus (83) Google Scholar], are well documented. Thus, repeated exposures to HCV, particularly with different genotypes, may have resulted in establishment of chronic HCV infection in many IDU subjects who initially cleared primary HCV infection. Primary sexual transmission of HCV via the heterosexual route on the other hand is relatively uncommon even in the setting of longstanding discordant relationships [[23]Vandelli C. Renzo F. Romano L. Tisminetzky S. De Palma M. Stroffolini T. et al.Lack of evidence of sexual transmission of hepatitis C among monogamous couples: results of a 10-year prospective follow-up study.Am J Gastroenterol. 2004; 99: 855-859Crossref PubMed Scopus (232) Google Scholar], thus subsequent re-infection may be less likely, even in the setting of ongoing re-exposure. The finding that the rate of negative HCV viraemia in those with homosexual contact was lower than rates observed in heterosexually acquired infection is intriguing. In recent years, a significant increase in sexually acquired acute HCV infection among HIV positive men who have sex with men (MSM) has been observed in many countries [24Gambotti L. Batisse D. Colin-de-Verdiere N. Delaroque-Astagneau E. Desenclos J.C. Dominguez S. et al.Acute hepatitis C infection in HIV positive men who have sex with men in Paris, France, 2001–2004.Euro Surveill. 2005; 10: 115-117PubMed Google Scholar, 25Ghosn J. Deveau C. Goujard C. Garrigue I. Saichi N. Galimand J. et al.Increase in hepatitis C virus incidence in HIV-1-infected patients followed up since primary infection.Sex Transm Infect. 2006; 82: 458-460Crossref PubMed Scopus (49) Google Scholar, 26van de Laar T.J. van der Bij A.K. Prins M. Bruisten S.M. Brinkman K. Ruys T.A. et al.Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission.J Infect Dis. 2007; 196: 230-238Crossref PubMed Scopus (231) Google Scholar, 27Rauch A. Rickenbach M. Weber R. Hirschel B. Tarr P.E. Bucher H.C. et al.Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study.Clin Infect Dis. 2005; 41: 395-402Crossref PubMed Scopus (181) Google Scholar, 28Danta M. Brown D. Bhagani S. Pybus O.G. Sabin C.A. Nelson M. et al.Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours.AIDS. 2007; 21: 983-991Crossref PubMed Scopus (340) Google Scholar, 29Matthews G.V. Hellard M. Kaldor J. Lloyd A. Dore G.J. Further evidence of HCV sexual transmission among HIV-positive men who have sex with men: response to Danta et al.AIDS. 2007; 21: 2112-2113Crossref PubMed Scopus (52) Google Scholar]. A case control study performed in London demonstrated that acquisition in this setting was associated with a particular set of high-risk behaviours including group sex, use of non parenteral recreational (‘party’) drugs, traumatic sexual practices and the co-existence of other sexually transmitted infections [[28]Danta M. Brown D. Bhagani S. Pybus O.G. Sabin C.A. Nelson M. et al.Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours.AIDS. 2007; 21: 983-991Crossref PubMed Scopus (340) Google Scholar]. Re-infection following spontaneous clearance of sexually acquired HCV in an HIV positive MSM has recently been described [[12]Vispo E. Martinez-Alarcon J. Poveda E. Toro C. Soriano V. Initial spontaneous clearance and re-infection with a distinct hepatitis C virus genotype leading to chronic hepatitis C in an HIV+ intravenous drug user.AIDS. 2008; 22: 318Crossref PubMed Scopus (4) Google Scholar] and there is further preliminary data to suggest that rates of re-infection in this setting may be high [[14]Jones R, Brown D, Nelson M, Bhagani S, Atkins M, Danta M, et al. Hepatitis C viremia following sustained virological response to pegylated interferon and ribavarin in HIV+ men who have sex with men – re-infection or late relapse? In: Programs and abstracts of the 15th conference on retroviruses and opportunistic infections [Abstract 61LB]; 2008; Boston, MA; 2008.Google Scholar], presumably due to repeated exposures and lack of modification of ongoing high-risk behaviours. Again, no further details on risk factor behaviour in the homosexual group were provided in the study by Shores et al. [[30]Shores N.J. Maida I. Soriano V. Núňez M. Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients.J Hepatol. 2008; 49: 323-328Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] so any conclusions must be speculative, but the perceived ‘low rate of spontaneous clearance’ in the homosexually acquired cases may in fact represent instead a high rate of HCV re-exposure through ongoing high-risk sexual behaviour, similar to that observed in IDUs. In summary, the true rate of spontaneous viral clearance after primary HCV infection cannot be adequately determined through a cross-sectional study performed at an indeterminate time following initial infection. Whilst the rate of clearance in subjects with low or absent ongoing risk behaviour may be relatively accurate (the estimated rate of clearance of 25% in the heterosexually infected group was consistent with that of other reported studies [[1]Micallef J.M. Kaldor J.M. Dore G.J. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.J Viral Hepat. 2006; 13: 34-41Crossref PubMed Scopus (646) Google Scholar]), the rate of spontaneous clearance may be falsely estimated in groups with ongoing high-risk behaviour due to recurrent HCV re-exposure. Re-infection incidence, and the contribution of any degree of protective immunity, can only be truly assessed in well-designed longitudinal prospective cohorts of high-risk individuals. The collection of appropriate virological, immunological and behavioural data in such studies will not only contribute significantly to future understanding of this complex area but also help inform crucial public health messages.