Spontaneous Viral Clearance Following Acute Hepatitis C Infection: A Systematic Review of Longitudinal Studies

J. M. Micallef; J. M. Kaldor; G. J. Dore


J Viral Hepat. 2006;13(1):34-41. 

In This Article


Examination of the natural history of acute hepatitis C has been limited through small study populations. Our systematic review of 31 longitudinal studies with a total of 675 study subjects indicates that spontaneous viral clearance occurs in approximately one in four people with acute hepatitis C. Studies of acute clinical hepatitis C had higher clearance rates than post-transfusion and sero-incident hepatitis C studies. Female gender was also predictive of viral clearance.

A limitation in estimation of viral clearance in this systematic review is the heterogeneity of studies in terms of sample size, inclusion criteria and follow-up assessments. Mean follow-up was <12 months for many studies, and the majority of studies required both detection of HCV RNA and abnormal ALT level at baseline for case selection. Both these factors could bias the estimate of viral clearance in various ways. As viral clearance often occurs within the first 12 weeks of infection,[13] acute hepatitis C cases may have been excluded from studies on the basis of a negative HCV RNA on initial assessment. This may be a particular bias among sero-incident studies, some of which detected with a wide window period. We have recently completed a retrospective cohort study of 99 sero-incident acute HCV infection cases (based on anti-HCV antibody seroconversion within a 2-year window period) among injecting drug users. Analyses from this study estimated viral clearance as ~26% at 2 years within subjects who were HCV RNA positive at anti-HCV antibody seroconversion.[9] However, more than a third of the cohort were HCV RNA negative at seroconversion, and estimates of clearance were higher (~40%) where both HCV RNA-positive and -negative cases at seroconversion were included. This suggests that cases of acute HCV may have been excluded from papers reviewed, based on HCV RNA definition. Consequently, the clearance rate of 26% may be an underestimate. Although viral clearance generally occurs within the initial 6 months of infection, recent studies have suggested that spontaneous clearance extends beyond this point.[7,34,35] Thus, longer-term follow-up in these studies may have also produced higher viral clearance proportions. Although study sample size had a wide range, estimates of viral clearance by weighted and unweighted means were very similar.

Our estimate of 26% spontaneous viral clearance is higher than the 10–15% estimate often provided in reviews of hepatitis C natural history.[51] Given the limitations inherent in studies of acute hepatitis C, particularly the exclusion of initially HCV RNA-negative subjects, the true extent of viral clearance may be even higher. Higher estimates of viral clearance would have important public health implications at both the individual and population levels. The potential for viral clearance needs to be factored into individual counselling. For example, a higher viral clearance rate may act as a disincentive to undertake treatment in early infection. Individual counselling should also cover the risk of HCV reinfection following viral clearance, particularly among individuals at ongoing risk of exposure such as injection drug users. At a population level, estimates and projections of hepatitis C disease burden need to consider the proportion of people with viral clearance. These studies are generally based on population level estimates of HCV antibody prevalence, as opposed to HCV RNA prevalence.

The lack of individual-level demographic and clinical data linked to outcome data in a large proportion of subjects reported in the studies reviewed here made assessment of factors associated to viral clearance difficult. Despite this limitation, viral clearance was associated with gender, with around 40% of female subjects undergoing clearance compared with 19% of male subjects. In contrast, there was no association between viral clearance and age at infection or HCV genotype. The mechanism for the association between spontaneous viral clearance and female gender is uncertain. Various studies have reported high clearance rates in women.[10,52–54] The relationship between female gender and better response rates to interferon therapy has also been demonstrated.[55] It has been hypothesized that HCV clearance in women may be facilitated by oestrogen hormone.[52,55] The higher proportion of subjects with viral clearance in the acute clinical hepatitis C studies is consistent with an association between more symptomatic acute hepatitis C and viral clearance which may be the result of a vigorous broad-based immune response during early HCV infection.[13–16]

Although providing important information on the natural history of acute HCV infection, our systematic review highlights the need for larger prospective studies with longer-term follow-up. Ideally, these studies should recruit both acute clinical and sero-incident cases, be representative in terms of demographics and modes of HCV acquisition, and examine behavioural, virological and immunological determinants of both viral clearance and HCV reinfection. Particular emphasis is required to recruit young injecting drug users with acute hepatitis C, as they make up the majority of cases in industrialized country settings.

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