Incidence of hepatitis C re-infection and clearance may be understimated

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The incidence of hepatitis C re-infection among high-risk individuals who have spontaneously cleared the infection may be higher than previously assumed, a modelling study published in the May 1st edition of the Journal of Infectious Diseases suggests.

The study has implications for the design of a hepatitis C vaccine and more immediately for prevention campaigns. It also has implications for assumptions about rates of sustained virological response after completion of hepatitis C therapy, Prof. Jason Grebeley of the Kirby Institute, University of New South Wales, one of the authors of the study, told delegates at the International Liver Congress in Barcelona.

“Are we detecting re-infection or failure of treatment? It depends on the [viral] sequence being examined,” he told a symposium on hepatitis C virus (HCV) prevention and treatment in injecting drug users, organised by the European Liver Patients Association (ELPA). He noted that sequencing needed to distinguish between reactivation of low-level quasispecies of HCV that had not been fully suppressed by treatment, and infection with a new variant of HCV.



In HIV, synonym for superinfection. In hepatitis C, used when someone who has been cured of the virus is infected with hepatitis C again.

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

mathematical models

A range of complex mathematical techniques which aim to simulate a sequence of likely future events, in order to estimate the impact of a health intervention or the spread of an infection.

therapeutic vaccine

A vaccine-like product used with the aim of improving the immune function of someone who already has an infection, rather than of preventing the infection.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.


People receiving HCV treatment need to be counselled about the risk of re-infection, both during treatment and after treatment, he added.

Recent research in HIV-positive gay men who have undergone treatment and been cured of hepatitis C infection has shown substantial rates of re-infection due to ongoing risk behaviour.

There have been important recent advances in hepatitis C therapy. Nevertheless, incidence of new infections remains high. Many of these are in injecting drug users, but there is also an epidemic of sexually transmitted hepatitis C in HIV-positive gay men.

Spontaneous clearance of the virus occurs in approximately a quarter of patients with primary hepatitis C infection. This does not provide immunity against subsequent re-infection, but there is some evidence that it is associated with better subsequent control of the virus and a more attenuated course of disease. Some investigators are hopeful that learning more about spontaneous clearance and its correlates will assist in the development of a therapeutic vaccine against the infection.

Moreover, understanding the risk of re-infection has important implications for the design of hepatitis C prevention campaigns for at-risk populations.

Seven studies have looked at the incidence of re-infection and spontaneous clearance following re-infection. Estimates of the incidence of re-infection range from a low of 1.8 per 100 person years to a high of 47 per 100 person years. There is also wide variability in estimated probability of spontaneous clearance of re-infection (29 to 100%).

The interval between testing in these studies ranged between one and sixteen months.

An international team of investigators hypothesised that this variability in testing intervals could explain the lack of concordance between the findings of these studies. The investigators were especially concerned that testing intervals of over three months would miss many cases of re-infection and spontaneous clearance.

They therefore designed a model which simulated the dynamics of re-infection and clearance in a simulated cohort of 50 injecting drug users who were followed for 48 months.    

Their initial calculations were based on the earlier study with the shortest testing interval (one month) which found a re-infection incidence of 32 per 100 years and that the probability of subsequent spontaneous clearance was 75%.

Results of their analysis confirmed that if the testing interval is greater than the time taken for spontaneous clearance, then the incidence of re-infection is likely to be considerably underestimated.

For example, if the testing interval was three months and the re-infection clearance duration was two months, then the estimated incidence of re-infection would be reduced to 23 per 100 person years, some 28% lower than the real re-infection incidence of 32 per 100 person years.

“Studies using long HCV RNA testing intervals underestimate the incidence of HCV re-infection and the probability of spontaneous HCV clearance following re-infection,” comment the authors. “The results of these studies have important implications for HCV vaccine design because they suggest that, although absolute protection against primary re-infection (sterilizing immunity) is probably overestimated, the rate of spontaneous clearance of re-infection (partial protective immunity against persistent HCV re-infection) is also underestimated.”

The findings are also likely to be relevant to those working to control the hepatitis C epidemic. A high and rising incidence of sexually transmitted hepatitis C has been seen in HIV-positive gay men. UK care guidelines recommend annual testing for this group and more frequent screening for those at greatest risk. However, the average interval between HIV care appointments in the UK is three to four months. The results of this study suggest a substantial number of infections may be occurring but are spontaneously cleared between follow-up appointments.


Vickerman P et al. The more you look, the more you find: effects of hepatitis C testing interval on reinfection incidence and clearance and implications for future vaccine study design.  J Infect Dis, 201: 205-50, 2012 (click here for the free abstract).