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.
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
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
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