Acute Hepatitis C in HIV-infected Men who have Sex with Men: An

Emerging Sexually Transmitted Infection

Thijs J.W. van de Laar; Gail V. Matthews; Maria Prinsa; Mark Dantad

Abstract

Since 2000 outbreaks of acute hepatitis C virus (HCV) among HIV-positive men who have sex
with men (MSM) who denied injecting drug use have been reported from Europe, the United
States, Canada and Australia. Given the burden of liver disease, in particular HCV, on the
morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the
rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-
income countries is alarming. This relates to a significant change in the epidemiology of HCV
that has occurred, with HCV emerging as a sexually transmitted infection within this population.
Work to date suggests that this permucosal HCV transmission results from high-risk sexual and
noninjecting drug use behaviours, reopening the discussion on the importance of sexual
transmission. Given this occurs almost exclusively in HIV-infected MSM, HIV probably has a
critical role mediated either through behavioural and/or biological factors. Finally, the
management of acute HCV in HIV infection is complicated by concomitant HIV infection and
combination antiretroviral therapy. This review will synthesize the most recent epidemiological,
immunological and management issues that have emerged as a result of the epidemic of acute
HCV among HIV-infected MSM.

Introduction

Hepatitis C virus (HCV) was first identified in 1989 as the principal cause of posttransfusion
non-A non-B hepatitis.[1] Worldwide an estimated 170 million people are infected with HCV; due
to shared routes of transmission, 4–5 million are coinfected with HIV.[2] HCV is usually
transmitted parenterally. Within high-income countries, HCV transmission through blood
products has effectively been halted, leaving injecting drug use (IDU) as the major cause of new
HCV infections.[3] In medium and low-income countries, however, iatrogenic HCV transmission
still accounts for a significant proportion of incident infections.[4]

Permucosal sexual transmission of HCV remains controversial. Differences in sexual orientation

and risk behaviour of the study population; study design; the presence of unmeasured parental
routes of HCV transmission; and the use of molecular epidemiological techniques to confirm
transmission between partners, might explain conflicting results.[5] Anti-HCV prevalence rates up
to 28% have been reported among spouses of HCV-infected individuals, increasing with
relationship duration.[6–8] However, sexual transmission has often been ruled out using molecular
typing.[9–11] Even when molecular typing confirmed a common source of infection, other possible
routes of transmission within the household could not be excluded.[12] Based on prospective
cohort studies, sexual transmission of HCV is relatively rare in monogamous heterosexual
relationships and varies from 0 to 0.6% per year.[13–16] A slightly higher risk, 0.4–1.8% per year,
has been reported for heterosexuals with multiple partners or those at risk for sexually
transmitted infections (STIs).[5]
Since 2000 outbreaks of acute HCV among HIV-positive men who have sex with men (MSM)
who denied IDU have been reported from Europe,[17–22] the United States[23–25] and Australia.[26]
Remarkably, the majority of HCV infections were related to permucosal rather than parenteral
risk factors, reopening the discussion on the importance of sexual transmission. This review will
synthesize the most recent epidemiological, immunological and management issues that have
emerged as a result of the epidemic of acute HCV among HIV-infected MSM. Studies were
identified by MEDLINE using appropriate keywords and supplemented with perusal of reference
lists of relevant publications and abstracts of recent relevant conferences.

Hepatitis C Virus Prevalence

In early cross-sectional studies, anti-HCV prevalence among MSM ranged from 0 up to 23%,
which was higher than that observed among voluntary blood donors and heterosexuals at risk for
STI (reviewed in [3,27–29]). However, many of these studies did not incorporate information on
IDU. The studies that did, revealed an anti-HCV prevalence of 1–7% among MSM who denied
IDU versus 25–50% among MSM with a history of IDU.[20,30–32] HCV prevalence was also
consistently higher in HIV-positive MSM (3–39%) than MSM without HIV (0–19%).[20,30,31,33–35]
It was concluded that IDU was responsible for the majority of HCV infections in MSM and that
HIV might play a role in HCV transmission.

Recent outbreaks of HCV among HIV-positive MSM who denied IDU in Europe, USA and
Australia suggest sexual transmission of HCV.[17–24,26] A study from the UK showed that
acquisition of HCV in MSM with primary HIV infection increased from 0% in 1999 to 4% in
2006.[36] In the Netherlands, a bi-annual cross-sectional survey among STI-clinic attendees
showed an alarming increase in HCV prevalence among HIV-infected MSM from 15% in 2007
to 21% in 2008, compared to an estimated HCV prevalence of 1–4% before 2000. [37] Only 5% of
HIV-positive MSM reported IDU, and a relatively high proportion was diagnosed with acute
HCV infection. In contrast, a large study among 2268 HIV-infected MSM in Europe who were
recruited between 1995 and 2003 showed a HCV prevalence of 6.6%,[38] which is in line with the
HCV prevalence observed at the beginning of the HIV epidemic. The HCV prevalence among
HIV-negative MSM who deny IDU is low and comparable to that of the general population.[37,39–
41]

Hepatitis C Virus Incidence

Time trends based solely on the rise in acute HCV cases might simply reflect the progressive
introduction of HCV screening due to increased awareness. To date, 12 studies have determined
the HCV incidence among MSM participating in well defined cohorts;[20,40–50] one study estimated
the incidence based on denominators of HIV-positive MSM from other records,[51] and for one
the design is not clear.[17] The results of these studies are summarized in Table 1.[42–51] All recent
studies that investigated temporal trends in HCV incidence[17,20,45,47,49–51] indicate that after the
introduction of combination antiretroviral therapy (cART) in 1996, the HCV incidence in HIV-
positive MSM increased from about 1–3 per 1000 person years to over 10 per 1000 person years.

The HCV incidence in HIV-negative MSM is still low, indicating that these men remain largely
unaffected by the current outbreak of HCV.[20,40] Only one study has observed a rise in non-IDU-
acquired HCV among MSM with a negative or unknown HIV status attending an English STI
clinic.[47] As no similar trend was observed in other sexual health clinics in the same area, [51] this
rise in HCV incidence may be attributed to MSM with an unknown HIV status, in particular
because some of these MSM eventually were diagnosed with HIV at their first positive HCV test
result.[52] Another limitation of that study is that 41% of MSM were excluded from this analysis
because they had not been tested for HCV during the study period.

Molecular Epidemiology

HCV sequencing data of HIV-positive MSM recently diagnosed with acute HCV in Europe
show 90% are infected with difficult-to-treat HCV genotypes 1a and 4d.[18–21,53] Phylogenetic
analysis revealed robust monophyletic transmission clusters of HCV within the MSM
populations of major cities in England, France, the Netherlands and Germany.[20–22,54] An
international collaborative study confirmed the presence of one large European MSM-specific
transmission network, linking the independently reported outbreaks in London, Paris,
Amsterdam and Berlin.[55] Based on the reported risk factors from the individual cohorts, this
appears to be a sexual network. Evolutionary analysis based on the genetic divergence within
MSM-specific HCV strains of genotype 1 and 4 in Europe suggests multiple independent
introductions of HCV into the MSM community, some as early as the 1980s.[20] Most likely,
these strains were introduced from the IDU population.[20,37]

Molecular clock analysis suggests that this expansion of these MSM-specific HCV strains
increased after 1996.[21,55] Interestingly, this sudden emergence in HCV coincides with a rise in
sexual risk behaviour and increased STI rates among MSM due to a decrease in the perceived
threat of HIV/AIDS in the cART era.[56–58] The fact that multiple strains of different HCV
genotypes circulate among HIV-positive MSM also suggests behavioural factors in the MSM
population rather than evolution of the virus into a specific more virulent variant are responsible
for the recent transmission of HCV in this population.[55]

Phylogenetically, the HCV outbreak in Australia shows very limited overlap with the network
that exists in Europe.[55] In Australia, approximately 50% of acute HCV infections among HIV-
positive MSM are attributable to IDU, which might explain why HCV genotype 3a is more
prevalent among Australian MSM (33%) than European MSM (7%).[26] HCV strains obtained
from Australian HIV-positive MSM do show a high degree of phylogenetic clustering. Robust
monophyletic clusters of MSM-specific HCV strains were identified, in which there is mixing of
sexually and IDU-acquired HCV.[59] In the United States, HCV genotype 1a predominates among
HIV-positive MSM; however, no information on MSM-specific clustering is available yet.[60]

What are the Risk Factors for Hepatitis C Virus Transmission in Men who
have Sex with Men?

Early studies carried out among MSM in Sydney, San Francisco, Pittsburgh and Amsterdam
indicated that HIV infection and IDU were independently associated with presence of HCV
antibodies.[20,30,31,34] In univariate analysis, the evidence for sexual transmission was weak with
some studies describing associations between HCV infection and sexual risk behaviour, such as
unprotected anal intercourse, fisting, enema use and STI,[31,34,35,42] whereas others did not.[20,61–63]
Since the recent outbreak of HCV among HIV-positive MSM, two longitudinal cohorts,[44,51] one
cross-sectional study[37] and one case–control study[21] have examined the independent
relationship of sexual risk behaviour with HCV, by comparing sexual risk behaviour of HCV-
infected and HCV-uninfected MSM. In the prospective Swiss cohort study, unsafe sex and
syphilis infection were significantly associated with acquiring HCV among MSM without a
history of IDU.[44] However, limited data on specific sexual risk behaviours were available in this
study. Only fisting remained associated with HCV in multivariate analysis of a longitudinal
cohort of MSM attending the STI clinic in London.[51] However, risk behaviour was collected at
baseline making it difficult to imply causal effects. A cross-sectional study from Amsterdam
found that HIV infection, IDU, fisting and noninjecting recreational drug use, especially the use
of gamma hydroxyl butyrate (GHB), were independently associated with HCV infection.[37] As
this study was conducted among MSM with prevalent HCV infection, the actual HCV
transmission event might have considerably preceded reported risk behaviour. Only one case–
control study, HIV/HCV coinfection versus HIV monoinfection, explicitly investigated sexual
risk factors and drug use among MSM diagnosed with acute HCV.[21] Although limited by a
retrospective design, it suggests that permucosal traumatic sexual techniques, particularly when
practised in the context of group sex and/or noninjecting recreational drug use, were associated
with acute HCV infection.[21] These studies underline, however, that most MSM with HCV report
a combination of various, potentially high-risk, sexual and drug practices. The interaction
between sex and drugs is complex, and many of these factors are highly correlated and difficult
to disentangle. Intranasal and rectal drug use in itself could favour HCV transmission via shared
contaminated implements. It is more likely, however, that the association with drug use reflects
residual confounding: unmeasured sexual risk behaviour due to disinhibition and sexual arousal.
Based on current knowledge, sexual transmission of HCV is probably mediated by factors such
as traumatic sexual techniques and ulcerative STI that may cause mucosal damage in the rectum.
Nevertheless, acute cases of HCV have been described among MSM that deny all risk factors
mentioned above.

Immunology and Natural History

It is striking that the recent outbreak almost exclusively affects HIV-infected MSM. The natural
history of HCV is determined by host–viral interactions, which are perturbed in HIV coinfection,
resulting in accelerated liver fibrosis, higher HCV loads and poorer responses to interferon-based
therapy when compared with HCV monoinfection.[64] Critical to an understanding of the HCV
natural history is an understanding of early immunological control and clearance of HCV, and
how HIV infection may affect this.

What Constitutes a Successful Immune Response to Hepatitis C Virus?

The emerging consensus is that early control and clearance of HCV infection is the result of a
strong cellular immune response accompanied by innate mediators.[65] In the absence of HIV,
approximately 25% of individuals will spontaneously clear HCV infection, whereas others have
persistent infection marked by ongoing viraemia.[66] A successful immune response to HCV
requires strong, broad, early and sustained HCV-specific CD4 and CD8 T-cell responses, in
particularly directed against the nonstructural proteins.[67–71] Although most individuals mount
measurable CD4 and CD8 T-cell responses, patients who failed to clear HCV either did not
mount CD4 T-cell responses or, after initial virological control, do not sustain these responses
with a subsequent relapse of HCV.[68] Chimpanzee studies have also demonstrated a loss of
control of HCV related to depletion of CD4 and CD8 T cells.[72,73] HCV-specific T-cell responses
were persistent and have been detectable up to two decades following resolution of HCV in a
group of women who had been infected from human rhesus immunoglobulin.[74]

There are a number of hypotheses as to how HCV evades these cell-mediated responses that
have recently been reviewed.[65] The concept of T-cell exhaustion postulates that persistent
stimulation of lymphocytes with high-level antigenaemia in HCV leads to reduced T-cell
responses and apoptosis. Interestingly, this may be mediated by an inhibitory molecule
programmed death-1 (PD-1). Furthermore, in HIV infection, exhaustion of CD8 T cells has been
shown to occur following loss of CD4 T cells.[75] Another proposed mechanism may be induction
of T-regulatory cells that inhibit antigen-specific T cells, such as CD8 T cells in HCV.[76] Finally,
the rapid mutation of HCV has been shown to lead to escape mutation within specific CD8 T-cell
epitopes.[77,78]

Recently, there has been great interest in polymorphisms in the interleukin (IL) 28B gene on
chromosome 19, which has been shown to predict spontaneous clearance and sustained
virological response to combination HCV treatment.[79,80] The different racial distributions of this
polymorphism may explain some of the racial differences in response to HCV treatment. There
is also evidence that in HCV infection, there is a delayed cytokine responses when compared
with other chronic viral infections such as HIV.[81]

What is the Impact of HIV on the Immune Response to Acute Hepatitis C

Virus?

In HIV coinfection, the rate of spontaneous clearance is significantly lower than that in HCV
monoinfection, with reported rates ranging from 5 to 24%.[82–84] Furthermore, the viral set point is
increased in HIV infection with one large cohort demonstrating an HCV load more than 1 log
higher than that of HCV monoinfected individuals.[83] In chronic HCV infection, HIV-positive
men are more likely to shed HCV RNA in semen than their HIV-negative counterparts.[85]
Interestingly, the humoral response to HCV appears to be delayed in HIV infection. In a London
cohort of 43 HIV-positive individuals with acute HCV, the proportion who had a negative HCV
antibody results was 37, 10 and 5% at 3, 9 and 12 months after their first HCV RNA positive test
result, respectively.[86] As a result, some have suggested that HCV-RNA testing should be
performed for screening high-risk populations.

The poor control of HCV is the result of HIV's impact on the cell-mediated immune responses. It
is clear that in chronic coinfection, HIV significantly impairs the cell-mediated responses to
HCV antigens.[87] A large study of chronic HCV/HIV coinfected individuals found that lower
CD4 cell counts were associated with reduced CD8 T-cell responses.[88] A UK cohort analysed
immune responses in the acute phase of HCV infection, demonstrating that the immune defect to
HCV occurs early in established HIV coinfection, even in individuals with relatively preserved
CD4 cell counts (>500 cells/μl).[83] Recently, a prospective French study of acute HCV cell-
mediated responses in HIV coinfection demonstrated low frequency interferon gamma and weak
HCV-specific memory T-cell responses.[84]

Chronic HCV/HIV coinfection is associated with more rapid liver fibrosis with an estimated
fibrosis progression rate of 0.15 versus 0.11 fibrosis units per year for HCV monoinfection. [89]
Data are now emerging that acquisition of HCV following HIV may be associated with
accelerated fibrosis.[23,90] In a small prospective series of 11 patients, nine (82%) had grade 2 liver
fibrosis on liver biopsy.[23] This is a higher rate than has been reported in acute HCV
monoinfection. In a recent immunological review of HCV and HIV coinfection, [91] a number of
potential mechanisms contributing to accelerated liver fibrosis were described, including altered
cytokines, increased hepatocyte and lymphocyte apoptosis, and increased oxidative stress;
bacterial translocation with increased levels of lipopolysaccharides (LPS); and external factors
such as steatosis, insulin resistance and hepatotoxicity associated with antiretrovirals.

It is also likely that the immunological changes associated with HIV are contributing to the
changing epidemiology in HIV-positive MSM. Although high-risk behaviours are certainly
associated with transmission, there are specific immunological mechanisms that may also be
contributing. First, HIV perturbations of the gastrointestinal immune system have become a
major focus for the immunopathogenesis in HIV.[92] The compromised mucosal barrier,
associated with viral replication and CD4 T-cell destruction, with consequent bacterial
translocation are thought to be major drivers of AIDS progression. Although it has not yet been
elucidated, it is conceivable that defects in mucosal immunity are also facilitating permucosal
transmission of HCV. In addition, defects in cell-mediated responses are associated with reduced
HCV clearance[92,93] and higher HCV viral loads in serum[94] and semen.[85]

Treatment of Acute Hepatitis C in HIV-positive Individuals

Chronic HCV is generally a slowly progressive disease with cirrhosis estimated to occur in up to
20% of individuals over a 40-year period.[95] Even in HIV-infected individuals, in whom disease
progression is accelerated,[96] end-stage liver disease is unlikely to occur in less than 5–10 years
after initial infection.[97] The rationale, therefore, for treating HCV in the acute stages of infection
is based on evidence suggesting that early treatment of acute HCV results in higher rates of
sustained virological response (SVR) than treatment in established chronic HCV, presenting a
window of therapeutic opportunity. In a seminal paper, Jaeckel et al.[98] reported 44 HIV-
negative patients with acute HCV who were treated with standard interferon therapy for 24
weeks leading to an SVR of 98%. No subsequent study has managed to confirm such high rates
of SVR in acute HCV infection, despite the introduction of pegylated interferon (PEG): SVR
rates remain higher than those in chronic hepatitis C [at least for HCV genotype 1 (HCV-1)
infections] at between 71 and 94%[99–103] versus 40 and 50% in chronic HCV-1.[104,105] However,
these studies were heterogeneous with regard to the populations studied, delay before
commencement of treatment and duration of therapy. Large randomized clinical trials on the
optimal treatment of acute HCV are difficult to perform, due largely to difficulties in identifying
incident cases and in accurately assessing the timing of infection. Consequently, there remain
many areas in which the guidelines for treating acute HCV are not yet fully evidence-based. This
is particularly true of acute HCV in HIV-positive individuals in whom there is even greater
uncertainty around optimal management. To date, published data on treatment outcomes in this
setting are limited to 10 studies reporting HIV-positive individuals using various study designs
and treatment regimens[22,24,50,53,82,106–110] (Table 2). SVR ranged from 0 to 91%[53] across studies,
with most studies reporting rates between 60 and 80%. The treated French, UK and German
cohorts (n = 150) were recently combined with a reported overall SVR of 62%.[111] Given that the
predominant genotype was 1 or 4 in all these studies, this would support the theory that in HIV-
positive, as in HIV-negative populations, treatment in the acute phase of HCV is indeed more
successful than treatment in chronic HCV.

When to Start Treatment for Acute Hepatitis C Virus in HIV-positive

Individuals?

Although HIV-infected individuals are less likely to spontaneously clear acute HCV infection
than HIV-negative individuals, spontaneous eradication can occur.[66,82–84,112] It is still not clear
how long should a patient be observed to allow for this possibility before commencing therapy.
In a randomized study of acute HCV monoinfection in Egypt, SVR rates were compromised by a
delay in start of PEG to 20 weeks from time of first positive HCV-RNA test result (76% SVR),
but were similar in those starting 8 (95% SVR) or 12 (92% SVR) weeks after diagnosis. [101] The
majority of patients in this study were infected through occupational exposure and it should be
noted that in this study, a short duration of 12 weeks of treatment only was used. In HCV
monoinfection, a 'watch and wait' policy of 12 weeks before commencing treatment is advised,
and current guidelines on HIV-positive individuals similarly recommend waiting 12 weeks from
estimated date of exposure to ensure that spontaneous clearance does not occur. [113] Recently, a
week 4 HCV-RNA drop of more than 2 logs has been identified as a predictor of spontaneous
viral clearance, which suggests early treatment could be targeted.[114]

Is there an Advantage of Combination HCV Therapy Over Monotherapy?

In HIV-negative individuals, acute HCV is almost always treated with PEG monotherapy as
SVR rates have been typically high with these regimens. Only one study in this population has
reported a comparison between PEG monotherapy and PEG in combination with ribavirin (RBV)
finding no significant benefit of using combination therapy.[102] In HIV-positive individuals, there
has been much greater variation in the regimens employed, with a general trend towards the use
of combination rather than PEG monotherapy and guidelines now recommend the use of
standard PEG/RBV combination for 24 weeks in HIV-positive individuals.[113] However, there is
a paucity of evidence to support this. In three of the seven studies, the protocols were amended to
combination therapy, either after an initial two patients failed treatment with PEG
monotherapy[82] or as a consequence of another study that reported a high overall SVR rate of
91% and used PEG/RBV in five of 11 HIV-positive individuals with acute HCV.[53] In fact, in
the subsequent German study, which used PEG/RBV in 21 participants and PEG monotherapy in
15 participants, there was no benefit observed with the addition of RBV. [108] Finally, dosing of
RBV was inconsistent in these studies, making interpretation of effect difficult. In summary,
there is very little evidence that RBV enhances treatment outcomes in this setting and may add
significant risk of toxicity and drug interactions.
What is the Optimal duration and Monitoring of Therapy?

Increasing attention has been given recently to the possibility of shortening the duration of
therapy in acute HCV in HIV-negative individuals to 12 weeks. A number of studies on HIV-
negative patients have examined this issue with encouraging results.[103,115,116] One study using 12
weeks of therapy with PEG monotherapy resulted in SVR more than 90%, provided therapy was
initiated within 12 weeks of infection. No study on HIV-positive patients has reported outcomes
with short-course therapy. The utility of early virological response monitoring in the HIV setting
has been reported in one study only. In 20 HIV-positive patients treated for 24 weeks in the
Australian Trial in Acute Hepatitis C (ATAHC) study, rapid virological response (RVR) was
observed in 44% of individuals and had 100% positive predictive value for SVR.[107] Conversely,
lack of early virological response (EVR) at week 12 may be an important predictor of
nonresponse to therapy.

Predictors of Treatment Response in HIV-positive Individuals with Acute

Hepatitis C Virus

Due to the small numbers in the published studies, identification of predictors of response is very
difficult. Until recently, HCV genotype has been recognized as the strongest predictor of
successful treatment in chronic HCV monoinfection. No single treatment study has been able to
demonstrate an effect of genotype on treatment outcome of acute HCV in HIV-positive patients,
probably due to small numbers. The majority of participants were infected with HCV genotype 1
or 4 and had an overall SVR rate of 57% ( Table 2 and Table 3 ). This compares to an overall
SVR rate of 87% in genotype 2/3 participant and suggests that there may be an effect by
genotype on treatment response similar to that observed in chronic HCV infection. Recently,
polymorphism of IL28 has been identified as the most important predictor of treatment response
in HCV. Interestingly, a German group has recently reported no IL28 impact on treatment of
acute HCV/HIV coinfection,[117] whereas two other studies did report improved SVR with IL28
C/C alleles in chronic coinfection.[117,118] Furthermore, polymorphisms in both IL6 and tumour
growth factor (TGF) have also been correlated with treatment outcome in acute HCV/HIV
coinfection.[119,120]

Discussion

Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV
patients in the cART era, the rapid and significant rise in the incidence of HCV in HIV-infected
MSM living in high-income countries is alarming.[121–123] A significant change in the
epidemiology of HCV has occurred, with HCV emerging as a STI among HIV-positive MSM.
[124]
The molecular phylogenetic studies have been important for providing robust evidence of
common source transmission, in particular, demonstrating the existence of a large international
transmission network in Europe. The molecular work implies, through identification of different
genotypes and subtypes of HCV in this network, that the recent transmission is not the result of
the HCV becoming more virulent, but more likely the result of other factors such as behavioural
change. Work to date suggests that this permucosal HCV transmission results from high-risk
sexual and non-IDU drug behaviours.[21,37,44,51] However, the complex interaction between these
risks has not yet been fully elucidated. Based on our current knowledge, permucosal
transmission of HCV is probably mediated by factors such as traumatic sexual practices and
ulcerative STI that may cause mucosal damage in the rectum. The characterization of the precise
mechanisms and risk factors will have to involve qualitative studies of transmission events and
attitudes, in addition to the quantitative studies that have been done to date. As MSM-specific
HCV strains in Europe are almost exclusively of difficult-to-treat HCV genotypes 1 and 4, a
virological component cannot entirely be excluded. In particular, when we assume multiple
introductions of HCV from the IDU population into the MSM population, the absence of
genotype 3a, which is highly prevalent among European injecting drug users, remains
unexplained.

The emergence of HIV as an STI has been limited to HIV-positive MSM. [20,41] The central role of
HIV could relate to behavioural and biological factors. Interestingly, the data suggest that the
HCV incidence in HIV-infected MSM has increased significantly following the introduction of
cART and the subsequent rise in sexual risk behaviour and STI in the late 1990s.[17,45,47,49,51,124]
This, however, cannot explain why there is no evidence for permucosal transmission of HCV in
the 1980s, a period in which STI and sexual risk-taking were highly prevalent among MSM. As a
result of the increased life expectancy of people living with HIV/AIDS and the ongoing
transmission of HIV among MSM, the recent increase in permucosal HCV transmission could
relate to changing sexual behaviours in the context of an increasing pool of HIV-infected MSM.
The current HIV prevention strategy of serosorting, whereby MSM of concordant HIV status
have negotiated unprotected sex, might be an important factor. In a review of changing MSM
behaviours after the introduction of cART, serosorting, wherein MSM of concordant HIV status
have unprotected sex, has become more prevalent and is certainly contributing to higher risk
behaviours.[125] Although serosorting prevents HIV transmission, it does not prevent other STIs.
In line with this review, several studies have suggested that internet and travel behaviour might
be associated with the recent spread of HCV among HIV-positive MSM.[21,37] Of concern is the
potential bridging of HCV transmission from the HIV-positive into the HIV-negative MSM
population. Only one epidemiological study suggests potential bridging between HIV-positive
and HIV-negative MSM,[47] but as discussed before, this study has serious limitations. Molecular
HCV data obtained from HIV-positive and HIV-negative MSM in the Australian ATAHC study
revealed that a small proportion (6%) of HCV sequences obtained from HIV-negative MSM
were part of MSM-specific clusters.[59] In conclusion, sporadic transmission from the HIV-
positive population might occur, but currently the HCV incidence is low among HIV-negative
MSM and the majority of HCV infections appear to be of an unrelated source, mostly IDU.
[20,37,41,59]
However, temporal trends in acute HCV infections in HIV-negative MSM should be
closely monitored to allow timely initiation of interventions to prevent transmission in this
group.

Biologically, there are a number of potential mechanisms related to HIV that might result in
enhanced infectivity and susceptibility to HCV, including increased HCV loads in serum and
semen[83,85] and defects in the gastrointestinal immune system.[92] The cell-mediated immune
lesions leading to increased chronicity and higher HCV loads probably also contribute to the
changing epidemiology of HCV and complicate its management. It is not yet known whether
lower CD4 cell count increases the risk of acquiring HCV, but the fact that many MSM with
acute HCV have relatively preserved CD4 cell counts suggests this may not be a critical factor.
Although permucosal HCV transmission is probably occurring across gastrointestinal mucosa in
these individuals, the specific immune defect in the mucosal cell-mediated immunological
control mechanism localized in the gastrointestinal tract has not been identified. [92] Further
studies, exploring prospective serum and semen HCV load in acute infection with HIV
parameters and comparing HIV characteristics, including cART use between HIV-infected MSM
with and without HCV would inform the importance of HIV and identify factors that could be
used to reduce infection. Alternatively, it is plausible that HIV is transmitted more efficiently
sexually compared to HCV, and hence in the vast majority of MSM who engage in high-risk
sexual behaviour with HIV-positive MSM, acquisition of HIV will, therefore, precede HCV
infection.[36] As studies on the impact of HCV on HIV outcome have predominantly been
conducted in injecting drug users and haemophiliacs in whom HCV usually preceded HIV
infection, future studies should also investigate the impact of HCV on HIV progression in this
new group of coinfected MSM who acquired their HCV infection after HIV infection and at an
older age. In particular because it might be associated with accelerated liver fibrosis.[23,90]

Currently, the management of acute HCV in HIV-infected patients is based on experience of

retrospective studies and data from HCV monoinfection studies. Recently, a large prospective
study enrolling both HIV-infected and HIV-uninfected individuals with recently acquired HCV
infection reported a 74% SVR rate after 24 weeks of PEG/RBV combination therapy in
coinfected participants, higher than that in the monoinfected participants. These data suggest that
early treatment was efficacious in this group and should be considered irrespective of HCV
genotype and baseline HCV-RNA level.[126] With the development of the specifically targeted
antiviral therapies for HCV (STAT-C), there will be a paradigm shift in our approach to
treatment of HCV. HCV protease and polymerase inhibitors are currently in trial and appear to
be highly efficacious.[127] There are also now study protocols that use a combination of STAT-Cs
without an interferon backbone with encouraging preliminary results.[128] There is no doubt that
this new class of antiviral therapies will have an important role in the future management of
acute and chronic HCV/HIV coinfection. However, the majority of the STAT-C agents in
development are targeted at genotype 1 HCV infection, though a significant proportion of the
recent HCV in HIV has been nongenotype 1. Therefore, in the short-term, PEG with or without
RBV will remain the standard of care. Given this, it is important to be able to stratify individuals
to treatment. As outlined, there is some emerging data on the use of early viral kinetics, such as
week 4 HCV-RNA in predicting spontaneous clearance and SVR. In addition, other markers
such as IL28b polymorphisms may become valuable predictors of HCV spontaneous clearance
and response to interferon-based treatments. The role of individualizing treatment is incomplete,
in part because of the piecemeal way the case series have been reported. Factors such as the
specific therapy, timing and length of treatment in this population should ideally be addressed
within appropriately powered randomized clinical trials. At the very least, large international
collaborations that combine data across cohorts in a consistent manner are important to establish.

Targeted prevention such as raising awareness, regular screening and treatment of acute and
chronic infections are needed to stop the further spread among MSM. Very limited data are
available on HCV in MSM in middle and low-income countries. A hallmark of the successful
HIV/AIDS response has been the underpinning of HIV education and prevention by sound
epidemiological data. Although these issues are complex, improving our understanding of the
risk behaviours and attitudes would help public health interventions to be appropriately focused.
HCV education and prevention materials for MSM have already been developed based on
current data and implemented in countries such as UK and the Netherlands. It is clear that a
message of 'safe sex' through condom use during anal intercourse could be provided, but given
the practice of negotiated unprotected sex among HIV-infected MSM might not be accepted. In
addition, it may not cover practices that increase risk of blood-to-blood contact (e.g. fisting).
Furthermore, MSM population needs to be informed that reinfection is an ongoing risk, given the
recent reports of HCV reinfection following successful treatment and documented clearance of
HCV.[129] Characterization of biological factors not only has implications for the MSM
population involved in unprotected anal intercourse, but may also have implications for the wider
HCV/HIV coinfected population.[130] Recognition of the current problem should lead to
collaborative efforts to identify strategies to mitigate and manage this important growing
problem.

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