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.
Epidemiology of hepatitis C virus in men who have sex with men
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.
;)
Table 1: Studies determining hepatitis C virus incidence in men having sex with men.
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.
Table 2: Studies of acute hepatitis C treatment outcomes in HIV-positive individuals.
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% (Tables 2 and 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].
Table 3: Diagnostic criteria and delay before commencement of therapy for acute hepatitis C in studies of HIV-positive individuals.
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.
Acknowledgement
M.D. and G.M. received NHMRC project grant 568859. M.D. received St Vincent's Clinic Foundation grant 2009. T.V.L. received Public Health Service R&D grant 2007, AIDS foundation HIV/AIDS Research grant 2008026. M.P. received AIDS foundation HIV/AIDS Research grant 2008026, Zonmw grant 7115 0001.
The authors declare no conflict of interest.
References
1. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359–362.
2. Alter MJ. Prevention of spread of hepatitis C. Hepatology 2002; 36(5 Suppl 1):S93–S98.
3. Memon MI, Memon MA. Hepatitis C: an epidemiological review. J Viral Hepat 2002; 9:84–100.
4. Madhava V, Burgess C, Drucker E. Epidemiology of chronic hepatitis C virus infection in sub-Saharan Africa. Lancet Infect Dis 2002; 2:293–302.
5. Terrault NA. Sexual activity as a risk factor for hepatitis C. Hepatology 2002; 36(5 Suppl 1):S99–105.
6. Chang TT, Liou TC, Young KC, Lin XZ, Lin CY, Shin JS,
et al. Intrafamilial transmission of hepatitis C virus: the important role of inapparent transmission. J Med Virol 1994; 42:91–96.
7. Kao JH, Hwang YT, Chen PJ, Yang PM, Lai MY, Wang TH,
et al. Transmission of hepatitis C virus between spouses: the important role of exposure duration. Am J Gastroenterol 1996; 91:2087–2090.
8. Akahane Y, Kojima M, Sugai Y, Sakamoto M, Miyazaki Y, Tanaka T,
et al. Hepatitis C virus infection in spouses of patients with type C chronic liver disease. Ann Intern Med 1994; 120:748–752.
9. Sun CA, Chen HC, Lu CF, You SL, Mau YC, Ho MS,
et al. Transmission of hepatitis C virus in Taiwan: prevalence and risk factors based on a nationwide survey. J Med Virol 1999; 59:290–296.
10. Chayama K, Kobayashi M, Tsubota A, Koida I, Arase Y, Saitoh S,
et al. Molecular analysis of intraspousal transmission of hepatitis C virus. J Hepatol 1995; 22:431–439.
11. Zylberberg H, Thiers V, Lagorce D, Squadrito G, Leone F, Berthelot P,
et al. Epidemiological and virological analysis of couples infected with hepatitis C virus. Gut 1999; 45:112–116.
12. Caporaso N, Ascione A, D'Antonio M, Di Costanzo GG, Galeota LA, Tremolada F,
et al. Prevalence of anti-HCV among spouses and offspring of anti-HCV positive subjects: an Italian multicentre study. Ital J Gastroenterol 1995; 27:5–7.
13. Tahan V, Karaca C, Yildirim B, Bozbas A, Ozaras R, Demir K,
et al. Sexual transmission of HCV between spouses. Am J Gastroenterol 2005; 100:821–824.
14. Vandelli C, Renzo F, Romano L, Tisminetzky S, De PM, 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; 99:855–859.
15. Piazza M, Sagliocca L, Tosone G, Guadagnino V, Stazi MA, Orlando R,
et al. Sexual transmission of the hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. A randomized controlled trial. Arch Intern Med 1997; 157:1537–1544.
16. Boonyarad V, Chutaputti A, Choeichareon S, Bedi K, Theamboonlers A, Chinchai T,
et al. Interspousal transmission of hepatitis C in Thailand. J Gastroenterol 2003; 38:1053–1059.
17. Browne R, Asboe D, Gilleece Y, Atkins M, Mandalia S, Gazzard B,
et al. Increased numbers of acute hepatitis C infections in HIV positive homosexual men: is sexual transmission feeding the increase? Sex Transm Infect 2004; 80:326–327.
18. Gotz HM, van Doornum G, Niesters HG, den Hollander JG, Thio HB, de Zwart O. A cluster of acute hepatitis C virus infection among men who have sex with men: results from contact tracing and public health implications. AIDS 2005; 19:969–974.
19. Gambotti L, Batisse D, Colin-de-Verdiere N, Delaroque-Astagneau E, Desenclos JC, 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; 10:115–117.
20. van de Laar TJ, Van der Bij AK, Prins M, Bruisten SM, Brinkman K, Ruys TA,
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; 196:230–238.
21. Danta M, Brown D, Bhagani S, Pybus OG, Sabin CA, 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; 21:983–991.
22. Serpaggi J, Chaix ML, Batisse D, Dupont C, Vallet-Pichard A, Fontaine H,
et al. Sexually transmitted acute infection with a clustered genotype 4 hepatitis C virus in HIV-1-infected men and inefficacy of early antiviral therapy. AIDS 2006; 20:233–240.
23. Fierer DS, Uriel AJ, Carriero DC, Klepper A, Dieterich DT, Mullen MP,
et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study. J Infect Dis 2008; 198:683–686.
24. Luetkemeyer A, Hare CB, Stansell J, Tien PC, Charlesbois E, Lum P,
et al. Clinical presentation and course of acute hepatitis C infection in HIV-infected patients. J Acquir Immune Defic Syndr 2006; 41:31–36.
25. Holubar M, Taylor L, Wu K, Bosch R, Mayer K, Tashima K.
Hepatitis C virus (HCV) antibody seroconversion in a U.S. HIV-infected male clinical trials population[abstract LB14]. 60th Annual Meeting of the American Association for the Study of the Liver (AASLD); 30 October to 1 November 2009; Boston, USA.
26. Matthews GV, Hellard M, Kaldor J, Lloyd A, Dore GJ. Further evidence of HCV sexual transmission among HIV-positive men who have sex with men: response to Danta
et al.. AIDS 2007; 21:2112–2113.
27. Marcellin P, Colin JF, Martinot-Peignoux M, Pham BN, Lefort V, Picault AB,
et al. Hepatitis C virus infection in anti-HIV positive and negative French homosexual men with chronic hepatitis: comparison of second- and third-generation anti-HCV testing. Liver 1993; 13:319–322.
28. Esteban JI, Esteban R, Viladomiu L, Lopez-Talavera JC, Gonzalez A, Hernandez JM,
et al. Hepatitis C virus antibodies among risk groups in Spain. Lancet 1989; 2:294–297.
29. Tedder RS, Gilson RJ, Briggs M, Loveday C, Cameron CH, Garson JA,
et al. Hepatitis C virus: evidence for sexual transmission. BMJ 1991; 302:1299–1302.
30. Bodsworth NJ, Cunningham P, Kaldor J, Donovan B. Hepatitis C virus infection in a large cohort of homosexually active men: independent associations with HIV-1 infection and injecting drug use but not sexual behaviour. Genitourin Med 1996; 72:118–122.
31. Buchbinder SP, Katz MH, Hessol NA, Liu J, O'Malley PM, Alter MJ. Hepatitis C virus infection in sexually active homosexual men. J Infect 1994; 29:263–269.
32. Corona R, Prignano G, Mele A, Gentili G, Caprilli F, Franco E,
et al. Heterosexual and homosexual transmission of hepatitis C virus: relation with hepatitis B virus and human immunodeficiency virus type 1. Epidemiol Infect 1991; 107:667–672.
33. Tor J, Llibre JM, Carbonell M, Muga R, Ribera A, Soriano V,
et al. Sexual transmission of hepatitis C virus and its relation with hepatitis B virus and HIV. BMJ 1990; 301:1130–1133.
34. Ndimbie OK, Kingsley LA, Nedjar S, Rinaldo CR. Hepatitis C virus infection in a male homosexual cohort: risk factor analysis. Genitourin Med 1996; 72:213–216.
35. Ricchi E, Borderi M, Costigliola P, Miniero R, Sprovieri G, Chiodo F. Antihepatitis C virus antibodies amongst Italian homo-bisexual males. Eur J Epidemiol 1992; 8:804–807.
36. Fox J, Nastouli E, Thomson E, Muir D, McClure M, Weber J,
et al. Increasing incidence of acute hepatitis C in individuals diagnosed with primary HIV in the United Kingdom. AIDS 2008; 22:666–668.
37. Urbanus AT, van de Laar TJ, Stolte IG, Schinkel J, Heijman T, Coutinho RA,
et al. Hepatitis C virus infections among HIV-infected men who have sex with men: an expanding epidemic. AIDS 2009; 23:F1–F7.
38. Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, Horban A,
et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis 2005; 192:992–1002.
39. Myers T, Allman D, Xu K, Remis RS, Aguinaldo J, Burchell A,
et al.
The prevalence and correlates of hepatitis C virus (HCV) infection and HCV-HIV co-infection in a community sample of gay and bisexual men.Int J Infect Dis 2009;
13:730–739.
40. Alary M, Joly JR, Vincelette J, Lavoie R, Turmel B, Remis RS. Lack of evidence of sexual transmission of hepatitis C virus in a prospective cohort study of men who have sex with men. Am J Public Health 2005; 95:502–505.
41. Jin F, Prestage GP, Matthews G, Zablotska I, Rawstorne P, Kippax SC,
et al. Prevalence, incidence and risk factors for hepatitis C in homosexual men: data from two cohorts of HIV-negative and HIV-positive men in Sydney, Australia. Sex Transm Infect 2010; 86:25–28.
42. Melbye M, Biggar RJ, Wantzin P, Krogsgaard K, Ebbesen P, Becker NG. Sexual transmission of hepatitis C virus: cohort study (1981-9) among European homosexual men. BMJ 1990; 301:210–212.
43. Giuliani M, Caprilli F, Gentili G, Maini A, Lepri AC, Prignano G,
et al. Incidence and determinants of hepatitis C virus infection among individuals at risk of sexually transmitted diseases attending a human immunodeficiency virus type 1 testing program. Sex Transm Dis 1997; 24:533–537.
44. Rauch A, Rickenbach M, Weber R, Hirschel B, Tarr PE, Bucher HC,
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; 41:395–402.
45. Ghosn 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; 82:458–460.
46. Turner JM, Rider AT, Imrie J, Copas AJ, Edwards SG, Dodds JP,
et al. Behavioural predictors of subsequent hepatitis C diagnosis in a UK clinic sample of HIV positive men who have sex with men. Sex Transm Infect 2006; 82:298–300.
47. Richardson D, Fisher M, Sabin CA. Sexual transmission of hepatitis C in MSM may not be confined to those with HIV infection. J Infect Dis 2008; 197:1213–1214.
48. Ruan Y, Luo F, Jia Y, Li X, Li Q, Liang H,
et al. Risk factors for syphilis and prevalence of HIV, hepatitis B and C among men who have sex with men in Beijing, China: implications for HIV prevention. AIDS Behav 2009; 13:663–670.
49. van der Helm J, Geskus RB, del Amo J, ChĂªne G, Gill J, Hamouda O,
et al.
Hepatitis C epidemic among HIV+ men who have sex with men started before 2000 [abstract 643].17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco, USA.
50. Stellbrink H-J, Schewe CK, Vogel M, Hoffmann C, Noah C. I
ncidence, genotype distribution, and prognosis of sexually transmitted acute hepatitis C in a cohort of HIV-infected patients [abstract 645].17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco, USA.
51. Giraudon I, Ruf M, Maguire H, Charlett A, Ncube F, Turner J,
et al.
Increase in newly acquired hepatitis C in HIV positive men who have sex with men across London and Brighton, 2002-2006. Is this an outbreak?
Sex Transm Infect 2008;
84:111–115.
52. van de Laar TJW, Urbanus AT, Bruisten SM, de Vries HJC, Thiesbrummel HFJ, Coutinho RA,
et al. Reply to Richardson
et al. Sexual transmission of hepatitis C in MSM may not be confined to those infected with HIV infection. J Infect Dis 2008; 197:1214–1215.
53. Vogel M, Bieniek B, Jessen H, Schewe CK, Hoffmann C, Baumgarten A,
et al. Treatment of acute hepatitis C infection in HIV-infected patients: a retrospective analysis of eleven cases. J Viral Hepat 2005; 12:207–211.
54. Vogel M, van de Laar T, Henke J, Kupfer B, KĂ¼mmerle T, Birtel A,
et al.
Cluster of acute HCV genotype 4 infections among HIV-positive men who have sex with men (MSM) in Germany [abstract 785].60th Annual Meeting of the American Association for the Study of the Liver (AASLD); 30 October to 1 November 2009; Boston, USA.
55. van de Laar T, Pybus O, Bruisten S, Brown D, Nelson M, Bhagani S,
et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology 2009; 136:1609–1617.
56. Stolte IG, Dukers NH, Geskus RB, Coutinho RA, de Wit JB. Homosexual men change to risky sex when perceiving less threat of HIV/AIDS since availability of highly active antiretroviral therapy: a longitudinal study. AIDS 2004; 18:303–309.
57. Elford J, Bolding G, Sherr L. High-risk sexual behaviour increases among London gay men between 1998 and 2001: what is the role of HIV optimism? AIDS 2002; 16:1537–1544.
58. Crepaz N, Passin WF, Herbst JH, Rama SM, Malow RM, Purcell DW,
et al. Meta-analysis of cognitive-behavioral interventions on HIV-positive persons' mental health and immune functioning. Health Psychol 2008; 27:4–14.
59. Matthews GV, Grebely J, Pham S, Hellard M, Oon A, Marks P,
et al.
Epidemiology of recently acquired hepatitis C virus (HCV) infection in HCV and HCV/HIV infected participants in the Australian Trial in Acute Hepatitis C (ATAHC) study [abstract].Australian AIDS Conference; Brisbane, Australia; 9–11 September 2009.
60. Fierer DS, Fishman S, Uriel AJ, Carriero DC, Factor S, Mullen MP,
et al.
Characterization of an outbreak of acute HCV in HIV-infected men in New York City [abstract 802].16th Conference on Retroviruses and Opportunistic Infections (CROI); 8–11 February 2009; Montreal, Canada.
61. Osella AR, Massa MA, Joekes S, Blanch N, Yacci MR, Centonze S,
et al. Hepatitis B and C virus sexual transmission among homosexual men. Am J Gastroenterol 1998; 93:49–52.
62. Donahue JG, Nelson KE, Munoz A, Vlahov D, Rennie LL, Taylor EL,
et al. Antibody to hepatitis C virus among cardiac surgery patients, homosexual men, and intravenous drug users in Baltimore, Maryland. Am J Epidemiol 1991; 134:1206–1211.
63. Gasparini V, Chiaramonte M, Moschen ME, Fabris P, Altinier G, Majori S,
et al. Hepatitis C virus infection in homosexual men: a seroepidemiological study in gay clubs in north-east Italy. Eur J Epidemiol 1991; 7:665–669.
64. Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med 2007; 356:1445–1454.
65. Klenerman P, Kim A. HCV-HIV coinfection: simple messages from a complex disease. PLoS Med 2007; 4:e240.
66. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat 2006; 13:34–41.
67. Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T, Jung MC,
et al. Possible mechanism involving T-lymphocyte response to nonstructural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 1995; 346:1006–1007.
68. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R,
et al. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 1999; 117:933–941.
69. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194:1395–1406.
70. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P,
et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000; 191:1499–1512.
71. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 2005; 436:946–952.
72. Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, Reimann KA,
et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 2003; 197:1645–1655.
73. Grakoui A, Shoukry NH, Woollard DJ, Han JH, Hanson HL, Ghrayeb J,
et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 2003; 302:659–662.
74. Takaki A, Wiese M, Maertens G, Depla E, Seifert U, Liebetrau A,
et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med 2000; 6:578–582.
75. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD,
et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998; 188:2205–2213.
76. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P,
et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005; 79:7852–7859.
77. Cox AL, Mosbruger T, Mao Q, Liu Z, Wang XH, Yang HC,
et al. Cellular immune selection with hepatitis C virus persistence in humans. J Exp Med 2005; 201:1741–1752.
78. Ray SC, Fanning L, Wang XH, Netski DM, Kenny-Walsh E, Thomas DL. Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J Exp Med 2005; 201:1753–1759.
79. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ,
et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461:399–401.
80. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C,
et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461:798–801.
81. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J,
et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 2009; 83:3719–3733.
82. Gilleece YC, Browne RE, Asboe D, Atkins M, Mandalia S, Bower M,
et al. Transmission of hepatitis C virus among HIV-positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin. J Acquir Immune Defic Syndr 2005; 40:41–46.
83. Danta M, Semmo N, Fabris P, Brown D, Pybus OG, Sabin CA,
et al. Impact of HIV on host-virus interactions during early hepatitis C virus infection. J Infect Dis 2008; 197:1558–1566.
84. Schnuriger A, Dominguez S, Guiguet M, Harfouch S, Samri A, Ouazene Z,
et al. Acute hepatitis C in HIV-infected patients: rare spontaneous clearance correlates with weak memory CD4 T-cell responses to hepatitis C virus. AIDS 2009; 23:2079–2089.
85. Briat A, Dulioust E, Galimand J, Fontaine H, Chaix ML, Letur-Konirsch H,
et al. Hepatitis C virus in the semen of men coinfected with HIV-1: prevalence and origin. AIDS 2005; 19:1827–1835.
86. Thomson EC, Nastouli E, Main J, Karayiannis P, Eliahoo J, Muir D,
et al. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. AIDS 2009; 23:89–93.
87. Capa L, Soriano V, Garcia-Samaniego J, Nunez M, Romero M, Cascajero A,
et al. Influence of HCV genotype and co-infection with human immunodeficiency virus on CD4(+) and CD8(+) T-cell responses to hepatitis C virus. J Med Virol 2007; 79:503–510.
88. Kim AY, Lauer GM, Ouchi K, Addo MM, Lucas M, Schulze Zur WJ,
et al. The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1. Blood 2005; 105:1170–1178.
89. Benhamou Y, Bochet M, Di M, Charlotte V, Azria F, Coutellier FA,
et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 1999; 30:1054–1058.
90. Osinusi A, Kleiner D, Wood B, Polis M, Masur H, Kottilil S. Rapid development of advanced liver fibrosis after acquisition of hepatitis C infection during primary HIV infection. AIDS Patient Care STDS 2009; 23:403–406.
91. Kim AY, Chung RT. Coinfection with HIV-1 and HCV: a one-two punch. Gastroenterology 2009; 137:795–814.
92. Lackner AA, Mohan M, Veazey RS. The gastrointestinal tract and AIDS pathogenesis. Gastroenterology 2009; 136:1965–1978.
93. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005; 434:1093–1097.
94. Matthews-Greer JM, Caldito GC, Adley SD, Willis R, Mire AC, Jamison RM,
et al. Comparison of hepatitis C viral loads in patients with or without human immunodeficiency virus. Clin Diagn Lab Immunol 2001; 8:690–694.
95. Freeman AJ, Dore GJ, Law MG, Thorpe M, Von OJ, Lloyd AR,
et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 2001; 34(4 Pt 1):809–816.
96. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T,
et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:562–569.
97. Thein HH, Yi Q, Dore GJ, Krahn MD. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS 2008; 22:1979–1991.
98. Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M,
et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001; 345:1452–1457.
99. Santantonio T, Fasano M, Sinisi E, Guastadisegni A, Casalino C, Mazzola M,
et al. Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance. J Hepatol 2005; 42:329–333.
100. Wiegand J, Buggisch P, Boecher W, Zeuzem S, Gelbmann CM, Berg T,
et al. Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study. Hepatology 2006; 43:250–256.
101. Kamal SM, Fouly AE, Kamel RR, Hockenjos B, Al TA, Khalifa KE,
et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006; 130:632–638.
102. Kamal SM, Ismail A, Graham CS, He Q, Rasenack JW, Peters T,
et al. Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology 2004; 39:1721–1731.
103. Calleri G, Cariti G, Gaiottino F, De Rosa FG, Bargiacchi O, Audagnotto S,
et al. A short course of pegylated interferon-alpha in acute HCV hepatitis. J Viral Hepat 2007; 14:116–121.
104. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R,
et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358:958–965.
105. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr,
et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975–982.
106. Dominguez S, Ghosn J, Valantin MA, Schnuriger A, Simon A, Bonnard P,
et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS 2006; 20:1157–1161.
107. Matthews GV, Hellard M, Haber P, Yeung B, Marks P, Baker D,
et al. Characteristics and treatment outcomes among HIV-infected individuals in the Australian trial in acute hepatitis C. Clin Infect Dis 2009; 48:650–658.
108. Vogel M, Nattermann J, Baumgarten A, Klausen G, Bieniek B, Schewe K,
et al. Pegylated interferon-alpha for the treatment of sexually transmitted acute hepatitis C in HIV-infected individuals. Antivir Ther 2006; 11:1097–1101.
109. Hare B, Marks K, Luetkemeyer A, Charlebois E, Glesby M, Talal A,
et al.
Kinetically guided PED alfa-2a and RBV therapy for HIV+ adults with acute HCV infection [abstract 639].17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco.
110. Lambers F, van den Berk G, van der Meer J, Spijkerman I, Molenkamp R, Coutinho R,
et al.
Treatment outcome of acute HCV infection in HIV-infected MSM: effect of treatment length [abstract 641].17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco.
111. Vogel M, Dominguez S, Bhagani S, Azwa A, Page E, Guiguet M,
et al. Treatment of acute HCV infection in HIV-positive patients: experience from a multicentre European cohort. Antivir Ther 2010; 15:267–279.
112. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S,
et al. Protection against persistence of hepatitis C. Lancet 2002; 359:1478–1483.
113. Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M,
et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007; 21:1073–1089.
114. Vogel M, Page E, Matthews GV, Guiguet M, Dominguez S, Dore GJ,
et al.
Use of week 4 HCV RNA after acute HCV infection to predict chronic HCV infection [abstract 640].17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco, USA.
115. Kamal SM, Moustafa KN, Chen J, Fehr J, Abdel MA, Khalifa KE,
et al. Duration of peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology 2006; 43:923–931.
116. De Rosa FG, Bargiacchi O, Audagnotto S, Garazzino S, Cariti G, Calleri G,
et al. Twelve-week treatment of acute hepatitis C virus with pegylated interferon- alpha -2b in injection drug users. Clin Infect Dis 2007; 45:583–588.
117. Nattermann J, Vogel M, Baumgarten A, Naumann U, Stellbrink H-J, Danta M,
et al.
Genetic variation in IL28B and treatment-induced clearance of HCV in HCV/HIV coinfected patients [abstract 164].17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco, USA.
118. Pineda JA, Caruz A, Camacho A, Neukam K, Salas I, Mira J,
et al.
Interleukin 28 B genotype is a potent predictor of response to therapy with pegylated interferon plus ribavirin in HIV/HCV coinfected patients [abstract 656].17th Conference on Retroviruses and Opportunistic Infections (CROI); 16–19 February 2010; San Francisco, USA.
119. Nattermann J, Vogel M, Nischalke HD, Danta M, Ahlenstiel G, Michalk M,
et al. The transforming growth factor-beta high-producer genotype is associated with response to hepatitis C virus-specific therapy in HIV-positive patients with acute hepatitis C. AIDS 2008; 22:1287–1292.
120. Nattermann J, Vogel M, Berg T, Danta M, Axel B, Mayr C,
et al. Effect of the interleukin-6 C174G gene polymorphism on treatment of acute and chronic hepatitis C in human immunodeficiency virus coinfected patients. Hepatology 2007; 46:1016–1025.
121. Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O,
et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006; 166:1632–1641.
122. Marin B, Thiebaut R, Bucher HC, Rondeau V, Costagliola D, Dorrucci M,
et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 2009; 23:1743–1753.
123. Smit C, van den BC, Geskus R, Berkhout B, Coutinho R, Prins M. Risk of hepatitis-related mortality increased among hepatitis C virus/HIV-coinfected drug users compared with drug users infected only with hepatitis C virus: a 20-year prospective study. J Acquir Immune Defic Syndr 2008; 47:221–225.
124. van de Laar TJ, Molenkamp R, van den BC, Schinkel J, Beld MG, Prins M,
et al. Frequent HCV reinfection and superinfection in a cohort of injecting drug users in Amsterdam. J Hepatol 2009; 51:667–674.
125. Elford J. Changing patterns of sexual behaviour in the era of highly active antiretroviral therapy. Curr Opin Infect Dis 2006; 19:26–32.
126. Dore GJ, Hellard M, Matthews GV, Grebely J, Haber PS, Petoumenos K,
et al. Effective treatment of injecting drug users with recently acquired hepatitis C virus infection. Gastroenterology 2010; 138:123–135.
127. McHutchinson JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R,
et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360:1827–1838.
128. Gane E, Roberts S, Stedman C, Angus P, Ritchie B, Elston R,
et al.
Combination therapy with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor in HCV: safety, pharmacokinetics and virological results from INFORM-1 [abstract 193].60th Annual Meeting of the American Association for the Study of the Liver (AASLD); 30 October to 1 November 2009; Boston, USA.
129. Jones R, Brown D, Nelson M, Low E, Bhagani S, Atkins M,
et al. Re-emergent hepatitis C viremia after apparent clearance in HIV-positive men who have sex with men: reinfection or late recurrence? J Acquir Immune Defic Syndr 2010; 53:547–550.
130. Frederick T, Burian P, Terrault N, Cohen M, Augenbraun M, Young M,
et al. Factors associated with prevalent hepatitis C infection among HIV-infected women with no reported history of injection drug use: the Women's Interagency HIV study (WIHS). AIDS Patient Care STDS 2009; 23:915–923.
