Hepatitis C virus

HCV is a major global health problem affecting an estimated 115 million people worldwide, and 20%–30% of the 34 million people living with HIV/AIDS.3 If left untreated, 65%–80% of the affected people develop chronic HCV infection, which can in time progress to serious liver disease including cirrhosis, portal hypertension, liver decompensation and hepatocellular carcinoma (HCC). Globally, approximately 25% of cases of cirrhosis and HCC are attributed to HCV.4 HCV primarily is a bloodborne pathogen but the increasing number of HIV-positive MSM with acute HCV diagnosed in the early 2000s suggested that its epidemiology was changing.5 Using a phylogenetic approach, the independently reported HCV outbreaks in various large cities across Europe proved to be part of one large international MSM-specific HCV transmission network.6 Evolutionary analysis based on sequence homology of these MSM-specific HCV strains, implied incidental introductions but limited spread of HCV among MSM before 1996, followed by the rapid expansion of HCV transmission after 1996. This timescale coincides with the introduction of combination antiretroviral treatment (cART), less concern about HIV and increased sexual risk-taking among MSM. As the vast majority of MSM reported high-risk sexual behaviour in the absence of classical blood-related risk factors, it suggested that HCV was indeed an emerging STI among HIV-positive MSM.6

Increasing HCV incidence and prevalence rates have now been reported in HIV-positive MSM in Europe, North America, Australia and Asia.6–9 In the Netherlands, the HCV prevalence among HIV-positive MSM visiting the Amsterdam STI clinic gradually increased from 5.6% in 1995 to an alarming 20.9% in 2008.10 In the period 1984–2012, the HCV incidence among HIV-positive MSM participating in the Amsterdam Cohort Studies increased 10-fold from approximately 0.1/100 person-years (PY) before the introduction of cART to a stable 1.2/100 PY in 2010–2012.11 No incident HCV infections were found among the 1565 HIV-negative MSM. Globally, the HCV prevalence rate in HIV-positive MSM has increased significantly over time, and affects an estimated 6.7% and 40% of non-injecting and injecting MSM, respectively.12 Two studies, with pooled data of approximately 13 000 and 6000 HIV-positive MSM worldwide, revealed a threefold (from 0.42 to 1.34/100 PY between 1990 and 2012) and 20-fold (from 0.07 to 1.8/100 PY between 1991 and 2014) rise in HCV incidence among HIV-positive MSM in the era of cART.13 ,14 Although HIV infection is no prerequisite for sexually acquired HCV, HIV-negative MSM remain largely unaffected.11 ,15 ,16 Heterosexual transmission of HCV among monogamous couples is also rare, with an estimated maximum incidence rate of 1 per 190 000 sexual contacts or 0.07% per year. A higher risk of 0.4%–1.8% per year has been reported for heterosexuals with multiple partners, HIV coinfection or those at risk for STI.17

Sexual acquisition of HCV in HIV-positive MSM has been independently associated with unprotected anal intercourse (UAI), a higher number of sexual partners, recent (ulcerative) STIs, in particular lymphogranuloma venereum (LGV) and syphilis, group sex, fisting, rectal bleeding, the use of sex toys and/or anal enema and recreational drug use before or during sex7 ,9 ,18–21 (figure 1). Sexual HCV transmission requires exchange of HCV-infected body fluids across mucosal surfaces, most likely semen. Detection rates of HCV RNA in semen from men with chronic HCV infection vary between 10% and 44%, with the frequency increasing to 56.7% during longitudinal sampling.22 HCV RNA levels in blood and semen are highly correlated, with seminal levels typically being 4.0–5.0 log lower than those in blood.22 ,23 Although this suggests limited passive transfer of HCV RNA over the blood–semen barrier, the average ejaculate would contain 50–6630 IU of virus and exceeds the 10–20 HCV particles needed to establish productive infection through parenteral exposure.23 UAI with a higher number of partners directly enhances the chance of being exposed to HCV-infected semen, and hence the chance of acquiring HCV. Fisting, ulcerative STI, the use of anal enema and sex toys most likely facilitate HCV transmission by physically damaging the integrity of the anorectal mucosal, either via microabrasions or bleeding. Decreased mucosal integrity allows a more efficient transfer of the relatively low inoculum of HCV introduced by semen. Blood seems less likely as the causative infectious bodily fluid during sex, as the stratified squamous epithelium of the penis is basically impermeable to HCV and the penis itself almost never bleeds during sex. Small amounts of blood could be exchanged between multiple receptive partners in the context of group sex, if sex toys (or insertive partners) are shared without disinfection (or without renewing gloves or condoms) before changing partners.24 Non-injection recreational drug use, if not applied rectally, does not inflict direct mucosal damage, but in highly sexualised settings, drug-induced disinhibition might result in increased sexual risk-taking with multiple partners, longer sexual encounters or more traumatic sexual practices.25 Most HIV/HCV-infected MSM report two, three or more HCV-associated risk factors and suggest the presence of ‘core groups’ of high-risk MSM.10 ,20 ,21 Indeed in the Swiss Cohort Studies, location of MSM on the HIV phylogeny was predictive of both HCV incidence and prevalence and highlights the overlap in high-risk sexual networks for HCV and HIV.26 Of particular concern is the increased reporting of injection drug use (IDU) and needle-sharing among MSM at sex parties in the UK, also referred to as slamming.25 Previous studies investigating determinants of acute HCV among MSM typically had 10%–20% of MSM reporting IDU.9 ,18 ,21 Increasing popularity of IDU will provide an alternative more efficient mode of HCV transmission that further fuels the ongoing HCV epidemic among MSM.

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Figure 1

Proposed model for sexual transmission of hepatitis C virus (HCV) among men who have sex with men. HCV-infected semen is transmitted across the mucosal surface of the rectum, facilitated by factors that directly or indirectly cause physical or immunological deterioration of the natural mucosal barrier.

Why are HIV-infected MSM disproportionally affected compared with HIV-negative MSM? Rapid and irreversible immunological deterioration of the gastrointestinal mucosal barrier—the portal of entry for sexually acquired HCV—might increase host susceptibility to small inoculums of HCV, even in HIV-infected MSM with preserved CD4 counts.27 The latter could also explain the conflicting result regarding increased sexual acquisition of HCV with lower CD4 count (or CD4 nadir) in blood.7 ,18 ,19 HIV-positive MSM might also be more likely to shed HCV RNA in semen compared with men who are HIV negative as a consequence of higher HCV viral loads in blood.22 ,23 If individuals who are HIV positive indeed transmit HCV more easily, serosorting for HIV (ie, establishing HIV concordance before engaging in condomless sex) might attribute to a limited spread of HCV from individuals who are HIV positive to individuals who are HIV negative.28 Alternatively, the reason why we see few HCV infections in HIV-negative MSM might be largely stochastic. HIV has higher background levels and is more infectious through sex compared with HCV, resulting in HIV infection preceding HCV infection in the vast majority of MSM who engage in high-risk sexual practices.24 If true, the increased uptake of pre-exposure prophylaxis (PrEP), which proved highly successful in preventing HIV infection in MSM at high risk of becoming HIV infected, could eventually lead to the emergence of HCV in high-risk HIV-negative MSM using PrEP29 ,30 or post-exposure prophylaxis (PEP).31 HIV-negative MSM with sexually acquired HCV often report HIV-positive sexual partners,15 ,29 ,31 continuous introductions of HCV among the population without HIV might eventually result in an expanding HCV epidemic irrespective of HIV status. The increased popularity of Internet, mobile phone geosocial networking applications, MSM tourism and circuit (sex) parties may have provided an ideal platform for high-risk HIV-positive and HIV-negative MSM to extend their sexual networks.5 ,32 The formation of highly interconnected high-risk sexual networks may partly explain the successful expansion and rapid international dissemination of newly introduced STIs in recent years.6

Spontaneous resolution of HCV occurs in 25% (range 11%–49%) of individuals who are HIV negative, with female sex, favourable IL28B genotype, symptomatic infection and mode of acquisition as its most important positive predictors.33 ,34 Sexually acquired HCV infections generally have a more favourable outcome compared with HCV acquired through IDU.34 Nonetheless, spontaneous HCV clearance occurs in only 10%–15% of HIV-positive MSM.35 ,36 Second, HIV coinfection has been associated with rapid onset and accelerated progression to hepatic fibrosis.36 ,37 Convergence toward similar progression rates as observed during chronic infection, however, cannot be excluded.37 ,38 Third, individuals who have HIV coinfection have multiple risk factors for liver disease, including drug toxicity and metabolic liver disease.39 With the availability of highly effective direct-acting antivirals (DAAs), the outcome of HCV treatment in patients who have HIV/HCV coinfection has greatly improved: 12-week DAA combination regimens typically achieve sustained virological response (SVR) in 95%–100% of patients who have HIV/HCV coinfection.40 ,41 Compared with the era of interferon-based treatments, the medical need for early diagnosis and treatment might have become less stringent. However, deferring HCV treatment could induce disengagement in care and loss to follow-up, limit short-course treatment options and increase liver-related morbidity and mortality in HIV-coinfected MSM.24 ,39 From a public health perspective, less time spend with viral replication may prevent onward HCV transmission and curb the HCV epidemic among MSM (treatment for prevention). However, the HCV reinfection rate after SVR is typically 20 times higher than the initial HCV seroconversion rate.13 ,42 ,43 Mathematical modelling studies suggest that scaling up treatment cannot revert the HCV epidemic if high-risk behaviour continues to increase as it has over the last decade. Reducing high-risk behaviour, independent of treatment interventions, would be the most effective intervention for HIV-positive MSM.44 ,45 In addition, DAA treatment is costly and antiviral resistance might be lurking.46 Unfortunately, currently, there is a lack of evidence-based behavioural interventions that reduce HCV-associated risk behaviour among MSM. On the contrary, less concern about HCV and HIV given the availability of DAAs, cART and PrEP might result in continuous or renewed high-risk sexual behaviour and require altered strategies regarding sexual health counselling and the implementation of prevention measures in both HIV-positive and HIV-negative MSM.

Human papillomavirus

HPV is one of the most common STIs. About 40 HPV types can infect the human anogenital and upper digestive tract: low-risk HPV types (lrHPV) are associated with genital warts and mild dysplasia, while persistent infection with one or multiple high-risk HPV types (hrHPV) can cause high-grade dysplasia and progression to anogenital and oropharyngeal cancers.47 Early on in the HIV epidemic, it became evident that HPV-induced cervical cancers were more prevalent, more aggressive and occurred at younger age in women who were HIV positive compared with women who were HIV negative.48 Not until after the introduction of cART, there was a marked increase in the incidence of HPV-related anal cancers. The incidence of anal squamous cell carcinoma (ASCC) in HIV-positive MSM currently exceeds those of cervical cancer in women who are HIV negative before the introduction of pap screening.49

Approximately 80%–90% of ASCC is associated with hrHPV, in particular HPV-16.49 Other risk factors include HIV infection, the lifetime number of sexual partners, receptive anal intercourse, anogenital warts, smoking and older age.47 ,50 ,51 In the Netherlands, penile and anal hrHPV infections were found in 32% and 65% of HIV-positive and 16% and 45% of HIV-negative MSM.52 The incidence of penile and anal hrHPV in HIV-positive MSM were 1.5 times higher compared with HIV-negative MSM, and more often resulted in persistent anal but not penile hrHPV infection.53 A large meta-analysis confirmed that indeed the prevalence of anal hrHPV infection is significantly higher in HIV-positive MSM compared with HIV-negative MSM (73.5% vs 37.2%).49 Concordantly, the incidence of ASCC was significantly higher among HIV-positive MSM (45.9/100000 PY) compared with HIV-negative MSM (5.1/100000 PY) (figure 2)(reference 44). The age adjusted incidence rate of ASCC in the general population of the USA is 1.8/100000 PY.54 Although receptive anal sex is a strong predictor for anal hrHPV, heterosexual men and women who are HIV positive also have higher prevalence rates of anal HPV, and in recent years a higher chance of developing ASCC.55

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Figure 2

Incidence of anal squamous cell carcinoma in men who have sex with men, by HIV status. Reprinted with permission from Elsevier, Machalek et al.49 HAART, highly active antiretroviral therapy.

Men and women who are HIV positive are at particular risk for HPV- and HPV-related malignancies.56 ,57 ASCC commonly occurs at the transformation zone, where the squamous epithelium of the anal canal transitions in the columnar epithelium of the distal rectum.58 HIV might facilitate initial HPV infection through the disruption of epithelial tight junction.59 Decreased immunity due to HIV infection might hinder spontaneous HPV viral clearance, cause reactivation of latent HPV infection and/or result in faster progression to HPV-associated cancerous lesions.60 The ASCC incidence among HIV-positive MSM has increased from 21.8/100 000 PY to 77.8/100 000 PY pre-cART versus post-cART (figure 2).49 As there is no evidence that the incidence of hrHPV itself has increased in recent years, neither in MSM nor in heterosexuals with HIV, it suggests that immune restoration with cART does not (fully) prevent the increased risk of HPV-induced malignancies in an ageing population affected by HIV. It remains unclear to what extent CD4 nadir, time spent with low CD4 count and/or current CD4 count, contribute to HPV disease progression.41 ,55 ,56 Hence, the current recommendations to initiate cART as early as possible after HIV diagnosis might result in decreasing ASCC incidence among individuals who are HIV positive in the years to come.

ASCC is preceded by the development of precancerous lesions termed high-grade anal intraepithelial neoplasia (HGAIN).58 HGAIN is very common in HIV-positive MSM with a prevalence rate up to 50%.^w1 The estimated progression rate of HGAIN to ASCC is 1 in 377 patients per year, which would pose a substantial lifetime risk for, in particular, MSM who acquire HIV at a young age.41 Therefore, screening and treatment of HGAIN in risk groups, and prophylactic HPV vaccination of boys, in addition to girls, are subject of much debate. The current practice in HGAIN diagnostics is histopathological evaluation of suspect lesions visualised via high-resolution anoscopy. Although no official guidelines exist for the treatment of anal intraepithelial neoplasia (AIN), various studies indicate that the best treatment option for intra-anal lesions is ablation (electrocautery, infrared cautery, laser), whereas perianal lesions are best treated with the topical administration of imiquimod. However, efficacy of AIN treatment remains poor, with high recurrence rates, continuing diagnostics and repeated treatment sessions.^w2–w4 To evaluate the potential usefulness of ASCC screening programmes, large clinical trials (eg, the ANCHOR study and the LOPAC trial) are currently ongoing comparing drug treatment and/or ablative treatment with close observation (wait-and-see) in individuals who are HIV positive with biopsy-proven HGAIN. With regards to HPV vaccination, recently high population effectiveness against HPV was shown, with virtual eradication of all vaccine-targeted HPV types among (young) heterosexual men within a few years after vaccination of the young Australian female population.^w5 However, Australian findings also suggest that MSM likely receive little benefit from herd immunity in the heterosexual population and remain susceptible to HPV-associated disease.^w6 MSM would clearly benefit from HPV vaccination as HPV immunisation has shown to strongly reduce AIN, including HGAIN, in young MSM.^w7 On the other hand, MSM only represent a small fraction of the male population, which might not justify general male HPV vaccination. Targeted vaccination of MSM appears to be cost-effective, but its clinical impact could suffer from low vaccination coverage and the fact that sexual debut will often precede HPV vaccination.^w8,w9 To date, only a few countries have introduced HPV vaccination campaigns for boys, which in the USA includes catch up vaccination up to the age of 26, specifically for MSM.