Since 2000, sexual transmission of hepatitis C virus (HCV) has been ongoing among HIV-positive men who have sex with men (MSM).1,2 The incidence and prevalence of HCV among HIV-negative MSM have been low and stable over time.3–12 This is presumably explained by HIV itself and by different sexual behavior and sexual networks of HIV-positive versus HIV-negative MSM.13
A study among HIV-negative MSM attending the large sexually transmitted infection (STI) clinic in Amsterdam from 2007 to 2010 showed a stable HCV antibody (anti-HCV) prevalence of around 0.5%.5 However, recently an unexpectedly increased anti-HCV prevalence of 4.8% (95% confidence interval [CI], 2.9%–7.5%) was found at baseline among 375 HIV-negative MSM enrolled in the Amsterdam preexposure prophylaxis (PrEP) project (AMPrEP).14 Phylogenetic analysis among those who were HCV RNA positive (83.3%) showed that these MSM were infected with HCV strains already circulating among HIV-positive MSM, suggesting an overlap of sexual networks of HIV-positive and HIV-negative MSM. However, because AMPrEP participants were included based on their high risk to acquire HIV,15 they might not be representative of the larger population of HIV-negative MSM. Nevertheless, these findings are of concern because HCV may also be spreading unnoticed among HIV-negative MSM. Consequently, questions arose whether routine HCV testing should be offered to HIV-negative MSM at risk for STI.
We therefore measured the HCV prevalence among HIV-negative MSM attending the STI clinic in Amsterdam. In addition, the performance of the HCV-MOSAIC risk score, which was developed and validated to identify HIV-positive MSM with an acute HCV infection,16 was evaluated in HIV-negative MSM. This risk score might be of added value to assist HCV testing among HIV-negative MSM at high risk for HCV infection.
MATERIALS AND METHODS
Study Population and Procedures
Consecutive MSM attending the STI outpatient clinic of the Public Health Service of Amsterdam (hereafter referred to as “Amsterdam STI clinic”) for a new STI consultation in October 2016 were eligible for inclusion in our survey if they were HIV negative or opted out of HIV testing. They were offered HCV testing in addition to the STI-clinic's standard protocol17 and could opt out of HCV testing. They received the result of the HCV test. AMPrEP participants visiting for an extra STI consultation outside of the AMPrEP protocol were able to participate in our study. As part of this survey, all 6 questions included in the HCV-MOSAIC risk score16 were asked by the nurse or physician during consultation. Men who have sex with men who tested HCV positive completed an additional short questionnaire on traditional HCV risk factors, such as ever having received a blood transfusion.
The prevalence of HCV (anti-HCV positivity) observed in the 2016 survey was compared with the HCV prevalence found in 1877 HIV-negative MSM participating in (bi)annual cross-sectional anonymous surveys performed at the Amsterdam STI clinic from 2007 to 2012.5 Additional data were used from 370 consecutive HIV-negative MSM attending the Amsterdam STI clinic in 2015, whose stored sera were retrospectively and anonymously tested for anti-HCV for monitoring purposes. In addition, we used data from the most recent monitoring study among 513 HIV-negative MSM attending the Amsterdam STI clinic tested for anti-HCV in October 2017. In both monitoring studies, no additional data were collected. Only in the latter monitoring study, MSM received the result of the HCV test.
The Medical Ethics Review Committee of the Academic Medical Center in Amsterdam confirmed that the Medical Research Involving Human Subjects Act (WMO) did not apply to this survey (reference number W16_226 # 16.293).
All participants were tested for the presence of anti-HCV (LIAISON XL; Diasorin, Saluggia, Italy) and HCV RNA. Testing for HCV RNA was performed using a validated in-house polymerase chain reaction targeting a conserved part of the 5′ noncoding region and using an internal extraction control. Primers and probe have been described previously.18,19 The amplification was performed using Fast-Virus One step master mix (ThermoFisher/Life Technologies, Bleiswijk, the Netherlands) in a RotorGene (Qiagen, Hilden, Germany). All anti–HCV-positive test results were confirmed by Immunoblot (INNO-LIA HCV Score; Fujirebio Europe, Gent, Belgium). Acute, chronic, and cleared HCV infection were defined as being anti-HCV negative and RNA positive, both anti-HCV and RNA positive, and anti-HCV positive and RNA negative, respectively.
Prevalence of HCV infection and its 95% CI were calculated. Descriptive statistics were used to compare characteristics between HCV-positive and HCV-negative MSM. For each MSM, the HCV-MOSAIC risk score was calculated as described previously,16 and its performance was evaluated by calculating the sensitivity and specificity to predict acute and prevalent HCV infection using the optimal cutoff (≥2.0).16 Because the questions in the HCV-MOSAIC risk score refer to the last 6 or 12 months (behavior that corresponds with the time when an acute HCV infection was acquired), we also evaluated an adjusted risk score for prevalent HCV infections, in which the questions in the risk score refer to behavior over lifetime. The area under the receiver operating characteristic curve (AUROC) was calculated to assess accuracy of the risk score. The trend in HCV prevalence over time was modeled via logistic regression with calendar year as a continuous variable using restricted cubic splines. The knots were chosen based on the 5, 35, 65, and 95 percentiles. Analyses were performed using Stata version 1320 and R version 188.8.131.52P values less than 0.05 were considered statistically significant.
From the 3rd till 28th of October 2016, 561 MSM were eligible, of whom 508 (90.6%) were included. For those 53 who were not included, the exact reasons why they were not included were unknown. Four MSM were only tested for either HCV RNA or anti-HCV because insufficient material was collected and were therefore excluded from the analyses, leaving 504 MSM in total. Five MSM were anti-HCV positive (HCV prevalence, 1.0%; 95% CI, 0.4%–2.3%). All 504 MSM were HCV RNA negative; thus, all 5 HCV-positive MSM had a cleared infection. Two were already aware of their positive HCV status and had been successfully treated for the infection, and the other 3 had not been aware of their HCV infection and had spontaneously cleared the virus. One was a participant of the AMPrEP project. An additional questionnaire was completed by 3 of 5 HCV-positive MSM. These 3 MSM did not report any traditional risk factors. The median age and the proportion that reported HCV testing in the past were higher among HCV-positive MSM (46 years vs. 32 years [P = 0.02] and 40.0% vs. 6.6% [P = 0.03], respectively; Table 1). Other variables such as the proportion engaging in chemsex,22 condomless receptive anal intercourse (cRAI), and injecting drug use (IDU) were higher among those who were HCV positive, but these associations were not statistically significant (Table 1).
Performance of the HCV-MOSAIC Risk Score, October 2016
Because we did not find any acute HCV infections, we were unable to evaluate the performance of the HCV-MOSAIC risk score to detect acute HCV infections. When using this original HCV-MOSAIC score referring to recent behavior to detect prevalent instead of acute HCV infections, sensitivity and specificity were 20.0% (95% CI, 3.6%–62.4%) and 80.2% (95% CI, 76.4%–83.4%), respectively. The proportion to be tested (proportion of all MSM with a risk score of ≥2.0) was 19.8%, and the AUROC was 0.63 (95% CI, 0.38–0.87). When using the adjusted risk score (in which the questions refer to behavior over lifetime) to detect prevalent HCV infections, sensitivity became 80.0% (95% CI, 37.6%–96.4%) and specificity became 56.1% (95% CI, 51.7%–60.4%). The proportion to be tested was 44.2%, and the AUROC was 0.71 (95% CI, 0.51–0.90).
HCV Prevalence Over Time, 2007 to 2017
The overall anti-HCV prevalence among 3264 HIV-negative MSM participating in the (bi)annual cross-sectional anonymous surveys and monitoring studies of the Amsterdam STI clinic from 2007 to 2017 was 0.8% (26/3264; 95% CI, 0.5%–1.2%; range, 0.0%–1.7%) and did not change significantly over time (P = 0.55; Fig. 1).
Concerned by the high HCV prevalence found in HIV-negative MSM starting PrEP in our AMPrEP demonstration project, we measured the HCV prevalence among HIV-negative MSM attending the Amsterdam STI clinic. Anti-HCV prevalence was 1.0%, which was almost 5 times lower than the baseline AMPrEP prevalence (i.e., 4.8%). This confirms our hypothesis that HIV-negative MSM participating in AMPrEP are not representative of the larger population of HIV-negative MSM and have a higher prevalence of HCV infection. In addition, HCV prevalence remained stable over the last 10 years. Because we did not detect any acute HCV infections, we were unable to evaluate the performance of the HCV-MOSAIC risk score to identify acute infections among HIV-negative MSM. To predict anti-HCV positivity, we changed the time frame of the HCV-MOSAIC risk score questionnaire to behavior over lifetime instead of a recent period. The sensitivity and specificity to identify prevalent HCV infections in HIV-negative MSM were 80% and 56.1%, respectively. However, the CI around the sensitivity of the risk score is quite broad (37.6%–96.4%), as power was limited because we found only 5 HCV infections.
As opposed to MSM starting PrEP for whom regular HCV screening is advised in the Netherlands,23 we would not recommend routine HCV testing among the larger population of HIV-negative MSM, as HCV prevalence in the latter group is low and stable over time. We recommend continued periodic monitoring of anti-HCV prevalence among a random sample of the larger population of HIV-negative MSM, for timely detection of changes in HCV prevalence and adjustment of testing policy if necessary. When routine testing is deemed necessary, the adjusted HCV-MOSAIC risk score could be used to assist, limiting the number of men requiring testing. However, we must emphasize that a proportion of MSM with HCV infection will be missed when using the risk score because sensitivity was 80%.
Sexual transmission of HCV among MSM is still subject to debate. Many studies have shown an association between high-risk sexual practices, such as cRAI or fisting, and HCV acquisition among HIV-positive MSM, of whom the majority never injected drugs.13 Also, the association with certain recent STIs suggests a shared route of transmission. However, although the positivity rates of other STIs such as gonorrhea, syphilis, and lymphogranuloma venereum seem to increase among HIV-negative MSM attending Dutch STI clinics,24 this has not been the case for HCV, as we have shown in this study. This is in contrast with HIV-positive MSM, where the HCV incidence and prevalence have increased. This suggests that HIV increases the risk of sexually acquired HCV, which can be explained both biologically (e.g., HIV may cause immunologic changes to gastrointestinal mucosa, which increases susceptibility to HCV25) and behaviorally (e.g., HIV serosorting by HIV-positive MSM decreases the chance of HCV introduction into sexual networks of HIV-negative MSM). An alternative hypothesis may be that HIV is more easily transmitted through sex than HCV and therefore often precedes HCV infection in MSM.
In contrast with HIV-positive MSM, limited data on the possible risk factors for HCV acquisition among HIV-negative MSM are available. Among MSM starting PrEP in our AMPrEP demonstration project, prevalent HCV infection was associated with younger age, more partners with whom cRAI was reported, an STI in the preceding 6 months, recent IDU, and use of γ-hydroxybutyrate/γ-butyrolactone, mephedrone, and/or methamphetamine during sex.14 These associations are in line with those found in the few other studies among HIV-negative MSM10–12,26 and are also largely comparable to the risk factors for HCV among HIV-positive MSM.13,27 In our survey, although not statistically significant, which was probably due to the small number of HCV-positive MSM, the proportion of MSM engaging in chemsex, cRAI, or IDU was higher among those who were HCV positive compared with those who were HCV negative.
Although all participants were recruited at the Amsterdam STI clinic, a limitation of our study is that the HCV prevalence estimates we used were derived from 4 different studies, which could have influenced the comparability. However, because the methodology of these studies only slightly differed, the influence on the comparability will have been limited.
In conclusion, HCV antibody prevalence among HIV-negative MSM attending the Amsterdam STI clinic in October 2016 was 1.0% and we did not observe a significant trend in HCV prevalence over time. Therefore, we do not recommend routine HCV screening of HIV-negative MSM at the STI clinic, but periodic monitoring of HCV prevalence remains important.
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