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Prevalence and Incidence of Human Papillomavirus Infection in Men Having Sex With Men Enrolled in a Pre-exposure Prophylaxis Study: A Sub-study of the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales "Intervention Preventive de l'Exposition aux Risques avec et pour les hommes Gays" Trial
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Download the PDF here
Download the PDF here
Clinical Infectious Diseases, 1 January 2021 - pdf attached
Laurent Cotte,1,2,a David Veyer,3,a Isabelle Charreau,4 Helene Pere,3,5 Eric Cua,6 Diane Carette,4 Julie Chas,7 Catherine Capitant,4 Christian Chidiac,1,8
Jean-Francois Flejou,9,10 Sebastien Fouere,11 Isabelle Heard,12,13 Laurence Meyer,4,14,15 Julien Puech,16 Cecile Tremblay,17 Constance Delaugerre,18,19
and Jean-Michel Molina19,20
Abstract
Background
Human papillomavirus (HPV) infection is more frequent in men having sex with men (MSM) who are living with human immunodeficiency virus (HIV) than in MSM without HIV. There are currently no data regarding HPV infections in preexposure prophylaxis (PrEP)-using MSM.
Methods
MSM living without HIV who were enrolled in the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales "Intervention Preventive de l'Exposition aux Risques avec et pour les hommes Gays" PrEP study were prospectively enrolled. Anal, penile, and oral samples were collected at baseline and every 6 months for HPV detection and genotyping. Anal swabs for cytology were obtained at baseline and at 24 months.
Results
We enrolled 162 participants. The prevalences of any HPV genotypes at baseline were 92%, 32%, and 12% at the anal, penile, and oral sites, respectively. High-risk (HR) HPV genotypes were observed in 84%, 25%, and 10% of anal, penile, and oral baseline samples, respectively. Nonavalent HPV vaccine genotypes were observed in 77%, 22%, and 6% of anal, penile, and oral baseline samples, respectively. Multiple infections were observed in 76%, 17%, and 3% of cases at the anal, penile, and oral sites, respectively. The most frequent HR genotypes were HPV 53, 51, and 16 in anal samples; HPV 33, 39, and 73 in penile samples; and HPV 66 in oral samples. The incidence of any HPV genotype at the anal site was 86.2/1000 person-months and the incidence of HR-HPV genotypes was 72.3/1000 person-months. The baseline cytology was normal in 32% of cases and was classified as atypical squamous cells of undetermined significance, low-grade squamous intra-epithelial lesion, high-grade squamous intra-epithelial lesion (HSIL), and atypical squamous cells that cannot exclude HSIL in 23%, 40%, 5%, and 1% of cases, respectively.
Conclusions
PrEP users have a similar risk of HPV infection as MSM living with HIV and the risk is much higher than that previously reported in MSM living without HIV.
Human papillomavirus (HPV) is responsible for approximately 630 000 cancers worldwide each year. While most of the cases are reported in women, 60 000 HPV-related cancers occur annually in men (head and neck, 30 200; anal, 17 000; penile, 13 000) [1]. The incidence of anal, oral, and penile HPV-induced cancers appears to be consistently higher in people living with human immunodeficiency virus (HIV) than in the general population [2,-4]. The prevalence of HPV infections, HPV persistence, and the risk of developing HPV-induced cancers are also increased in men who have sex with men (MSM), as compared to heterosexual men [5, 6]. Among MSM, a higher HPV prevalence is consistently reported in patients living with HIV, as compared to those without HIV [2]. Consequently, the prevalence of anal dysplasia and high-grade anal intraepithelial lesions appears consistently higher in MSM living with HIV, as compared to those without HIV [7, 8].
As in the cervix, HPV16 is the most carcinogenic type in the anus [9, 10]. Paradoxically, the fraction of cancer attributable to HPV16 appears smaller in MSM living with HIV, as compared to those without HIV, probably due to the high frequency of multiple infections in MSM living with HIV [11]. The quadrivalent HPV vaccine Gardasil 4 (Merck, Sharp & Dohme), conferring immunity against low-risk (LR) HPV 6 and 11 and high-risk (HR) HPV 16 and 18, has demonstrated its efficacy against anal HPV infections and anal intraepithelial neoplasia in men [12, 13]. Therefore, the vaccination of males has been recommended in several countries. In France, HPV vaccination was initially recommended and reimbursed only for females between 12 and 20; since 2016, the HPV vaccine has also been available for MSM younger than 27 years. The benefit of the nonavalent Gardasil 9 vaccine (G9; Merck, Sharp & Dome), conferring immunity against LR-HPV 6 and 11 and HR-HPV 16, 18, 31, 33, 45, 52, and 58, has been less studied in MSM [14]. We report the molecular epidemiology of anal, oral, and penile HPV infections in MSM enrolled in the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales "Intervention Preventive de l'Exposition aux Risques avec et pour les hommes Gays" (ANRS IPERGAY) HIV preexposure prophylaxis (PrEP) study, and the potential impact of the G9 HPV vaccine in PrEP users.
Incidence and Clearance Over Time
Overall, 150 participants had at least 2 valid HPV genotyping samples. The median follow-up was 23 months (IQR, 18-24), for a total follow-up of 2913 PM.
At the anal site, 120/142 participants (85%) acquired at least 1 new HPV genotype, 107/139 (77%) acquired at least 1 new HR-HPV genotype, and 82/141 (58%) acquired at least 1 new LR-HPV genotype. The incidences of any new HPV, HR-HPV, and LR-HPV infections were 86.2/1000PM, 72.3/1000PM, and 44.3/1000PM, respectively. Meanwhile, 112/129 (87%) participants cleared at least 1 HPV genotype, with an overall clearance rate of 83.5 per 1000PM. The incidences of any new HPV, HR-HPV, and LR-HPV infection were similar in the treated (104.5/1000PM, 97.1/1000PM, and 65.1/1000PM, respectively) and in the placebo groups (79.1/1000PM, 62.2/1000PM, and 48.8/1000PM, respectively).
At the oral site, 34/144 (24%) participants acquired at least 1 new HPV genotype, 29/144 (20%) acquired at least 1 new HR-HPV genotype, and 11 /144 (8%) acquired at least 1 new LR-HPV genotype. The incidences of any new HPV, HR-HPV, and LR-HPV infections were 13.7/1000PM, 11.5/1000PM, and 4.1/1000PM, respectively. Meanwhile, 9/15 (60%) participants cleared at least 1 HPV genotype, with an overall clearance rate of 42.5/1000PM.
At the penile site, 42/115 (37%) participants acquired at least 1 new HPV genotype, 31/115 (27%) acquired at least 1 new HR-HPV genotype, and 25/99 (25%) acquired at least 1 new LR-HPV genotype. The incidences of any new HPV, HR-HPV, and LR-HPV infections were 22.0/1000PM, 15.4/1000PM, and 13.8/1000PM, respectively. Meanwhile, 31/39 (79%) participants cleared at least 1 HPV genotype, with an overall clearance rate of 82.0/1000PM. There were 9 genotypes that presented an incidence rate greater than 10/1000PM at the anal site, including HR-HPV genotypes HPV16, 18, 31, 51, 52, 53, and 59 and LR-HPV42 and 54. Incidence rates were much lower at the other sites, where HPV16 had the highest incidence rate. HPV16 also presented the lowest clearance rate (12.6/1000PM) at the anal site. The clearance rates were difficult to analyze at the other sites, due to the limited prevalences at these sites.
Table 3 summarizes the incidence and clearance rate of each genotype per site. Figure 2 presents the distribution of persisting, incident, intermittently detectable, and cleared HPV infections per genotype at the anal site.
DISCUSSION
PrEP-using MSM have a high rate of sexually transmitted infections [16]. However, there are limited data regarding HPV infections in this population. Our study reveals that HPV infections in PrEP users appear much closer to those of MSM living with HIV, as compared to those without HIV. Indeed, the prevalence (92%) and the incidence (86.2/1000PM) of anal HPV infections in this population were of the same order of magnitude as observed in patients living with HIV (74-95%) [8, 17,-21] and much higher than previously reported in MSM without HIV (57.5-71.5%) [8, 17, 19,-21]. Similarly, multiple HPV infections were found in 76% of participants, which is a higher rate than previously reported in MSM without HIV (17.6-47%) [17, 20,-23] and most participants (84%) harbored an HR-HPV genotype at baseline. As a consequence, anal dysplasia was also highly prevalent at baseline (67.5%) and the rate appeared similar to rates previously reported in MSM living with HIV (57.2%) [2], while only 13% of participants exhibited a normal cytology at their last follow-up. However, high-grade dysplasia (HSIL or ASC-H) was barely observed at baseline (5%) but significantly increased during follow-up (15%). Since HIV infection and immunodepression are independent factors associated with the progression of anal dysplasia, we cannot infer from these data that the resulting risk of anal carcinoma will be the same in these patients than in patients living with HIV [2, 24-26], but PrEP-using MSM should definitely be considered a high-risk population regarding anal HPV infection and the associated risk of complications.
Similarly, the overall prevalence of penile HPV infection appeared at the upper end of reported prevalences in MSM living with HIV [4, 19], much higher than previously reported in MSM without HIV [4, 19, 27]. Only 1 study previously reported a higher prevalence in MSM without HIV [23], but penile and anal samples were combined in that study, probably resulting in over-estimating penile infections. In comparison, the prevalence of oral HPV appeared relatively low despite a good performance of the sampling process, and was closer to what was previously reported in MSM without HIV [28-31] than in MSM living with HIV [28, 30, 31]. Whether this result could be related to the selection of participants in the IPERGAY study, where enrollment was based upon a history of unprotected anal sex with at least 2 partners during the prior 6 months, or to another phenomenon remains unclear.
The distribution of genotypes varied widely across the 3 sites. Unlike previous reports [29, 32,-34], multisite infections by the same genotypes were not uncommon (16%). Whether this difference was related to sexual practices in PrEP users remains unclear. The most frequent anal HR-HPV genotypes were HPV53, 51, and 16, which are genotypes frequently encountered both in MSM living with HIV [6, 8, 19,-21, 28, 32, 35,-37] or living without HIV [8, 17, 20, 22, 27, 36, 38]. Similarly, the most frequent penile HR-HPV genotypes, HPV33 and 39, are also frequently encountered in those living with HIV [6, 19]. However, while HR-HPV genotype HPV16 has been reported as the most frequent penile genotype in both MSM living with and without HIV [19], this genotype was barely observed at this site in our cohort. The distribution of oral genotypes was more difficult to analyze, due to the limited number of positive samples. Surprisingly, the most frequent LR-HPV genotype was HPV42, a genotype less frequently reported in the literature [30]. There was no clear explanation regarding the discrepancy in HPV genotype distributions across sites, since the probability of contact with a given genotype was probably the same whatever the site.
None of the participants were vaccinated against HPV. Despite the high prevalence of HPV infections in this population, 21% of participants were not infected by any of the G9 HPV genotypes at baseline, with no effect of age. Additionally, 4 of the 7 G9 HR-HPV genotypes presented a high incidence rate at the anal site, including HPV16 and 18, suggesting susceptibility to these genotypes. Similar trends have been previously reported both in MSM living with HIV [18, 34, 35, 39, 40] and living without HIV [3, 38, 40]. Thus, even if we cannot exclude the probability that most participants may have already encountered and cleared 1 or more G9 HPV genotypes, the G9 HPV vaccine could still have a theoretically preventive effect in this highly HPV-exposed population. However, the 2 most prevalent HR genotypes at the anal site, HPV53 (23%) and HPV51 (22%), are not present in the G9 vaccine. Both genotypes are frequently encountered in MSM living without HIV, as well as in those living with HIV. HPV53 is considered as possibly carcinogenic by the International Agency for Research on Cancer (group 2B), while HPV51 is considered as carcinogenic for humans (group 1). None of them has been shown to be involved in the etiology of anal cancer, while HPV16, the third most prevalent genotype in our study, is clearly associated with progression to cancer.
No clear pattern was observed among the different classes of ages. Indeed, there was no difference in the prevalence of any HPV, HR-HPV, any G9 HPV, and G9 HR-HPV genotypes in participants under and over 27 years old, suggesting that the age-based vaccination strategy currently recommended in France is not relevant.
This study has several strengths. Notably, it was a prospective and planned sub-study within a randomized trial. To our knowledge, this is the first study of HPV infection in PrEP-using MSM without HIV. The design of the study allowed us to make a site-specific prevalence analysis, as well as to estimate the HPV incidence. However, some limits should be noted: (1) the limited number of participants in this sub-study, as compared to the total number of participants; (2) the limited duration of follow-up, which precludes definitive conclusions about the incidence and evolution of cytological lesions; and (3) the performance of penile samples, which appeared less satisfactory (70%) than anal (97%) and oral (98%) samples.
In conclusion, PrEP users have a similar risk of HPV infection as MSM living with HIV. This finding suggests recommending similar anal cancer screening and HPV vaccine strategies in both populations.
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