The Prevalence of High Carcinogenic Risk of HPV Genotypes among HIV-Positive and HIV-Negative MSM from Russia

Ilia Beliakov, Maria Senina, Yuriy Tyulenev, Elena Novoselova, Viktor Surovtsev, Alexander Guschin
Canadian Journal «Hindawi»
02.06.2021
Скачать

1. Introduction


Human papillomavirus (HPV) infection is the most common sexually transmitted infection (STI) worldwide. Mucosal HPV types from the alpha-genus infect squamous stratified epithelium from the mucosal tissues, and some infections may persist for many years with the potential to cause cancer of the cervix, vulva, vagina, penis, oropharynx, anus, and rectum [1, 2]. The HPV-attributable anogenital cancer includes 8500 vulva, 12000 vagina 35000 anus (half occurring in men), and 13000 penis. Anal squamous cell cancer, biologically similar to cervical cancer, is rare, but its incidence is increasing [3]. Almost all cervical cancer and more than 80% of anal cancer are attributable to high-risk HPV (HR HPV) infection including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 [4] and are mainly associated with HPV16 and HPV18 [5, 6].

These high-risk genotypes of HPV were identified to be distributed with different prevalence in both women and men with lesions or abnormal cytology worldwide [4, 7, 8]. Hindawi Canadian Journal of Infectious Diseases and Medical Microbiology Volume 2021, Article ID 6641888, 6 pages https://doi.org/10.1155/2021/6641888 ). The prevalence of HPV infection in heterosexual men and MSM in the Russian population was reported previously [9–11]. Also, infection of HPV and HSV I/II was evaluated in people living with human immunodeficiency virus or having high-risk sexual behavior including MSM from Russia [12, 13]. Comparison of HPV genotype prevalence and association with HIV status of MSM was previously reported in several populations [8, 14, 15]. However, there are no estimates of the prevalence of anal HPV and the distribution of high-risk HPV genotypes among HIV-negative and HIVpositive MSM from Russia [10, 11].

The HPV vaccines have been shown to be effective in preventing HPV infection and HPV-related low- and highgrade squamous intraepithelial lesions and cancer among both women and men [16, 17], and the 9-valent HPV vaccine has been shown to have a significantly increased potential impact compared with the quadrivalent vaccine among MSM [18]. The spectrum of high prevalent genotypes of HPV may be different in HIV-positive and HIV-negative MSM from Russia and influences the vaccine development [10, 11, 13].

HPV vaccination (bi- and quadrivalent HPV vaccines) is currently approved only for women in Russia. MSM do not receive the same benefits as heterosexual men from the herd effect of immunity from HPV vaccinations in girls [19, 20]. HPV vaccination is important among previously unvaccinated HIV-positive MSM aged up to and including 45 years [21–23].

2. Methods


2.1. Study Design. A cross-sectional study was conducted in Moscow, Russia, from November 2018 to October 2019. Participants were recruited by the nonprofit public organization “Step Fund” observed at the Moscow City Center for the Prevention and Control of AIDS and the Moscow Regional CDC. This study was approved by the Ethics Committee of the Institutional Review Board of the University of Peoples’ Friendship University (RUDN University) of Russia, and written informed consent was obtained from each participant.

2.2. Data Collection. Participants were interviewed by well-trained health staff, and our special questionnaire was used to collect epidemiological data. Sociodemographic characteristics including age, past STIs (HPV and genital herpes), and CMV coinfection were collected. Participants were also asked about their behavioral characteristics including sexual orientation, sexual risks, and sexual behaviors.

2.3. Sample Collection and Laboratory Tests. Participants were asked to self-collect biomaterial from the anal canal using a regular flocked swab as described previously [11, 24] and store it in a universal transport media (NextBio, Russia) at −20°C.

Total DNA extraction was performed on 200 μl of a sample using the MagnoPrime FAST kit (NextBio, IVD, Russia) on the Microlab STARLet platform (Hamilton Bonaduz AG, Switzerland) and eluted in 100 μl TE buffer. 10 μl of each DNA sample was analyzed using the AmpliPrime HR HPV genotyping system (NextBio, IVD, Russia), allowing for the detection of 14 high cancer risk HPV genotypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).

HSV and CMV DNA detection was performed in DNA from anal swabs of MSM participants both with AmpliPrime HSV/CMV kit (NextBio, IVD, Russia) and with reference kit AmpliSens HSV I, II-FL (Central Research Institute of Epidemiology, IVD, Russia).

2.4. Statistical Analyses. Statistical analysis was evaluated with suitable statistical criteria. Fisher exact test and chisquared test were used to compare the distribution of categorical variables. A two-sided p value.

3. Results


3.1. Sociodemographic Characteristics. A total of 60 HIV-positive and 60 HIV-negative MSM participants were included in the study. The median age was 29 years (interquartile range (IQR), 22–33.5) for HIV-positives and 33 years (IQR: 26–34) for HIV-negatives (Table 1).

3.2. Sexual Orientation. The HIV-positive participants declared their sexual orientation as homosexual (73.3%) and bisexual (26.6%). The sexual orientation reported by HIV-negative MSM was 68.3% homosexual and 31.6% bisexual.

3.3. Prevalence of HPV Infection in HIV-Positive and HIV-Negative MSM. Overall, the prevalence of high-risk HPV types was 73.3% among HIV-positive participants and 61.7% among HIV-negative men (p = 0.18) (Table 1). We found that multiple HPV types were not significantly more frequent in the group of HIV-positive MSM (p = 0.2). HPV genotyping data are presented in Figure 1.

Asterisk marks the positive correlation of HPV genotype and HIV status. The Fisher exact test analysis of HPV genotyping data revealed the significant association of five HR HPV genotypes with the HIV-positive status of the participants (Figure 1): HPV16 (p = 0.028), HPV18 (p = 0.00006), HPV58 (p = 0.003), HPV33 (p = 0.003), and HPV39 (p = 0.026). For other HPV genotypes, no significant correlations were shown.

3.4. Age and HR HPV Infection Depending on the HIV Status. We analyzed HPV infection prevalence in the two age groups: <30 years and ≥30. Among our participants. The prevalence of anal HPV infection was the smallest within the 30- to 39-year interval (data not shown). The prevalence of any of HR HPV among HIV positive participants was not significantly different: 44.2% (19/43) among those under 30 years old versus 56.8% (21/37) among the participants over 30 years (p = 0.27) and increased with age similar to HIV infection: 45.1% (MSM under 30) vs. 57.1% (MSM over 30).

Influence of risk factors on HIV-infection Total (n = 120) HIV-negative (n = 60) HIV-positive (n = 60) p value
No % No. % No. %
Demographic characteristics
Median age (IRQ)# 30 (24.5–34) 33 (26–34) 29 (22–33.5) 0.2
Age group <30 71 59.2 39 65 32 53.3
≥30 49 40.8 21 35 28 46.7
Sexual behavior
No. of lifetime male sex partners <100 47 41 26 47 21 35 0.16
100–500 64 54 32 50 32 58 0.38
>500 9 9 2 8 7 10 0.69
Median no. of anal sex partners last 6 months
No. of anal sex partners last 6 months ≤1 22 18 10 17 12 20 0.35
2–5 46 38 25 42 21 35 0.46
2–5 52 43 25 42 27 45 0.71
Study results
HPV infection vs HPV-negative 80 66.7 40 66.7 40 66.7 1
Multiple∗∗ HPV infection 66.7 50 34 56.7 26 43.3 0.044*
Single HPV infection 20 16.7 6 10 14 23.3
HPV16 27 22.5 8 13.3 19 31.7 0.028*
HPV18 23 19.2 3 5 20 33.3 0.00006*
HPV58 13 10.8 2 3.3 11 18.3 0.003*
HPV33 18 15 5 8.3 13 21.7 0.019*
HPV39 15 12.5 4 6.7 11 18.3 0.026*
HIV-positive MSM within age groups <30 71 59.2
≥30 49 40.8
Any HR HPV-positive within age groups <30 43 70.4 24 55.8 19 44.2 0.27
≥30 37 63.3 16 43.2 21 56.8
Co-infections
HSV 14 11.7 7 11.7 7 11.7 1
HSV I 4 3.3 3 5 1 1.7 0.37
HSV II 10 8.3 4 6.7 6 10 0.5
CMV 2 1.7 0 0 2 3.3
IQR: interquartile range. ∗A two-sided p value <0.05 was considered statistically significant; ∗∗multiple HPV: two and more HPV types.

Англ_Статья ВПЧ Картинка.pngPicture

Figure 1: HPV genotypes in HIV-positive and HIV-negative MSM (N = 120). Asterisk marks the significant correlation of HPV genotype and HIV status.

3.5. HSV and CMV Testing. HSV I/II was found in 11.7% (7/ 60) of HIV-positive participants (HSV I: 1/60, 1.7%; HSV II: 6/60, 10%) and in 11.7% (7/60) of HIV-negative (HSV I: 3/ 60, 5%; HSV II: 4/60, 6.7%). CMV DNA was identified in two HIV-positive participants (2/60, 3.3%), and no CMV was detected in HIV-negative participants.

4. Discussion


In this study, we showed the prevalence of anal HPV infection, genotype distribution, and the risk factors associated with the infection among MSM with or without HIV from Moscow, Russia. The average age in the two groups of our study was nearly equal (29.8 vs. 28.7 years). This study results confirmed data obtained from similar observations on the MSM population from Holland [25] and Russia [11]—HIV infection correlates with HPV infection.

HSV and CMV are known as the most frequent opportunistic infections among HIV-positive people, especially among MSM. It was previously shown by different authors HSV I/II and CMV coinfection in HIV-positive and HIV-negative MSM [26, 27]. Our data revealed a lower rate of HSV 1 coinfection in HIV-positive MSM in comparison with those in HIV-negative MSM (HSV1: 1.7% vs. 5%), and CMV was detected only in the HIV-positive group.

On the other side, the HIV-positive MSM tended to have more sexual partners and more sex episodes per lifetime than HIV-negative MSM [25]. We observed nearly equal sexual activity with both criteria: “a number of anal sex partners in the last 6 months” and “a number of lifetime male sex partners” in HIV-positive and HIV-negative groups. No significant correlation in sexual activity of MSM was observed in HIV-positive and HIV-negative groups. That might be due to the small number of participants in our study. It should be noted that the study participants had no health complaints at the moment of data and sample collection while CMV infections in the colon are common in HIV-infected people, often accompanied by anal ulcers in MSM.

It was found that HPV infection was associated with MSM and was detected with a high frequency (67.7%) regardless of HIV status. The most prevalent HR HPV genotypes reported in this study were HPV18 (33.3%), HPV16 (31.7%), HPV56 (28.3%), and HPV33 (21.7%) for HIV-positive MSM and HPV51 (20%), HPV56 (23.3%), and HPV66 (18.3%) for HIV-negative MSM. HPV16/18 previously showed 31.7% among MSM [11] compared to our data (40.8% (49/120) of all MSM tested). HPV16/18 were detected in the HIV-negative MSM group in 16.7% in the present study vs. 23% in the Wirtz study, and in the HIVpositive group, HPV16/18 were observed in 65% in our study vs. 41.4% in the Wirtz study [11].

We revealed association of five high-risk HPV genotypes with HIV status of MSM: HPV16 (p = 0.028), HPV18 (p = 0.00006), HPV58 (p = 0.003), HPV33 (p = 0.019), and HPV39 (p = 0.026). One of the reasons for the correlation between the detection of HPV coinfection as previously published was the lower rate of HPV clearance in HIV-positive men [28, 29].

The higher rate of HPV associated with anal cancer incidence worldwide was observed among HIV-positive MSM (46 per 100,000 per year) compared to HIV-negative MSM (5 per 100,000 per year) [8, 24, 28].

There were several limitations to the current study. First of all, the selection of the study participants was not random. Due to the limitation of time of the study, we restricted the number of participants to 60 HIV-positive MSM and also randomly chose an equal number of participants from a bigger HIV-negative group. Second, the risk behaviors were measured based on self-report, which might lead to information bias. Third, although health professionals were trained using a standard protocol, the self-collection of anal canal cell samples might not be completely successful, and the test kit for HPV included 14 genotypes, which might together lead to an underestimation of the prevalence.

Cancer prevention of HIV-positive MSM highly depends on HR HPV vaccination. The majority of anal cancer cases associated with HPV 16/18 types were underrepresented in HIV-positive MSM diagnosed with anal cancers. Only several or few studies were published for now about HPV prevalence in anal cancer among HIV-positive MSM (HPV16: 67%; HPV18: 24%; HPV 31/33/45/52/58: 26%) and more thorough investigations of HPV genotypes should be performed on MSM anal cancers [15, 30]. HPV16/18-positive, HIV-positive MSM were detected in 48.3% while HPV16/18-positive, HIV-negative MSM were detected in only 20% in our study. Probably, HPV unvaccinated MSM more frequently coinfected both HPV and HIV. For the current vaccines present on the market, the nine-valent vaccine can protect from nearly 100% of described previously HR HPV in anal cancers of MSM (for cardasil9: 16, 18, 31, 33, 45, 52, and 58). We revealed a statistically significant association of five HR HPVs infections with HIV-positive MSM: HPV16, HPV18, HPV58, HPV33, and HPV39 in this study population.

HPV vaccination is not approved for men in Russia [16–18]: the 4-valent Gardasil (HPV 6, 11, 16, and 18) (Merck) vaccine is routinely prescribed for women vaccination and the nine-valent vaccine is not yet approved in Russia. The only HPV39 was not included in vaccines available on the market. According to recent data, about 7% of HIV-positive anal carcinomas contain HPV39 genotype [30]. This is an important issue that requires further detailed study: HPV vaccination in young and old MSM for the prevention of cancer associated with HPV [19] in Russia.

Abbreviations


HR HPV: High-risk human papillomavirus

MSM: Men who have sex with men

STI: Sexually transmitted infection

IVD: In vitro diagnostic

HSV: Herpes simplex virus

HIV: Human immunodeficiency virus

CMV: Cytomegalovirus

AIN: Anal intraepithelial neoplasia.

Data Availability


The data used to support the findings of this study are available from the corresponding author upon request.

Ethical Approval


The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

Conflicts of Interest


The authors declare that they have no conflicts of interest.

Acknowledgments


The authors thank all the participants for their contribution to the study. This study was supported by the Ministry of Education and Science of the Russian Federation, project no. 03.G25.31.0226, March 3, 2017.

References


[1] H. zur Hausen, “Human papillomaviruses in the pathogenesis of anogenital cancer,” Virology, vol. 184, no. 9, pp. 9–13, 1991.

[2] E. Schwarz, U. K. Freese, L. Gissmann et al., “Structure and transcription of human papillomavirus sequences in cervical carcinoma cells,” Nature, vol. 314, no. 3, pp. 111–114, 1985.

[3] C. de Martel, M. Plummer, J. Vignat, and S. Franceschi, “Worldwide burden of cancer attributable to HPV by site, country and HPV type,” International Journal of Cancer, vol. 141, no. 8, pp. 664–670, 2017.

[4] M. Arbyn, M. Tommasino, C. Depuydt, and J. Dillner, “Are 20 human papillomavirus types causing cervical cancer?” 7e Journal of Pathology, vol. 234, no. 12, pp. 431–435, 2014.

[5] B. E. Hoots, J. M. Palefsky, J. M. Pimenta, and J. S. Smith, “Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions,” International Journal of Cancer, vol. 124, no. 5, pp. 2375–2383, 2009.

[6] M. Plummer et al., “Global burden of cancers attributable to infections in 2012: a synthetic analysis,” 7e Lancet Global Health, vol. 4, pp. e609–e616, 2016.

[7] M. Arbyn, A. Anttila, J. Jordan et al., “European guidelines for quality assurance in cervical cancer screening. Second editionsummary document,” Annals of Oncology, vol. 21, no. 3, pp. 448–458, 2010.

[8] D. A. Machalek, M. Poynten, F. Jin et al., “Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis,” 7e Lancet Oncology, vol. 13, no. 5, pp. 487–500, 2012.

[9] V. Smelov, K. M. Elfstrom, C. Eklund, O. Sokolova, and J. Dillner, “Determinants of the presence of human papillomaviruses in the anal canal of Russian men,” Journal of Medical Virology, vol. 90, no. 10, pp. 1643–1650, 2018.

[10] V. Smelov, R. Muwonge, O. Sokolova et al., “Beta and gamma human papillomaviruses in anal and genital sites among men: prevalence and determinants,” Scientific Reports, vol. 8, no. 5, p. 8241, 2018.

[11] A. L. Wirtz, C. E. Zelaya, A. Peryshkina et al., “Anal human papillomavirus and HIV: a cross-sectional study among men who have sex with men in Moscow, Russia, 2012–2013,” Eurosurveillance, vol. 20, no. 4, 2015.

[12] Y. A. Amirkhanian, J. A. Kelly, A. A. Kukharsky et al., “Predictors of HIV risk behavior among Russian men who have sex with men: an emerging epidemic,” AIDS-Acquired Immuno Deficiency Syndrome, vol. 15, no. 3, pp. 407–412, 2001.

[13] S. Baral, D. Kizub, N. F. Masenior et al., “Male sex workers in Moscow, Russia: a pilot study of demographics, substance use patterns, and prevalence of HIV-1 and sexually transmitted infections,” AIDS Care, vol. 22, no. 1, pp. 112–118, 2010.

[14] X. Liu, H. Lin, X. Chen et al., “Prevalence and genotypes of anal human papillomavirus infection among HIV-positive vs. HIV-negative men in Taizhou, China,” Epidemiology and Infection, vol. 147, no. 1, p. e117, 2019.

[15] C. de Martel, M. S. Shiels, S. Franceschi et al., “Cancers attributable to infections among adults with HIV in the United States,” AIDS-Acquired Immuno Deficiency Syndrome, vol. 29, no. 10, pp. 2173–2181, 2018.

[16] M. Arbyn, L. Xu, C. Simoens, and P. P. L. Martin-Hirsch, “Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors,” Cochrane Database of Systematic Reviews, vol. 5, no. 5, Article ID CD009069, 2018.

[17] E. J. Crosbie, M. H. Einstein, S. Franceschi, and H. C. Kitchener, “Human papillomavirus and cervical cancer,” Lancet, vol. 382, no. 7, pp. 889–899, 2013.

[18] A. S. Forster and R. Gilson, “Challenges to optimising uptake and delivery of a HPV vaccination programme for men who have sex with men,” Human Vaccines & Immunotherapeutics, vol. 15, pp. 1541–1543, 2019.

[19] M. Drolet, E. Benard, N. Perez, and M. Brisson, “HPV ´ Vaccination Impact Study Group. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis,” Lancet, vol. 394, no. 10, pp. 497– 509, 2019.

[20] G. L. Mortensen, “Drivers and barriers to acceptance of human-papillomavirus vaccination among young women: a qualitative and quantitative study,” BMC Public Health, vol. 10, no. 2, p. 68, 2010.

[21] M. A. Gerend, K. Madkins, G. Phillips, and B. Mustanski, “Predictors of human papillomavirus vaccination among young men who have sex with men,” Sexually Transmitted Diseases, vol. 43, no. 3, pp. 185–191, 2016.

[22] A. Lin, K. J. Ong, P. Hobbelen et al., “Impact and cost-effectiveness of selective human papillomavirus vaccination of men who have sex with men,” Clinical Infectious Diseases, vol. 64, no. 5, pp. 580–588, 2017.

[23] Joint Committee on Vaccination and Immunisation, JCVI statement on HPV vaccination of men who have sex with men 2015 [Available from: 2015, https://www.gov.uk/government/ publications/jcvi-statement-on-hpv-vaccination-of-men-whohave-sex-with-men].

[24] M. K. L. Poon, J. P. H. Wong, A. T. W. Li et al., “HIV-positive MSM’s knowledge of HPV and anal cancer self-sampling: a scoping review,” Current Oncology, vol. 25, no. 2, pp. e83–e89, 2018.

[25] E. Marra, A. King, E. van Logchem et al., “Anal HPV 16 and 18 viral load: a comparison between HIV-negative and -positive MSM and association with persistence,” Journal of Medical Virology, vol. 90, no. 1, pp. 76–83, 2018.

[26] W. Borena, S. Kruis, M. Kitchen et al., “Anal Ureaplasma spp. positivity among HIV positive men who have sex with men may be associated with high-risk-type HPV infections,” International Journal of Infectious Diseases, vol. 84, no. 7, pp. 75–79, 2019.

[27] L. E. Nelson, W. Tharao, W. Husbands et al., The epidemiology of HIV and other sexually transmitted infections in African, Caribbean and Black men in Toronto, Canada,” BMC Infectious Diseases, vol. 19, no. 3, p. 294, 2019.

[28] L. Darwich, S. Videla, M. P. Cañadas et al., “HIV-HPV Team, Distribution of human papillomavirus genotypes in anal cytological and histological specimens from HIV-infected men who have sex with men and men who have sex with women,” Diseases of the Colon & Rectum, vol. 56, no. 9, pp. 1043–1052, 2013.

[29] P. Patel, T. Bush, E. M. Kojic et al., “Prevalence, incidence, and clearance of anal high-risk human papillomavirus infection among HIV-infected men in the SUN study,” 7e Journal of Infectious Diseases, vol. 217, no. 6, pp. 953–963, 2018.

[30] C. Lin, S. Franceschi, and G. M. Clifford, “Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis,” 7e Lancet Infectious Diseases, vol. 18, no. 2, pp. 198–206, 2018.

Наборы реагентов, упоминаемых в публикации