The mean (SD) age at enrollment was 28.8 (6.9) years for HIV-positive and 28.9 (7.4) years for HIV-negative MSM (P = 0.9). None reported a history of cancers, and 14% were current smokers. Mean (SD) age at first sex was 18.0 (3.7) years for HIV-positive and 18.8 (3.7) years for HIV-negative MSM (P = 0.11). A history of having >5 lifetime sex partners was reported by 91.1% of HIV-positive MSM and 77.2% of HIV-negative MSM.
During the 3 months before study entry, 25.2% of HIV-negative MSM had at least 3 sexual partners compared with 8.1% of HIV-positive MSM (P = 0.005). Sex acts of ≥3 per week in the past 3 months were reported by 13.0% of HIV-negative and 9.8% of HIV-positive MSM (P = 0.32). Among those who practiced receptive anal sex in the past 3 months, 63.9% of HIV-positive MSM and 59.0% of HIV-negative MSM reported always using condoms (P = 0.82).
Among 123 HIV-positive MSM at baseline, the mean (SD) CD4 count was 353 (146) cells per cubic millimeter and 10% had plasma HIV RNA <40 copies per milliliter. At month 12, the mean (SD) CD4 count was 388 (130) cells per cubic millimeter and 33% had plasma HIV RNA <40 copies per milliliter. HAART use was reported by 13% of MSM at baseline and 47% of MSM at month 12. Plasma HIV RNA <40 copies per milliliter was achieved by 69% of those who were on HAART at baseline and 69% of those who reported HAART use at month 12.
Condyloma acuminata was identified in 15.5% of HIV-positive MSM and 13.8% of HIV-negative MSM, and the most common location was the perianal area (12.6%).
Anal HPV Prevalence and Incidence
Prevalent anal infection with any HPV type was detected in 85% of HIV-positive and 58.5% of HIV-negative MSM (P < 0.0001). The median number of HPV types was 3 [interquartile range (IQR), 2–5] for HIV-positive MSM and 3 (IQR, 2–4) for HIV-negative MSM.
Table 2 shows the prevalence and incidence of type-specific, high-risk, anal HPV infection among MSM, by baseline HIV status. Prevalent infection with any high-risk HPV type was identified in 57.5% of HIV-positive and 36.6% of HIV-negative MSM (P = 0.001). The median number of high-risk HPV types was 2.5 (IQR, 2–3) for HIV-positive and 2 (IQR, 2–3) for HIV-negative MSM.
HPV 16 was the most common high-risk HPV type detected in both HIV-positive MSM (22.5%) and HIV-negative MSM (9.8%). The other common high-risk types in HIV-positive MSM included HPV types 68 (13.3%), 58 (10.3%), 51 (10.3%), 39 (10.0%), and 18 (10.0%). For HIV-negative MSM, the other common high-risk types included HPV types 51 (8.1%), 52 (6.5%), 59 (5.7%), and 39 (5.7%). Compared with HIV-negative MSM, HIV-positive MSM had higher prevalence of high-risk types 16 (P = 0.008) and 68 (P = 0.015).
Among high-risk HPV types, HPV type 16 had the highest incidence of 16.1 episodes/1000 person-months in HIV-positive MSM, whereas HPV type 68 had the highest incidence of 8.3 episodes/1000 person-months in HIV-negative MSM. The incidence rate of any high-risk HPV type was higher in HIV-positive MSM than in HIV-negative MSM (64.9 vs. 28.2/1000 person-months, IRR, 2.3, 95% CI: 1.3 to 4.2, P = 0.008). There was a trend for higher incidence of HPV type 16 in HIV-positive MSM (IRR, 2.6, 95% CI: 0.98 to 7.1) than in HIV-negative MSM, but this was not statistically significant (P = 0.058). For non–high-risk HPV types, HPV type 6 was the only type with a significantly higher incidence rate in HIV-positive MSM compared with HIV-negative MSM (11.6 vs. 2.5/1000 person-months, P = 0.03).
Anal HPV Clearance and Persistence
Among HIV-positive MSM, high-risk HPV types 16, 68, and 51, which had the highest prevalence and highest incidence rates, showed low clearance rates of 52.0, 70.2, and 42.9 cleared episodes/1000 person-months, respectively (Table 3). The median time to clearance was 12.6 months for HPV type 16, 10.9 months for HPV type 68, and 11.3 months for HPV type 51. For HIV-negative MSM, HPV 16, the high-risk type with the highest prevalence and incidence rate, had a clearance rate of 101.2 cleared episodes/1000 person-months and a median time to clearance of 11.1 months. The CRR for HPV type 16 was 0.51 (95% CI: 0.22 to 1.22, P = 0.15) among HIV-positive compared with HIV-negative MSM. For HPV type 68, HIV-positive MSM had 70.2 cleared episodes/1000 person-months vs. 16.3 cleared episodes/1000 person-months among HIV-negative MSM. The CRR for HPV type 68 was 4.32 (95% CI: 0.66 to 28.2, P = 0.13).
HPV persistence was highest for high-risk HPV types 16 (16.7%), 68 (12.5%), and 51 (11.5%) in HIV-positive MSM and HPV types 68 (7.6%), 18 (3.8%), and 39 (3.8%) in HIV-negative MSM. Persistence of high-risk HPV types 16 (P < 0.001) and 51 (P = 0.001) was higher in HIV-positive MSM than in HIV-negative MSM. In addition, HIV-positive MSM had higher persistence of any high-risk HPV type (49.0% vs. 19.0%, P < 0.001) and higher persistence of multiple, high-risk HPV types (22.9% vs. 5.1%, P = 0.001) than HIV-negative MSM.
Risk Factors for Persistence of at Least 1 Specific Anal, High-Risk HPV Type
In a univariate model, HIV-positive status (OR: 4.09, 95% CI: 2.05 to 8.16, P < 0.001) and smoking (OR: 1.65, 95% CI: 1.05 to 2.60, P = 0.029) increased the risk of having any anal, high-risk HPV persistence in all MSM (Table 4). Current age, age at sexual debut, condom use for receptive anal intercourse, number of sex acts per week, and number of sex partners in the previous 3 months were not significantly associated with any high-risk HPV persistence in this univariate model. In multivariate analysis, HIV-positive status remained significantly associated with any high-risk HPV persistence with an OR of 4.45 (95% CI: 2.11 to 9.4, P < 0.001).
For HIV-positive MSM, a univariate model identified smoking (OR: 3.4, 95% CI: 1.25 to 9.22, P = 0.016) as a risk factor for persistence of any high-risk HPV infection. Current age between 24 and 29 years was associated with a trend for an increased risk of any high-risk HPV persistence (OR: 4.58, 95% CI: 1.28 to 16.4, P = 0.051), but there was no association with HAART use, nadir CD4 count, or plasma HIV RNA. Smoking was the only factor with significant association with any high-risk HPV persistence in the multivariate model (OR: 2.3, 95% CI: 1.17 to 4.5, P = 0.015).
For HIV-negative MSM, persistence of any high-risk HPV infection had a trend for an association with younger age at sexual debut (≤17 years old, OR: 3.86, 95% CI: 0.99 to 15.1, P = 0.08) in a univariate model, but this was not statistically significant in further analysis.
Our study demonstrated a high prevalence of anal HPV infection among Thai MSM—85% among HIV-positive and 58.5% among HIV-negative MSM. In addition, high-risk HPV types were identified in 57.5% of HIV-positive MSM and 36.6% of HIV-negative MSM. The higher prevalence of any anal HPV infection and high-risk HPV infection in HIV-positive MSM than HIV-negative MSM was in accordance with previous studies that specifically compared anal HPV prevalence between MSM with and without HIV infection in the United States.1,2
Although the 85% overall prevalence of anal HPV infection among Thai HIV-positive MSM in our study was slightly lower than those reported from HIV-positive MSM in the United States and Canada (ranging from 92% to 98%),1,2,8 this prevalence was higher than those reported from Brazil (66%),14 Taiwan (77%),13 and China (72%).12 The 57.5% high-risk anal HPV prevalence in our HIV-positive MSM was higher than the 41% prevalence reported from Taiwan and China12,13 but was comparable with the 56% prevalence reported from the United States.2 For HIV-negative MSM, previous data were only available from the United States and Latin America, where the overall anal HPV prevalence (ranging from 42% to 66%)1,2,11,15,16 and high-risk HPV prevalence (ranging from 22% to 42%)2,11,15 were comparable with our 58.5% overall anal HPV prevalence and 36.6% high-risk HPV prevalence.
HPV type 16 was the most common high-risk HPV type identified in both HIV-positive and HIV-negative MSM in our study. These data were consistent with previous studies, which also reported HPV type 16 to be the most common high-risk HPV type in the anus.8,11,13 In addition to being the most prevalent high-risk HPV type, HPV type 16 was also the type with highest incidence among HIV-positive MSM in our study. The incidence rate of HPV 16 in our study was comparable with that reported in Canadian HIV-positive MSM8 and was higher than that of HIV-negative MSM, although this was not statistically significant (P = 0.058). The incidence rate of HPV type 16 among HIV-negative MSM in our study was also similar to the rate reported in the HPV in men (HIM) study.11
HIV-positive MSM in our study tended to have a lower clearance rate of HPV 16 compared with HIV-negative MSM, although the difference was not statistically significant. Consistent with the lower clearance rate, HPV 16 was the most persistent high-risk HPV in HIV-positive MSM, with a significantly higher persistence compared with HIV-negative MSM. We also found higher persistence of at least 1 high-risk HPV type in HIV-positive MSM than in HIV-negative MSM.
The most common high-risk HPV type identified in anal cancers is type 16.4,5 Higher prevalence, a trend for higher incidence, and higher persistence of HPV type 16 in the anus of HIV-positive MSM compared with HIV-negative MSM found in our study are consistent with the higher risk of anal cancer in HIV-positive MSM than in HIV-negative MSM.7 Although HPV types from anal swab samples may not truly represent HPV types in the anal tissues, a previous study has demonstrated the concordance of HPV DNA detection between anal biopsy samples and anal swab samples from MSM.17
We identified HIV infection to be the main predictor for any high-risk HPV persistence in the anus. However, we could not identify an association between HPV persistence and HAART use. This should be interpreted with caution, as only 13% of HIV-positive MSM in our study reported HAART use at baseline and the proportion increased to 47% over the study duration. This was likely a result of measuring CD4 levels at the baseline visit, which subsequently led to linkage to HIV treatment and care, because there were no changes in national guidelines for initiation of HAART during the study period. Although there are currently no data to support this, it is possible that HAART, if initiated early and taken for a long period of time, may lower the risk of HPV persistence. Similar to a previous study from the United States,2 we did not find an association between HPV persistence and CD4 count.
Smoking significantly increased the risk of high-risk HPV persistence among our HIV-positive MSM. These data are consistent with a recent finding from the HIM study, which identified smoking as an independent risk factor for HPV persistence among MSM.11 In the 2011 Thai National Statistical Office Smoking and Drinking Behavior Survey, 35% of men in Bangkok, aged between 20 and 34 years, were current smokers.18 Only 14% of MSM participants reported current smoking in our study, which might reflect underreporting or a true difference in smoking patterns in Thai MSM than the general male population. The contribution of smoking to HPV persistence may consequently be underestimated in this analysis. Younger age at sexual debut among HIV-negative MSM in our study also showed a trend to be associated with high-risk HPV persistence. As these factors are potentially modifiable, they should be considered targets for interventions to possibly modify anal cancer risk among MSM.
Our study has several limitations. The number of MSM participants with and without HIV infection was small in our cohort, which limited the number of events of interest for statistical analyses. The number of HIV-positive MSM who were on HAART at baseline was small and limited our ability to evaluate the contributions of HAART use and its duration on the HPV end points. The short follow-up duration for this report may also limit our understanding of longer term HPV incidence and clearance data. Our definition of HPV clearance based on 1 negative sample and the inclusion of month 6 data from a subset of participants might also overestimate the clearance rate compared with a more conservative definition of ≥2 consecutive samples. This study, however, is the only study in Asia that prospectively followed HIV-positive and HIV-negative MSM with comprehensive data and sample collection for HPV-related end points. As additional follow-up visits occur in our cohort, our estimates should become more accurate.
Information from cohort studies of HIV-positive and HIV-negative MSM at a time when HIV has become a global, chronic disease with potentially long survival time are of great importance. Anal cancer is a non–AIDS-defining cancer with increased incidence since the introduction of HAART,7,19–21 which may be explained by the prolonged survival after HAART and the lack of routine screening for anal precancerous lesions allowing for the progression to anal cancer.22 As persistent, high-risk, anal HPV infection is an important risk factor for the development of anal cancer,4–6 anal precancer screening programs should consider integrating interventions such as smoking cessation to modify behavioral risk factors for high-risk HPV persistence whenever possible. Although cessation of smoking has not yet been demonstrated to improve outcomes for anal cancer development, it is plausible and has other health benefits.
The study team is grateful to the individuals who volunteered to participate in this study and to staff at the Thai Red Cross AIDS Research Centre and the Faculty of Medicine, Chulalongkorn University.
1. Palefsky JM, Holly EA, Ralston ML, et al.. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis. 1998;177:361–367.
2. Critchlow CW, Hawes SE, Kuypers JM, et al.. Effect of HIV infection on the natural history of anal human papillomavirus infection. AIDS. 1998;12:1177–1184.
3. Kreuter A, Brockmeyer NH, Hochdorfer B, et al.. Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol. 2005;52:603–608.
4. Daling JR, Madeleine MM, Johnson LG, et al.. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004;101:270–280.
5. Frisch M, Fenger C, van den Brule AJ, et al.. Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses. Cancer Res. 1999;59:753–757.
6. Palefsky JM, Holly EA, Gonzales J, et al.. Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res. 1991;51:1014–1019.
7. D'Souza G, Wiley DJ, Li X, et al.. Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr. 2008;48:491–499.
8. de Pokomandy A, Rouleau D, Ghattas G, et al.. Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study. J Infect Dis. 2009;199:965–973.
9. van der Snoek EM, van der Ende ME, den Hollander JC, et al.. Use of highly active antiretroviral therapy is associated with lower prevalence of anal intraepithelial neoplastic lesions and lower prevalence of human papillomavirus in HIV-infected men who have sex with men. Sex Transm Dis. 2012;39:495–500.
10. Shvetsov YB, Hernandez BY, McDuffie K, et al.. Duration and clearance of anal human papillomavirus (HPV) infection among women: the Hawaii HPV cohort study. Clin Infect Dis. 2009;48:536–546.
11. Nyitray AG, Carvalho da Silva RJ, Baggio ML, et al.. Six-month incidence, persistence, and factors associated with persistence of anal human papillomavirus in men: the HPV in men study. J Infect Dis. 2011;204:1711–1722.
12. Yang Y, Li X, Zhang Z, et al.. Association of human papillomavirus infection and abnormal anal cytology among HIV-infected MSM in Beijing, China. PLoS One. 2012;7:e35983.
13. Yu CT, Chao SC, Lee HC, et al.. High prevalence of anal human papillomavirus infection and associated risky behaviors in men infected with human immunodeficiency virus in Taiwan. AIDS Behav. 2013;17:1211–1218.
14. Guimaraes MD, Grinsztejn B, Melo VH, et al.. Anal HPV prevalence and associated factors among HIV-seropositive men under antiretroviral treatment in Brazil. J Acquir Immune Defic Syndr. 2011;57(suppl 3):S217–S224.
15. Chin-Hong PV, Vittinghoff E, Cranston RD, et al.. Age-specific prevalence of anal human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study. J Infect Dis. 2004;190:2070–2076.
16. Goldstone S, Palefsky JM, Giuliano AR, et al.. Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. J Infect Dis. 2011;203:66–74.
17. Gohy L, Gorska I, Rouleau D, et al.. Genotyping of human papillomavirus DNA in anal biopsies and anal swabs collected from HIV-seropositive men with anal dysplasia. J Acquir Immune Defic Syndr. 2008;49:32–39.
19. Silverberg MJ, Lau B, Justice AC, et al.. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis. 2012;54:1026–1034.
20. Piketty C, Selinger-Leneman H, Grabar S, et al.. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS. 2008;22:1203–1211.
21. Patel P, Hanson DL, Sullivan PS, et al.. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. 2008;148:728–736.
22. Palefsky JM. Antiretroviral therapy and anal cancer: the good, the bad, and the unknown. Sex Transm Dis. 2012;39:501–503.
Keywords:© 2013 by Lippincott Williams & Wilkins
anal; human papillomavirus; persistence; MSM; HIV