JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology and Social Science
Anal Sexually Transmitted Infections and Risk of HIV Infection in Homosexual Men
Jin, Fengyi PhD*; Prestage, Garrett P PhD*; Imrie, John PhD†; Kippax, Susan C PhD†; Donovan, Basil MD*†; Templeton, David J PhD*§; Cunningham, Anthony PhD‖; Mindel, Adrian PhD¶; Cunningham, Philip H BAppSc#; Kaldor, John M PhD*; Grulich, Andrew E PhD*
From the *National Centre in HIV Epidemiology and Clinical Research; and †National Centre in HIV Social Research, University of New South Wales, Sydney, New South Wales, Australia; ‡Sydney Sexual Health Centre, Sydney Hospital, Sydney, NSW; §RPA Sexual Health, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; ‖Centre for Virus Research, Westmead Millennium Institute; and ¶Sexually Transmitted Infections Research Centre, Westmead Hospital and University of Sydney; and #Centre for Immunology, St. Vincent's Hospital, Sydney, Australia.
Received for publication January 28, 2009; accepted June 8, 2009.
The National Centre in HIV Epidemiology and Clinical Research and the National Centre in HIV Social Research are funded by the Australian Government Department of Health and Ageing. The Health in Men Cohort study was funded by the National Institutes of Health, a component of the US Department of Health and Human Services (NIH/NIAID/DAIDS: HVDDT Award N01-AI-05395), the National Health and Medical Research Council in Australia (Project grant # 400944), the Australian Government Department of Health and Ageing (Canberra), and the New South Wales Health Department (Sydney). The herpes testing was funded by GlaxoSmithKline. The testing materials for gonorrhea and chlamydia were provided by Becton Dickinson Pty Ltd. F. J. is supported by the Deanapos;s Fellowship provided by the Faculty of Medicine, University of New South Wales.
Author contributions: F.J. performed the analyses and drafted the article; A.E.G. took overall responsibility for the project, drafted the analysis plan, and assisted in the analyses and drafting of the article; G.P.P., J.I., S.C.K., B.D., D.J.T., and J.M.K. assisted in formulating the analyses and drafting the article. P.H.C. supervised the laboratory testing for HIV, gonorrhea and chlamydia, and syphilis and assisted in drafting the article. A.C. and A.M. supervised the laboratory testing for HSV-1 and HSV-2 and assisted in drafting the article.
Conflict of interest: none.
Correspondence to: Dr. Fengyi Jin, PhD, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Level 2, 376 Victoria Street, Darlinghurst, New South Wales 2010, Australia (e-mail: firstname.lastname@example.org).
Background: We examined a range of common bacterial and viral sexually transmitted infections as risk factors for HIV seroconversion in a community-based cohort of HIV-negative homosexual men in Sydney, Australia.
Methods: Detailed information about HIV risk behaviors was collected by interview twice yearly. Participants were tested annually for HIV, anal and urethral gonorrhea and chlamydia, herpes simplex virus types 1 and 2, and syphilis. In addition, they reported annual diagnoses of these conditions and of genital and anal warts.
Results: Among 1427 enrolled participants, 53 HIV seroconverters were identified, giving an incidence of 0.78 per 100 person-years. After controlling for number of episodes of insertive and receptive nonseroconcordant unprotected anal intercourse, there were independent associations with anal gonorrhea (adjusted hazard ratio = 7.12, 95% confidence interval: 2.05 to 24.79) and anal warts (hazard ratio = 3.63, 95% confidence interval: 1.62 to 8.14).
Conclusions: Anal gonorrhea and anal warts were independently associated with HIV acquisition. The added HIV prevention value of more frequent screening of the anus to allow early detection and treatment of anal sexually transmitted infections in homosexual men should be considered.
Observational studies have shown that sexually transmitted infections (STIs) may facilitate the acquisition and transmission of HIV.1-3 However, randomized trials of STI-based interventions to prevent HIV infection in heterosexuals have produced mostly negative results.4,5 A consensus has emerged that STI prevention and treatment strategies are likely to be more effective in HIV prevention in populations in which there is a high prevalence of STIs and where HIV is transmitted more frequently in casual rather than in steady regular relationships.4,6 Although these conditions certainly apply in homosexual men,7-11 there have been relatively few longitudinal studies of the HIV-STI interaction in this population,12,13 and none has comprehensively examined the association between HIV incidence and the range of STIs that are common in homosexual men.
Increasing incidence of STIs in homosexual men has been reported worldwide over the past decade.14,15 In addition, surveillance data and cohort studies have demonstrated that homosexual transmission of HIV is increasing in Australia, Europe, North America, and some developing countries.16-19
In the presence of expanding epidemics of HIV and STIs in homosexual men, it is important to clarify the role of STIs in HIV transmission in this population. We examined the association between the range of common STIs and HIV risk in the Health in Men (HIM) study, a community-based prospective cohort in homosexual men in Sydney, Australia.
Participants were recruited from a wide range of community-based settings in Sydney between June 2001 and December 2004, as described in detail elsewhere.10 Men were eligible if they met the following criteria: (1) reported having sex with other men within the previous 5 years, (2) lived in Sydney or participated regularly in its gay community, and (3) tested HIV negative at baseline. Signed informed consent was obtained from all participants. Participants were followed up to the end of June 2007. Ethical approval was granted by the Human Research Ethics Committee at the University of New South Wales.
All eligible men willing to participate underwent annual face-to-face interviews, with 6 monthly telephone interview between these visits. At each interview, detailed quantitative data on the number of episodes of insertive and receptive unprotected anal intercourse (UAI) in the last 6 months were collected separately for regular and for casual partners, by HIV status of these partners (negative, positive, or unknown), and for receptive anal intercourse, by whether or not ejaculation occurred.
At each follow-up annual visit, participants also reported whether they had been diagnosed with 5 specific STIs since the last visit. These were gonorrhea, chlamydia, syphilis, anogenital warts, and anogenital herpes. These diagnoses between study visits were referred to as “interval diagnoses.” Participants were asked about interval diagnoses of these conditions since the commencement of the study in 2001, with the exception of anal chlamydia, which was introduced into the questionnaire in 2002.
Participants were required to be tested annually for HIV, using the AxSYM HIV antigen/antibody Combo (Abbott Diagnostics, Abbott Park, IL). Positive results were confirmed by a Western blot assay.
STI screening was offered annually to consenting participants, including syphilis, gonorrhea, Chlamydia, and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Diagnoses made at the study visits were referred to as “study visit diagnoses.”
Testing methods have been described previously. Briefly, syphilis testing occurred using an enzyme immunoassay test, and positive results were confirmed by supplementary tests.8 Annual testing for gonorrhea and chlamydia was introduced into the study in 2003. A nucleic acid amplification test (BDProbeTec) was used on participant-collected urine and anal swabs. Specimens initially positive for anal gonorrhea were confirmed using a second nucleic acid amplification test targeting a different gene.20 For HSV-1 and HSV-2 serotyping, a previously validated algorithm, utilizing the Enzygnost anti-HSV immunoglobulin-G enzyme-linked immunosorbent assay, type-specific HSV-1 and HSV-2 enzyme-linked immunosorbent assays (Focus Technologies, Cypress, CA), and Western blots were used as previously described and validated.10
Ascertainment of HIV Seroconversion and Estimation of Date of HIV Infection
Methods of ascertainment of HIV seroconversion and estimation of the date of HIV infection have been described in detail elsewhere.21 Briefly, incident HIV infections were identified through 2 sources. First, HIV diagnoses at the annual study visit (n = 31). Second, identifiers from the HIM study were matched against the national HIV register to identify HIV infections, which occurred in people who tested outside the study (n = 22).
The midpoint between the last HIV-negative test and first HIV-positive test was designated as being the date of HIV infection in 36 participants who had no data on HIV seroconversion symptoms. In 17 seroconverters, there were further data available on the completeness of the Western blot and the occurrence of HIV seroconversion symptoms from another HIV primary infection study.11,22
Statistical analyses were performed using STATA 10.0 (STATA Corporation, College Station, TX). The HIV incidence was calculated as the number of HIV seroconversions divided by the total person-years followed. The exact binomial method was used to calculate 95% confidence intervals (CIs). For risk factor analysis, person-years contributed by individual participants were from study entry to the last interview for those who remained HIV negative and to the estimated date of HIV infection for those who seroconverted. In 13 participants, whose HIV seroconversions were identified through matching with the HIV register, the estimated date of HIV infection was later than their last interview due to loss to follow-up. In these individuals, there were no behavioral data available at the time of estimated infection. Information obtained from the last interview was carried forward for risk factor analysis in 7 cases, in whom the estimated date of infection was less than 12 months after the last interview. Six cases whose estimated date of infection was more than 12 months were excluded from risk factor analysis.
Univariate and multivariate Cox regression models were developed to examine the association between STIs and HIV seroconversion. Hazard ratios (HRs) and their corresponding 95% CIs were calculated. In univariate analysis, the association of HIV seroconversion with a large variety of STIs was examined, including interval and study visit diagnoses. STI exposure was measured in the same interval as HIV seroconversion. For syphilis and HSV-1 and HSV-2 infections, the effect of history or prevalent infections identified at baseline and incident infections developed during the study were examined separately. A final model was developed which included all the individual STIs, which were significantly associated with HIV seroconversion (with a P value of less than 0.05 in the univariate analyses) to allow adjustment for number of episodes of nonseroconcordant UAI. These included insertive UAI with HIV status unknown and HIV-positive partners, receptive UAI with withdrawal with HIV status unknown and HIV-positive partners, and receptive UAI with ejaculation with HIV status unknown and HIV-positive partners.23 As all of these are potential means of HIV transmission, we controlled for all of them in the final model, regardless of their individual level of statistical significance.
A total of 1427 participants were enrolled between June 2001 and December 2004. The median age at enrollment was 35 years, ranging from 18 to 75 years. The great majority of participants (95.2%) self identified as gay or homosexual. Follow-up interviews at 1 and 2 years were attended by 87% and 81% of participants, respectively. By the end of study, there were 53 HIV seroconversions identified, giving an overall HIV incidence of 0.78 per 100 person-years (95% CI: 0.59 to 1.02).
Sexually Transmitted Infections and HIV Acquisition
The total follow-up time for risk factor analysis was 5160 person-years, and the median was 3.9 years per participant. Risk factor analysis was performed on 47 HIV seroconverters and 1334 nonseroconverters who completed at least 1 follow-up interview.
In univariate analyses, 2 bacterial anal infections were significantly associated with HIV seroconversion: anal gonorrhea (interval diagnoses HR = 3.50, 95% CI: 1.08 to 11.33 and study visit diagnoses HR = 8.50, 95% CI: 2.60 to 27.85; Table 1) and interval diagnoses of anal chlamydia (HR = 4.52, 95% CI: 1.61 to 12.67). Reporting either incident genital warts (HR = 4.02, 95% CI: 1.25 to 12.95) or incident anal warts (HR = 5.22, 95% CI: 2.44 to 11.18; Table 2) between annual study visits was associated with HIV seroconversion. In addition, those who tested positive to HSV-1 at baseline were at significantly increased risk of HIV seroconversion (HR = 3.01, 95% CI: 1.08 to 8.40, P = 0.035). There was no association between HSV-2 seropositivity at baseline, or HSV-2 seroconversion, and subsequent HIV infection.
After controlling for number of episodes of nonserocondordant UAI, the associations of HIV infection with study visit diagnosis of anal gonorrhea (HR = 7.12, 95% CI: 2.05 to 24.75) and interval diagnosis of anal warts (HR = 3.63, 95% CI: 1.62 to 8.14) remained significant. The association with HSV-1 seropositivity at baseline was of borderline significance (HR = 2.33, 95% CI: 0.91 to 5.93; Table 3).
In this community-based cohort of homosexual men, incident anal warts and anal gonorrhea were associated with acquisition of HIV. These associations remained significant after adjustment for the behavior, which leads to HIV transmission in this population, insertive and receptive UAI with a nonseroconcordant partner.
The 2 STIs which were significantly related to HIV infection were both anal STIs. Gonorrhea has been reported to be an independent risk factor for HIV acquisition in heterosexuals.24-26 In homosexual men, most studies have not distinguished the site of gonococcal infection. Of the 2 previously reported longitudinal studies, which have reported data on anal infection and HIV risk,27,28 one reported a significant association between rectal gonorrhea and HIV risk, and that was based on participant self-report.27 No previous community-based longitudinal study has examined the association between a clinical test for anal gonococcal infection on study participants and HIV. In our study, as in other community-based studies,29 the anal gonorrhea we diagnosed was in general asymptomatic.7 The lack of symptoms may mean that infection was relatively long standing, and it is plausible that such infection, possibly associated with rectal inflammation, was associated with HIV infection. Thus, screening and treatment for this anal STI may prevent some cases of HIV infection.
The only previously reported longitudinal study of the association between anogenital warts and HIV risk in homosexual men did not distinguish anal from genital warts.27 In our cohort, anal warts were highly prevalent and were about twice as common as genital warts. Incidence was highest in the young.9 There are at least 2 mechanisms by which anal warts may facilitate HIV transmission. First, warts may themselves disrupt or weaken the integrity of the epithelial barrier to HIV.30 Second, treatment of warts often produces ulceration and inflammation31 and may last for a period of weeks or months. It may be that it is treatment, rather than the warts themselves, which is related to the increased risk of HIV infection.
In contrast to most published studies in homosexual men,32-34 we found no association between either prevalent or incident HSV-2 infection and HIV incidence. However, we did find an association between prevalent HSV-1 infection and HIV incidence, although this association was no longer statistically significant when adjusted for behavior (P = 0.095). Such an association has not been previously reported. In recent years, HSV-1 has become an increasingly common cause of anogenital herpes in industrialized countries including Australia.35,36 In some settings, HSV-1 has become the most common cause of primary genital herpes in young people.36,37 In the HIM cohort, HSV-1 is a common STI transmitted through orogenital and oroanal sex.10 Even though genital lesions caused by HSV-1 are generally not thought to recur as frequently as lesions caused by HSV-2, this tendency may be less pronounced for perianal herpes.38,39 For these reasons, it is possible that HSV-1 may have taken over from HSV-2 as a potential cofactor for HIV transmission.
Some strengths and limitations should be taken into consideration when interpreting these results. First, we believe the control for confounding by sexual behavior in this study was as accurate as possible in an observational study and more accurate than in previously published studies in homosexual men. For all 9 modes of UAI that could represent a HIV transmission risk, we measured number of episodes of UAI separately for HIV-negative, HIV-positive, and HIV unknown partners. Thus we were able to adjust for all anal sexual behaviors that represented a direct risk for HIV transmission. We did not adjust for variables which are risk factors for STIs but only indirect markers of HIV risk, such as numbers of sexual partners, as it is likely that this would have led to overadjustment. In a series of sensitivity analyses, we adjusted for duration of follow-up, number of sexual partners reported in the last 6 months, and age in the existing final model. None were significant, and adjustment did not alter the final results. Second, the power of the study to detect the associations between STIs and HIV infection was limited by the relatively small numbers of incident STIs and HIV seroconversions. Third, the estimate of interval diagnoses of STIs was dependent upon participantsapos'; self-report, and validation against their medical record was not attempted. Given the high mobility of the gay community, it is likely that a substantial proportion of STIs were diagnosed by medical practitioners other than their regular doctors, making an accurate validation impossible. In any case, previous analyses from the HIM study have shown little difference in risk factors for infections when these conditions were excluded.7 Finally, as in all cohort studies of the association between HIV and STIs, it is not possible to be absolutely certain that the STI preceded HIV in every case of infection.
In conclusion, the HIM study has found that infection with certain anal STIs, including anal gonorrhea and anal warts, were independently related to HIV acquisition. These findings suggest that frequent sexual health screening and prompt treatment of STIs, particularly anal STIs, should be investigated as potential means of HIV prevention in homosexual men.
The authors wish to thank all the participants, the HIM study team, and the participating doctors and clinics. Thanks are also given to Ms Ann MacDonald for performing the match against the National HIV Register and to Dr. Tim Ramacciotti for providing the primary HIV infection data. We also thank Ms. Janette Taylor from the Westmead Millennium Institute for performing the HSV testing and Mr. Leon McNally from SydPath for performing the confirmatory Neisseria Gonorrhoeae Light Cycler (NGpapLC) testing.
1. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect
2. Rottingen J, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis
3. Freeman EE, Weiss HA, Glynn JR, et al. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS
4. Korenromp EL, White RG, Orroth KK, et al. Determinants of the impact of sexually transmitted infection treatment on prevention of HIV infection: a synthesis of evidence from the Mwanza, Rakai, and Masaka intervention trials. J Infect Dis
. 2005;191(Suppl 1):S168-S178.
5. Gray RH, Wawer MJ. Reassessing the hypothesis on STI control for HIV prevention. Lancet
6. White RG, Orroth KK, Korenromp EL, et al. Can population differences explain the contrasting results of the Mwanza, Rakai, and Masaka HIV/sexually transmitted disease intervention trials?: a modeling study. J Acquir Immune Defic Syndr
7. Jin F, Prestage GP, Mao L, et al. Incidence and risk factors for urethral and anal gonorrhoea and chlamydia in a cohort of HIV-negative homosexual men: the Health in Men Study. Sex Transm Infect
8. Jin F, Prestage GP, Kippax SC, et al. Epidemic syphilis among homosexually active men in Sydney. Med J Aust
9. Jin F, Prestage GP, Kippax SC, et al. Risk factors for genital and anal warts in a prospective cohort of HIV-negative homosexual men: the HIM study. Sex Transm Dis
10. Jin F, Prestage GP, Mao L, et al. Transmission of herpes simplex virus types 1 and 2 in a prospective cohort of HIV-negative gay men: the Health in Men study. J Infect Dis
11. Volk JE, Prestage G, Jin F, et al. Risk factors for HIV seroconversion in homosexual men in Australia. Sex Health
12. Bonell C, Weatherburn P, Hickson F. Sexually transmitted infection as a risk factor for homosexual HIV transmission: a systematic review of epidemiological studies. Int J STD AIDS
13. Bonell C, Hickson F, Beaumont M, et al. Sexually transmitted infections as risk factors for HIV infection among MSMs: systematic review. Sex Transm Dis
14. Centers for Disease Control and Prevention. Increases in unsafe sex and rectal gonorrhea among men who have sex with men-San Francisco, California, 1994-1997. MMWR Morb Mortal Wkly Rep
15. Stolte IG, Dukers NH, de Wit JB, et al. Increase in sexually transmitted infections among homosexual men in Amsterdam in relation to HAART. Sex Transm Infect
16. Centers for Disease Control and Prevention. Trends in HIV/AIDS diagnoses-33 states, 2001-2004. MMWR Morb Mortal Wkly Rep
17. Dukers NH, Spaargaren J, Geskus RB, et al. HIV incidence on the increase among homosexual men attending an Amsterdam sexually transmitted disease clinic: using a novel approach for detecting recent infections. AIDS
18. NCHECR (National Centre in HIV Epidemiology and Clinical Research). HIV/AIDS, Viral Hepatitis and Sexually Transmissible Infections in Australia: Annual Surveillance Report 2005
. Sydney, NSW: National Centre in HIV Epidemiology and Clinical Research; 2005.
19. van Griensven F, Thanprasertsuk S, Jommaroeng R, et al. Evidence of a previously undocumented epidemic of HIV infection among men who have sex with men in Bangkok, Thailand. AIDS
20. McNally LP, Templeton DJ, Jin F, et al. Low positive predictive value of a nucleic acid amplification test for nongenital Neisseria gonorrhoeae
infection in homosexual men. Clin Infect Dis
21. Jin F, Prestage GP, McDonald A, et al. Trend in HIV incidence in a cohort of homosexual men in Sydney: data from the Health in Men Study. Sex Health
22. Jin F, Prestage GP, Ellard J, et al. How homosexual men believe they became infected with HIV: the role of risk-reduction behaviors. J Acquir Immune Defic Syndr
23. Jin F, Crawford J, Prestage GP, et al. Unprotected anal intercourse, risk reduction behaviours, and subsequent HIV infection in a cohort of homosexual men. AIDS
24. Hanson J, Posner S, Hassig S, et al. Assessment of sexually transmitted diseases as risk factors for HIV seroconversion in a New Orleans sexually transmitted disease clinic, 1990-1998. Ann Epidemiol
25. Kassler WJ, Zenilman JM, Erickson B, et al. Seroconversion in patients attending sexually transmitted disease clinics. AIDS
26. Laga M, Alary M, Nzila N, et al. Condom promotion, sexually transmitted diseases treatment, and declining incidence of HIV-1 infection in female Zairian sex workers. Lancet
27. Craib KJ, Meddings DR, Strathdee SA, et al. Rectal gonorrhoea as an independent risk factor for HIV infection in a cohort of homosexual men. Genitourin Med
28. Williams DI, Stephenson JM, Hart GJ, et al. A case control study of HIV seroconversion in gay men, 1988-1993: what are the current risk factors? Genitourin Med
29. Lister NA, Smith A, Tabrizi S, et al. Screening for Neisseria gonorrhoeae
and Chlamydia trachomatis
in men who have sex with men at male-only Saunas. Sex Transm Dis
30. Quinn TC, Glasser D, Cannon RO, et al. Human immunodeficiency virus infection among patients attending clinics for sexually transmitted diseases. N Engl J Med
31. O'Mahony C. Genital warts: current and future management options. Am J Clin Dermatol
32. Brown EL, Wald A, Hughes JP, et al. High risk of human immunodeficiency virus in men who have sex with men with herpes simplex virus type 2 in the EXPLORE study. Am J Epidemiol
33. Renzi C, Douglas JM Jr, Foster M, et al. Herpes simplex virus type 2 infection as a risk factor for human immunodeficiency virus acquisition in men who have sex with men. J Infect Dis
34. Turner KR, McFarland W, Kellogg TA, et al. Incidence and prevalence of herpes simplex virus type 2 infection in persons seeking repeat HIV counseling and testing. Sex Transm Dis
35. Haddow LJ, Dave B, Mindel A, et al. Increase in rates of herpes simplex virus type 1 as a cause of anogenital herpes in western Sydney, Australia, between 1979 and 2003. Sex Transm Infect
36. Tran T, Druce JD, Catton MC, et al. Changing epidemiology of genital herpes simplex virus infection in Melbourne, Australia, between 1980 and 2003. Sex Transm Infect
37. Manavi K, McMillan A, Ogilvie M. Herpes simplex virus type 1 remains the principal cause of initial anogenital herpes in Edinburgh, Scotland. Sex Transm Dis
38. Janier M, Scieux C, Meouchi R, et al. Virological, serological and epidemiological study of 255 consecutive cases of genital herpes in a sexually transmitted disease clinic of Paris (France): a prospective study. Int J STD AIDS
39. Solomon L, Cannon MJ, Reyes M, et al. Epidemiology of recurrent genital herpes simplex virus types 1 and 2. Sex Transm Infect
anogenital warts; Australia; cohort study; gonorrhea; HIV acquisition; herpes simplex virus; homosexuality; male
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