INTRODUCTION
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.
METHODS
Participants
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.
Data Collection
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.
Laboratory Studies
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 Analysis
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.
RESULTS
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.
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TABLE 1: Univariate Analysis of Bacterial Sexually Transmitted Infections as Risk Factors for HIV Seroconversion in the HIM Cohort Study
TABLE 2: Univariate Analysis of Viral Sexually Transmitted Infections as Risk Factors for HIV Seroconversion in the HIM Cohort Study
Behavior-Adjusted Model
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).
TABLE 3: Behavior-Adjusted Model of Sexually Transmitted Infections as Risk Factors for HIV Seroconversion in the HIM Cohort Study
DISCUSSION
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.
ACKNOWLEDGMENTS
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.
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