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Link Between Circumcision and HIV Risk Unclear in MSM
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medpagetoday.com
There's not enough evidence to show that circumcision lowers the risk of HIV for men who have sex with men, researchers here said.
The finding, from a meta-analysis of observational studies, comes after randomized controlled trials showed that the procedure protects heterosexual men from HIV, according to Gregorio Millett, M.P.H., and colleagues at the CDC.
There was also no evidence that circumcision protects men who have sex with men from other sexually transmitted diseases, the researchers reported in the Oct. 8 issue of the Journal of the American Medical Association.
But it's too early to rule out a protective effect in the case of HIV, since studies conducted before the era of highly active anti-retroviral therapy (HAART) did show a benefit, the researchers said.
The benefit in those studies was roughly equivalent to the 50% to 60% reduction in risk seen in the heterosexual trials, they said, suggesting that further study is needed.
The researchers also found a trend toward protection among men who primarily practiced insertive anal sex, but it did not reach statistical significance.
A systematic search found 18 studies that quantitatively examined the association between circumcision status and HIV or sexually transmitted infections among men who have sex with men.
Of those studies, conducted from 1989 to 2007, three were excluded because of insufficient data, leaving 15 for the final meta-analysis. The final pool of study volunteers included 27,816 circumcised men and 25,751 who had not been circumcised.
The overall effect size was protective, but not significant, the researchers said, with an odds ratio of 0.86 and a 95% confidence interval from 0.65 to 1.13.
Among men who primarily engaged in insertive anal sex, the association was again protective but not significant, with an odds ratio of 0.71 and a 95% confidence interval from 0.23 to 2.22. (The pooled effect size was based on four studies.)
In the three studies conducted before the HAART era, circumcision had a significant protective association with HIV, with an odds ratio of 0.47 and a 95% confidence interval from 0.32 to 0.69.
The findings are limited by the nature of the studies in the meta-analysis, the researchers said -- all were observational and many were cross-sectional.
The three analyses of men who primarily practiced insertive anal sex probably included men who occasionally took the receptive role, which would bias the result toward the null, they said.
There was also some evidence of publication bias in the studies looking at circumcision and sexually transmitted infections, the researchers said.
A randomized controlled trial should be given "serious consideration" to clarify the issue, they added.
Indeed, "only randomized clinical trials will determine definitively" whether circumcision reduces HIV risk among men who have sex with men, said Sten Vermund, M.D., Ph.D., and Han-Zhu Qian, M.D., Ph.D., both of Vanderbilt University School of Medicine in Nashville.
Writing in an accompanying editorial, they said that such a trial should preferentially include men who prefer the insertive role, since men who prefer the receptive role are unlikely to benefit from being circumcised.
Editorial
Circumcision and HIV Prevention Among Men Who Have Sex With Men
No Final Word
Sten H. Vermund, MD, PhD; Han-Zhu Qian, MD, PhD
Institute for Global Health, Vanderbilt Epidemiology Center, and Departments of Pediatrics and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
JAMA. Oct 8 2008;300(14):1698-1700.
In the late 1980s, an ecological association between high rates of male circumcision and low human immunodeficiency virus (HIV) prevalence in Africa was noted from epidemiologic, geographic, and ethnographic data.1 A meta-analysis of epidemiological studies published prior to 2000 suggested a statistically significant protective association between circumcision and HIV infection among African heterosexual men.2 A causal relationship between HIV risk reduction and male circumcision seemed likely; there was biological plausibility and consistency between studies. The studies, however, did not confirm that circumcision predated HIV risk reduction or that confounding factors might not explain the association.
One complicating factor in African studies was the Islamic practice of circumcision in the context of polygamy and lower sexual risk, as well as norms against the consumption of alcohol.3 Circumcised Muslim men in Africa may have had multiple partners, but they were also less likely to have sex outside marriage (eg, with commercial sex workers or within extramarital affairs).3 Thus, adult male circumcision might appear to protect individuals from HIV, but the association could be confounded by sexually conservative social and religious norms, lower rates of sexually transmitted infections, and limited sexual networks. An ecological study in 118 developing countries suggested after controlling for the influence of religion, circumcision prevalence was negatively associated with HIV prevalence.4 However, a spurious ecological association could not be excluded.
To determine definitively whether male circumcision was a tool for HIV prevention in sub-Saharan Africa, investigators conducted clinical trials that resolved the issue of potential confounding among heterosexual men.5-7 Adult male circumcision reduced HIV acquisition among HIV-seronegative heterosexual men in South Africa, Kenya, and Uganda with effect sizes that were remarkably consistent and similar to those predicted by the earlier observational studies.2, 5-7 The biological plausibility of HIV protection resulting from male circumcision has been supported further by immunohistological and histopathological studies indicating the susceptibility of the inner foreskin for virus-target cell contact.8-9 Hence, a plausible risk factor (noncircumcised status) was suggested strongly by many epidemiological studies in heterosexual men, and circumcision was determined to protect against HIV in high-quality, well-powered clinical trials in 3 different nations of Africa. Based on the biological, histopathological, epidemiologic, and clinical trials evidence, global health leaders now promote circumcision for reducing HIV risk in heterosexual men.10-11
In this issue of JAMA, Millett and colleagues12 report the results of a meta-analysis evaluating the evidence for male circumcision in reducing risks of HIV and other sexually transmitted infections (STIs) in a group of men who were not well represented in the 3 African clinical trials of heterosexual men, that is, men who have sex with men (MSM). There are at least 4 reasons to assess whether MSM will benefit from circumcision as did at-risk heterosexual men. First, the biological plausibility for HIV protection is diminished by the fact that MSM may practice receptive anal sex, diluting the potential effect of circumcision.13 Second, evidence of an HIV protective effect is less consistent in studies of MSM (mostly from the western hemisphere and Europe) than in African studies of heterosexual men.2, 12 Third, the aggregate HIV protective effect size determined in the study by Millett et al12 was only an odds risk of 0.86 (95% confidence interval, 0.65-1.13), much lower than protective estimates noted in studies of heterosexual men.2, 5-7 Fourth, high circumcision rates in North America have not prevented MSM seroprevalence rates of HIV from exceeding rates found among heterosexual men in heavily affected areas of sub-Saharan Africa.
Investigators, peer review groups, and science policy makers will be faced with 3 important questions emerging from the results of this meta-analysis. First, is further research warranted to evaluate the effect of circumcision on HIV incidence in MSM? Most scientists and policy makers will argue a vigorous yes, because MSM continue to be disproportionately overrepresented in new HIV cases, particularly in Asia, Europe, Australia, and the Americas. There is a global need to know whether male circumcision should be considered a tool in the fight against HIV transmission among MSM.
Second, is a randomized clinical trial feasible? Peruvian-Ecuadorian investigators demonstrated strong support for a circumcision trial among MSM in their nations.13 Circumcision rates were less than 10% and follow-up rates in Peruvian cohort studies and clinical trials have been high.13 In contrast, circumcision rates among MSM in North America are greater than 70% to 80%, making the logistics and costs of a clinical trial much more involved with the need for extensive eligibility screening.14-15 Peruvian investigators have documented that even with increased condom use and declining rates of STIs, estimates of HIV seroincidence are likely high enough to support a circumcision trial among MSM in Peru, with HIV conversion as a primary end point.16
Third, should a randomized, controlled clinical trial of efficacy be conducted with HIV end points? Trial advocates will argue that observational studies will not address the question adequately. Trial skeptics will cite the uninspiring putative 15% protective effect suggested in the meta-analysis by Millett et al12 (a finding that may have been due to chance based on the nonsignificant P value). However, several of the observational studies included in this meta-analysis had methodological limitations that would tend to minimize the strength of an association. For instance, in some studies circumcision status and HIV infection were based on self-report,15, 17-24 there was low power for stratified analyses in heterogeneous studies that investigated insertive-sex predominance subgroups,15, 24-25 the temporal relationship of circumcision and HIV infection could not be established in cross-sectional studies,15, 17-18,21-23,25-26 and substantial effect modifications were likely to have reduced the magnitude of any protective association.15, 24-25
Future observational studies without the methodological limitations of earlier descriptive, less hypothesis-driven studies are warranted. However, only randomized clinical trials will determine definitively whether MSM receiving circumcision will reduce HIV risk. Since men who preferentially practice insertive sex are the individuals most likely to derive benefits of circumcision in preventing HIV,12 their overenrollment would increase an anticipated effect size and increase statistical power in the trial if a trial were to be conducted. Preferential recruitment into a future trial of men practicing insertive sex would contribute equipoise because individuals practicing receptive sex are less likely to benefit from circumcision.
The Agence Nationale de Recherche sur le SIDA et les Hpatites Virale and the National Institutes of Health provided most of the funds for the circumcision trials in African heterosexual men.5-7 Whether these agencies or other major funders in HIV prevention research (eg, the Bill and Melinda Gates Foundation) will fund a new trial of circumcision in high-risk MSM to assess protection against HIV remains to be determined.
The meta-analysis by Millett et al12 is likely to be used by both advocates and detractors of clinical trial investment; some will argue the benefit is likely to be too modest to justify a multimillion dollar clinical trial while others will argue that only a clinical trial will answer this important HIV prevention question. Barriers to circumcision among heterosexual men include human rights issues, ethical and legal issues, high cost, fear of pain, safety concerns, availability of surgery services, and sexual risk compensation if men overrate their degree of protection and ongoing risk.27-28 As in other HIV prevention trials (eg, HIV vaccines, microbicides, behavior change, opiate addition treatment, and antiretrovirals for prevention), circumcision would likely be insufficiently efficient to be universally effective in reducing HIV risk, and will have to be combined with other prevention modalities to have a substantial and sustained prevention effect.29-31 Stigma issues may arise if circumcision promotion campaigns were to be specifically targeted toward MSM. At the same time, MSM might be effectively mobilized by community campaigns, as has been successful before in decreasing high-risk behaviors.
Infant and adult circumcision are recommended in regions with high HIV prevalence as in sub-Saharan Africa.19 But the question as to whether MSM should be circumcised to reduce their HIV risk, particularly men who preferentially practice insertive sex, is one that only future research can answer.
The Study
Circumcision and Risk for HIV and STI Infection Among MSM
JAMA Oct 8 2008
"We found a protective, albeit statistically nonsignificant, association of circumcision with HIV infection in our meta-analysis of MSM observational studies, and a statistically nonsignificant association between circumcision status and STI. Our data revealed that male circumcision conferred a significant protective effect from HIV infection among MSM in studies conducted before HAART but not after, possibly due to documented increases in sexual risk behavior during the era since the availability of HAART.44-48 Additional studies are necessary to elucidate further the relationship between circumcision status and HIV infection or STIs among MSM.....
...Taken together, these findings indicate insufficient evidence among available observational studies conducted with MSM of an association between circumcision and HIV infection or other STIs.....
.....In this meta-analysis of 15 observational studies of the association of circumcision status and HIV infection among 53 567 MSM, the odds of being HIV positive were 14% lower among MSM who were circumcised than among MSM who were uncircumcised, but the difference was not statistically significant. When we restricted the analysis to studies of MSM who reported primarily engaging in insertive anal sex the aggregated findings also were statistically nonsignificant. The STI analyses similarly revealed no statistically significant association by circumcision status among MSM. Additionally, we had sufficient power for the HIV analyses and adequate power for most STI analyses.....
.....A total of 53 567 MSM participants (52% circumcised) were included in the meta-analysis. The odds of being HIV-positive were nonsignificantly lower among MSM who were circumcised than uncircumcised......Among MSM who primarily engaged in insertive anal sex, the association between male circumcision and HIV was protective but not statistically significant (odds ratio, 0.71; 95% confidence interval, 0.23-2.22; k = 4). Male circumcision had a protective association with HIV in studies of MSM conducted before the introduction of highly active antiretroviral therapy....
.....A separate analysis (not shown in Table 2) of 4 findings from 3 studies29, 33-34 reporting HIV infection and circumcision status for MSM who engaged exclusively or primarily in insertive anal intercourse (n = 2238) was protective, but not statistically significant (OR, 0.71; 95% CI, 0.23-2.22; k = 4).....
......Some patterns in the stratified HIV analyses are of interest as they point to the potentially protective role of circumcision among MSM.Although not statistically significant, circumcision had a stronger protective association with HIV infection in study samples in which circumcision prevalence was 50% or lower compared with samples with a greater than 50% circumcision prevalence. A similar pattern was apparent in stratified analyses by country. The aggregated US studies, where circumcision prevalence is relatively high,62 had a 9% reduction in odds of HIV infection among circumcised MSM. By contrast, the reduction in odds was higher in countries with lower adult circumcision rates than the United States63 (15% reduction in studies conducted in other developed countries and 51% reduction in developing countries). We also found a comparatively stronger, albeit nonsignificant, protective association of circumcision with HIV infection in MSM studies in which circumcision status was determined by genital examination, HIV status was determined by diagnostic test, multivariate analyses adjusted for confounders, and samples were limited to MSM who primarily engaged in insertive anal sex. Moreover, we found a 53% reduction in the odds of HIV infection among circumcised MSM during the era before HAART, which is comparable with the 50% to 60% reduction in the odds of HIV infection among circumcised heterosexual men in the 3 African RCTs1-3 and a previously published meta-analysis of heterosexual African men.64.....
.......In contrast, a statistically significant protective association (OR, 0.47; 95% CI, 0.32-0.69; k = 3; I2 = 0%) of circumcision with HIV infection was found for MSM studies conducted prior to the introduction of highly active antiretroviral therapy (HAART) in 1996. Of studies conducted after HAART, the association of circumcision and HIV infection was not statistically significant and heterogeneity among those studies was much higher.....
......Several important findings emerge from the results of our meta-analysis. First, we found a statistically significant protective association for circumcision among MSM in studies conducted before the advent of HAART, but a statistically nonsignificant association for studies conducted after HAART. A possible explanation for this difference may be related to an increase in the sexual risk behaviors of MSM after HAART. It has been well documented that beliefs that HAART limits HIV transmissibility are associated with increases in sexual risk behavior among MSM,43 and that the era since the advent of HAART has been defined by higher rates of sexual risk behaviors among MSM,44-48 outbreaks of STIs,49-51 and increasing rates of HIV infection.52-56 Higher rates of sexual risk behavior among MSM since the availability of HAART may diminish the relative effectiveness of male circumcision, and is supported by studies of MSM that report that behavioral risk factors (eg, unprotected anal sex) contribute comparatively more to HIV seroconversion than circumcision status.37"
Circumcision Status and Risk of HIV and Sexually Transmitted Infections Among Men Who Have Sex With Men
A Meta-analysis
Gregorio A. Millett, MPH; Stephen A. Flores, PhD; Gary Marks, PhD; J. Bailey Reed, MD, MPH; Jeffrey H. Herbst, PhD
Author Affiliations: Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.
JAMA. Oct 8 2008;300(14):1674-1684.
Context- Randomized controlled trials and meta-analyses have demonstrated that male circumcision reduces men's risk of contracting human immunodeficiency virus (HIV) infection during heterosexual intercourse. Less is known about whether male circumcision provides protection against HIV infection among men who have sex with men (MSM).
Objectives- To quantitatively summarize the strength of the association between male circumcision and HIV infection and other sexually transmitted infections (STIs) across observational studies of MSM.
Data Sources- Comprehensive search of databases, including MEDLINE, EMBASE, ERIC, Sociofile, PsycINFO, Web of Science, and Google Scholar, and correspondence with researchers, to find published articles, conference proceedings, and unpublished reports through February 2008.
Study Selection- Of 18 studies that quantitatively examined the association between male circumcision and HIV/STI among MSM, 15 (83%) met the selection criteria for the meta-analysis.
Data Extraction- Independent abstraction was conducted by pairs of reviewers using a standardized abstraction form. Study quality was assessed using the Newcastle-Ottawa Scale.
Data Synthesis- A total of 53 567 MSM participants (52% circumcised) were included in the meta-analysis. The odds of being HIV-positive were nonsignificantly lower among MSM who were circumcised than uncircumcised (odds ratio, 0.86; 95% confidence interval, 0.65-1.13; number of independent effect sizes [k] = 15). Higher study quality was associated with a reduced odds of HIV infection among circumcised MSM (β, -0.415; P = .01). Among MSM who primarily engaged in insertive anal sex, the association between male circumcision and HIV was protective but not statistically significant (odds ratio, 0.71; 95% confidence interval, 0.23-2.22; k = 4). Male circumcision had a protective association with HIV in studies of MSM conducted before the introduction of highly active antiretroviral therapy (odds ratio, 0.47; 95% confidence interval, 0.32-0.69; k = 3). Neither the association between male circumcision and other STIs (odds ratio, 1.02; 95% confidence interval, 0.83-1.26; k = 8), nor its relationship with study quality was statistically significant (β, 0.265; P = .47).
Conclusions- Pooled analyses of available observational studies of MSM revealed insufficient evidence that male circumcision protects against HIV infection or other STIs. However, the comparable protective effect of male circumcision in MSM studies conducted before the era of highly active antiretroviral therapy, as in the recent male circumcision trials of heterosexual African men, supports further investigation of male circumcision for HIV prevention among MSM.
INTRODUCTION
Randomized controlled trials (RCTs) conducted with men in Africa have shown that male circumcision reduces the likelihood of female-to-male transmission of human immunodeficiency virus (HIV) infection by 50% to 60%.1-3 Observational studies also suggest that male circumcision may protect heterosexual men against acquisition of other sexually transmitted infections (STI), such as syphilis, chlamydial infection, or genital ulcer disease.4-5 The protective effect of circumcision among heterosexual men has generated discussion about the potential role of circumcision in reducing the transmission of HIV and other STIs among men who have sex with men (MSM).6-7
Several factors may influence the protective effect of circumcision among MSM. Male circumcision may be most effective as an HIV prevention strategy in countries where HIV/STI prevalence is high and circumcision prevalence is low.8 Apart from HIV/STI and male circumcision prevalence, sexual position also plays an important role in the degree to which circumcision protects against disease acquisition among MSM. Circumcision among MSM may protect against HIV infection only among those who primarily or exclusively take the insertive role during unprotected anal intercourse7 because unprotected receptive anal intercourse-the riskiest sexual behavior for contracting HIV infection9-is independent of any protective effect afforded by circumcision.
An expert panel convened by the US Centers for Disease Control and Prevention (CDC) for a consultation on male circumcision and HIV infection recommended that evidence from existing observational studies be systematically reviewed before determining the usefulness of an RCT of male circumcision among MSM.10 Only 1 quantitative review has examined circumcision data from studies of MSM.11 However, that review included only 2 studies of male circumcision and HIV infection and did not consider unpublished studies or studies of other STIs.11 Given the increasing interest in circumcision as an HIV prevention strategy, a more thorough synthesis of available data on circumcision and HIV/STI risk among MSM is critical.
We systematically searched the scientific literature and performed a meta-analysis to examine the strength of the association of circumcision status with HIV infection and other STIs among MSM.
RESULTS
We identified 4337 citations of which 33 were considered relevant and obtained for further screening (Figure 1). Of these 33 studies, 18 quantitatively examined the association between male circumcision status and HIV or STI among MSM (number of studies and count of reference citations may not sum because Templeton et al has separate citations for HIV34 and STI35).22-23,25-41 Seventeen of the 18 studies examined the association between circumcision and HIV,22-23,25-31,33-34,36-41 and 7 of the 18 studies examined the association between circumcision and STI.22-23,27, 29, 32-33,35
Of the 17 studies that examined the association between circumcision and HIV infection among MSM, 9 of the original reports25-28,30-31,33-34,36 found no statistically significant association with HIV, 5 reported23, 37-40 that circumcision had a significant protective association with HIV, 1 reported22 a nearly significant protective association, 1 reported41 that circumcised MSM had a significantly greater odds of HIV infection, and 1 reported no statistically significant association in the overall sample but found a significantly protective effect among men who only engaged in insertive anal sex.29
Of the 7 studies that examined circumcision and STI among MSM, all except 1 reported data for both HIV and STI.32 Among the 7 STI studies, 4 of the original reports22, 27, 29, 33 found no statistically significant association between male circumcision and STIs, 2 reported a significantly protective effect for syphilis and no statistically significant association for other STIs,23, 35 and 1 reported no association for most STIs but a significantly greater odds of nonchlamydial nongonococcal urethritis.32
After excluding 3 of the 18 total studies due to insufficient data,28, 30, 38 a final set of 15 studies22-23,25-27,29, 31-37,39-41 were included in the meta-analysis (Table 1). The 15 studies were conducted between 1989 and 2007. Nine studies22-23,25-27,32-33,36-37 took place in North America, 9 were conducted22-23,25, 27, 32, 34-37,41 with primarily white participants, 4 had a prospective cohort design,26, 34-37 and 9 were unpublished abstracts or reports or previously unreported circumcision data.25-27,29, 31, 34-36,39, 41 The average quality of the studies, based upon the Newcastle-Ottawa Scale, was moderate (Table 1). Five studies that met 5 or more study quality criteria29, 34-37,40 were considered the highest quality; the remaining studies fulfilled fewer than 5 of the scale's 8 study criteria. Across all studies, the prevalence of male circumcision ranged from 4% to 88% (median = 60%). A total of 53 567 MSM were included in our analytical sample, 52% of whom were circumcised.
Fourteen studies22-23,25-27,29, 31, 33-34,36-37,39-41 contributed 15 findings for the association of circumcision and HIV infection (Figure 2). Our analysis included a total of 27 816 circumcised MSM and 25 751 uncircumcised MSM. The weighted overall effect size reflecting the association between circumcision and HIV infection among MSM was protective, but statistically nonsignificant (OR, 0.86; 95% CI, 0.65-1.13; k = 15). The power for the overall meta-analysis of HIV outcome studies was 0.78. There was moderate to high heterogeneity among the 15 findings (I2 = 64%), which warranted further examination via stratified analyses. Most of the stratified analyses revealed associations that were moderately protective, but not statistically significant (Table 2). Circumcision was not significantly associated with HIV infection when stratified by prevalence of HIV among study samples, prevalence of male circumcision among study samples, method used to determine either circumcision or HIV status, cross-sectional or prospective studies, bivariate or multivariate analysis, published or unpublished data, country in which the study was conducted (United States vs non United States), World Bank country classification (developed vs developing),42 or racial/ethnic composition of the study sample. However, there was moderately high heterogeneity among studies in each of these stratified analyses (I2 range, 33%-80%).
In contrast, a statistically significant protective association (OR, 0.47; 95% CI, 0.32-0.69; k = 3; I2 = 0%) of circumcision with HIV infection was found for MSM studies conducted prior to the introduction of highly active antiretroviral therapy (HAART) in 1996. Of studies conducted after HAART, the association of circumcision and HIV infection was not statistically significant and heterogeneity among those studies was much higher (I2 = 47%). We also found statistically nonsignificant results when we examined studies with moderate circumcision prevalence (22%-66%) and studies with large analytical samples (>1000 participants), but slightly more protective results for studies that used both a genital examination to determine circumcision status and a diagnostic test to determine HIV infection. The association between circumcision and HIV infection among the subset of higher-quality studies (determined by the Newcastle-Ottawa Scale) was protective, but statistically nonsignificant (OR, 0.79;95% CI, 0.44-1.40; k = 5; I2 = 53%). However, in the meta-regression, being circumcised was associated with a reduced odds of HIV infection as study quality scores increased (β, -0.415; P = .01).
A separate analysis (not shown in Table 2) of 4 findings from 3 studies29, 33-34 reporting HIV infection and circumcision status for MSM who engaged exclusively or primarily in insertive anal intercourse (n = 2238) was protective, but not statistically significant (OR, 0.71; 95% CI, 0.23-2.22; k = 4). The power for this analysis was 0.94. Although there was high heterogeneity among these 4 findings (I2 = 90%), too few findings were available for a stratified analysis.
Seven studies22-23,27, 29, 32-33,35 contributed 8 findings for the analysis of STIs other than HIV (Figure 3). All but 1 of the studies35 were cross-sectional and conducted in North or South America and the analysis included 15 233 circumcised MSM and 11 003 uncircumcised MSM. A study32 of 899 MSM that provided an effect size for the association between circumcision status and STI, but did not provide the prevalence of circumcised and uncircumcised MSM, was also included in the analytical sample. The weighted overall effect size for the association between circumcision status and STI among MSM was not statistically significant (OR, 1.02; 95% CI, 0.83-1.26; k = 8). The power for the meta-analysis of STI studies was 0.67 and heterogeneity was moderate (I2 = 36%). In stratified analyses (Table 3), circumcision was not significantly associated with STIs (bacterial or viral) generally, with specific STIs (ie, syphilis, herpes simplex virus) or with any of the other study or sample characteristics in Table 3. There was also no statistically significant association between study quality, based upon the Newcastle-Ottawa Scale, and the effect sizes of the STI studies (β, 0.265; P = .47).
METHODS
Study Selection
We searched widely used databases (ie, MEDLINE, ERIC, Sociofile, PsycInfo, EMBASE, Web of Science, Google Scholar) for relevant reports from the beginning of indexing for each database through February 2008. Searching key words and Medical Subject Headings (US National Library of Medicine) relevant to circumcision (ie, circumcision, circumcised, and uncircumcised), we cross-referenced the male circumcision citations and citations pertinent to homosexual men (ie, homosexual, bisexual, men who have sex with men, MSM, and gay). In addition, we searched the Web sites of HIV/STI-related conferences (ie, International Society for Sexually Transmitted Diseases Research, Conference on Retroviruses and Opportunistic Infections, International AIDS Conference, National HIV Prevention Conference) for relevant abstracts dating back to 1989. Last, we checked the reference lists of pertinent articles for additional citations and contacted investigators of published reports and conference abstracts to identify other possible sources.
Studies that met each of the following criteria were included in the review: (1) recruited MSM as part of the study; (2) included male circumcision as a study variable; and (3) reported quantitative data (either bivariate percentages or results of statistical tests) reflecting the association of circumcision status and HIV or STI prevalence among MSM. When necessary, study authors were contacted to obtain additional information or additional data to calculate effect sizes.
Data Extraction
Pairs of reviewers independently abstracted data from eligible articles. The study team used standardized abstraction sheets for recording study authors, publication year, enrollment period, study location, overall sample size of MSM, sample size of circumcised and uncircumcised MSM, racial/ethnic composition of the sample, study design (cross-sectional vs prospective), determination of circumcision status (self-report vs genital examination), data source (published vs unpublished), and type of analysis (univariate and/or multivariate). Although infrequent, disagreements between reviewers during the abstraction process were resolved by discussion.
Methodological Approach
Abstracted data were entered into a spreadsheet by one investigator and reviewed by a separate investigator. Several decision rules regarding participant characteristics and thoroughness of the data guided the preparation of data for analyses (Box).
Box. Methodological Approach for Analysis of Abstracted Data
1. Only data from circumcised and uncircumcised men who have sex with men were used to calculate effect sizes.
2. Only the most complete data (qualified for computing an odds ratio or data that included an effect size) were abstracted.
3. If bivariate and multivariate data were available in a given study, both were abstracted.
4. Unadjusted data from each study were used to calculate the overall weighted odds for human immunodeficiency infection or other sexually transmitted infection. Data from adjusted analyses were only used from a given study to calculate the weighted odds when bivariate data were unavailable.
5. Each study contributed only 1 effect size per outcome. For example, if a study reported associations between male circumcision and gonorrhea, nongonoccocal urethritis, and chlamydial infection, the effects of the 3 sexually transmitted infections were combined into 1 summary effect size.
6. To ensure independence of effects, studies could contribute more than one effect only when data from independent samples were analyzed separately.
Analytic Methods
Odds ratios (ORs) were used to estimate effect sizes. Abstracted data for circumcised MSM and uncircumcised MSM were converted, when necessary, into percentages that represented yes vs no for a given outcome. Standard meta-analytic methods were used to aggregate effects across studies.12 To estimate the overall effect size, each natural log OR (lnOR) was weighted by the inverse of its variance, the weighted lnOR summed across samples, and then divided by the sum of the weights.13 For the purpose of presentation and ease of interpretation, we converted effect sizes and 95% confidence intervals (CIs) back to ORs. An OR of less than 1 indicates a decreased odds of HIV infection or STI among circumcised compared with uncircumcised MSM. We used the I2 index to examine heterogeneity of individual effect sizes in the overall aggregations for HIV and STI and in stratified analyses.14 According to Higgins et al, I2 values of near or less than 25% indicate low heterogeneity, values near 50% indicate moderate heterogeneity, and values near 75% or higher indicate high heterogeneity.14 Under conditions of low heterogeneity (I2 25%), we used fixed-effects models and under conditions of higher heterogeneity (I2 > 25%) we used random-effects models.15-16 Using methods developed by Hedges and Pigott17 to calculate the statistical power of our meta-analysis, we specified a small effect size (15% relative reduction in odds of HIV infection among circumcised vs uncircumcised MSM) as an estimate of the true population value for the overall and stratified aggregations. Power was calculated using variance components derived from the primary studies, a 2-tailed test, and of .05.
Per recommendations from the Cochrane Collaborative Review Group on HIV Infection and AIDS,18 the quality of observational studies in this meta-analysis was assessed using the Newcastle-Ottawa Scale.19 This instrument assesses the quality of nonrandomized studies in 3 broad categories (patient selection [4 criteria], comparability of study groups [1 criterion], and assessment of the outcome [3 criteria]). Following quality assessment standards of previous meta-analyses,20 studies in our meta-analysis that met 5 or more of the Newcastle-Ottawa Scale criteria were considered to be of higher quality. The aggregated effect size of the higher-quality studies were compared with the aggregated effect size of all other studies. We also examined the association of the Newcastle-Ottawa Scale (sum score across the 3 categories) for each study with the respective effect sizes using a weighted generalized least squares meta-regression model.21 Study quality was examined further by focusing on a subset of studies with moderate (22%-66%) circumcision prevalence because studies with very high or very low male circumcision rates may not have had enough variability to detect an association with HIV and STI. Last, we assessed study quality by limiting analyses to studies with large analytical samples (> 1000 participants), and studies that determined circumcision by genital examination and also used diagnostic tests to assess HIV status.
The effect of potential outliers was examined by comparing the aggregated effect size with estimates obtained after iterations using k-1 findings (k = the number of independent effect sizes). Sensitivity analyses of the HIV results indicated that there was no evidence of an outlier among the studies. Sensitivity analyses of the STI results indicated that 2 studies22-23 may be outliers, but we did not treat either study as a statistical outlier because each of the k-1 estimates produced a 95% CI that overlapped with the 95% CI of the full STI sample. To evaluate the presence of publication bias, we used linear regression methods proposed by Sterne and Egger24 to investigate funnel plot asymmetry. There was no evidence of publication bias among the set of HIV studies in these analyses (β, 0.056; P = .84), but we found evidence of potential publication bias among the set of studies that examined STI (β, 0.824; P = .01).
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