Is circumcision an answer for HIV prevention in men who have sex with men? – Authors' reply

We thank Robert Van Howe for his comments on our meta-analysis.1Yuan T Fitzpatrick T Ko NY et al.Circumcision to prevent HIV and other sexually transmitted infections in men who have sex with men: a systematic review and meta-analysis of global data.Lancet Glob Health. 2019; 7: e436-e447Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar Despite the large sample sizes of the observational studies by Mor and colleagues2Mor Z Kent CK Kohn RP Klausner JD Declining rates in male circumcision amidst increasing evidence of its public health benefit.PLoS One. 2007; 2: e861Crossref PubMed Scopus (42) Google Scholar and Jozkowski and colleagues3Jozkowski K Rosenberger JG Schick V Herbenick D Novak DS Reece M Relations between circumcision status, sexually transmitted infection history, and HIV serostatus among a national sample of men who have sex with men in the United States.AIDS Patient Care STDS. 2010; 24: 465-470Crossref PubMed Scopus (17) Google Scholar mentioned in Van Howe's letter, those studies each had a high risk of bias (with crude odds ratios [ORs], single-centre setting, and self-reported HIV and circumcision), meeting only three2Mor Z Kent CK Kohn RP Klausner JD Declining rates in male circumcision amidst increasing evidence of its public health benefit.PLoS One. 2007; 2: e861Crossref PubMed Scopus (42) Google Scholar and one3Jozkowski K Rosenberger JG Schick V Herbenick D Novak DS Reece M Relations between circumcision status, sexually transmitted infection history, and HIV serostatus among a national sample of men who have sex with men in the United States.AIDS Patient Care STDS. 2010; 24: 465-470Crossref PubMed Scopus (17) Google Scholar of the seven Newcastle-Ottawa Scale criteria. In fact, restricting our analysis to the 14 studies that adjusted for confounders led to an increase in the protective association between circumcision and HIV (OR 0·64, 95% CI 0·45–0·93). Additionally, both the aforementioned observational studies2Mor Z Kent CK Kohn RP Klausner JD Declining rates in male circumcision amidst increasing evidence of its public health benefit.PLoS One. 2007; 2: e861Crossref PubMed Scopus (42) Google Scholar, 3Jozkowski K Rosenberger JG Schick V Herbenick D Novak DS Reece M Relations between circumcision status, sexually transmitted infection history, and HIV serostatus among a national sample of men who have sex with men in the United States.AIDS Patient Care STDS. 2010; 24: 465-470Crossref PubMed Scopus (17) Google Scholar were conducted in the USA. In our subgroup meta-analyses, circumcision was indeed not protective against HIV infection among MSM in high-income countries, but was protective in low-income and middle-income countries. We agree with Van Howe that the remaining 41 studies' sample sizes were not as large as those in the studies by Mor and colleagues and Jozkowski and colleagues; however, these studies contributed 58 137 patients in total and the sample size of each study was reflected by its weight in the meta-analysis. Combining multiple studies to increase the overall sample size and statistical power is the predominant advantage of meta-analysis. High between-study heterogeneity is a concern for any meta-analysis. However, the Oxford Centre for Evidence-based Medicine clearly states that not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant.4Oxford Centre for Evidence-based Medicine—levels of evidence.https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/Date: March 2009Date accessed: April 22, 2019Google Scholar Van Howe was referring only to statistical heterogeneity, while ignoring clinical heterogeneity, which is more relevant to the soundness of the results. We did sensitivity, subgroup, and meta-regression analyses to explore the possible sources of between-study heterogeneity, which helps health-care providers to appreciate the evidence in respective of clinical and public health advice. To detect outliers, we excluded one study at a time and recalculated pooled estimates and between-study heterogeneity for the remaining studies. This method is well established and commonly used. We do not know what method Van Howe used to detect the three to seven outlier studies mentioned in his letter; however, the study he cited stated that the exclusion of one or two studies suffices to decrease between-study heterogeneity in most cases.5Patsopoulos NA Evangelou E Ioannidis JP Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation.Int J Epidemiol. 2008; 37: 1148-1157Crossref PubMed Scopus (580) Google Scholar Given that the trim and fill method has been widely criticised by statisticians because of its biased estimation, especially in the case of high between-study heterogeneity,6Terrin N Schmid CH Lau J Olkin I Adjusting for publication bias in the presence of heterogeneity.Stat Med. 2003; 22: 2113-2126Crossref PubMed Scopus (472) Google Scholar, 7Peters JL Sutton AJ Jones DR Abrams KR Rushton L Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity.Stat Med. 2007; 26: 4544-4562Crossref PubMed Scopus (435) Google Scholar we opted not to use this method. Instead, we clearly acknowledged the presence of publication bias in our analyses and, accordingly, interpreted our results with great caution. As we made clear in our study, although circumcision has yet to be approved as a definitive tool for HIV prevention in MSM, our findings strongly suggest that circumcision could be an effective strategy to curb the HIV epidemic among MSM in some of the countries most burdened by HIV. We declare no competing interests. Circumcision to prevent HIV and other sexually transmitted infections in men who have sex with men: a systematic review and meta-analysis of global dataWe found evidence that circumcision is likely to protect MSM from HIV infection, particularly in countries of low and middle income. Circumcision might also protect MSM from HSV and penile HPV infection. MSM should be included in campaigns promoting circumcision among men in countries of low and middle income. In view of the substantial proportion of MSM in countries of low and middle income who also have sex with women, well designed longitudinal studies differentiating MSM only and bisexual men are needed to clarify the effect of circumcision on male-to-male transmission of HIV and other STIs. Full-Text PDF Open AccessIs circumcision an answer for HIV prevention in men who have sex with men?The meta-analysis1 and accompanying Comment2 addressing circumcision and HIV infection in men who have sex with men (MSM) might reflect a confirmation bias. As a consultant at the US Centers for Disease Control and Prevention's 2007 consultation on public health issues regarding male circumcision in the USA,3 I noted a palpable urgency among those invited—nearly all of whom were avowed circumcision advocates—to uncover or generate data proving that circumcision protects MSM from HIV infection. Now, 12 years later, circumcision advocates will be celebrating the accomplishment of this mission. 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