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However, there is a paucity of randomized control trials (RCTs) to test this hypothesis in the South African population. Due to the infeasibility of conducting RCTs, estimating marginal or average treatment effects with observational data increases interest. Using targeted maximum likelihood estimation (TMLE), a doubly robust estimation technique, we aim to provide evidence of an association between medical male circumcision (MMC) and two STI outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>HIV and HSV-2 status were the two primary outcomes for this study. We investigated the associations between MMC and these STI outcomes, using cross-sectional data from the HIV Incidence Provincial Surveillance System (HIPSS) study in KwaZulu-Natal, South Africa. HIV antibodies were tested from the blood samples collected in the study. For HSV-2, serum samples were tested for HSV-2 antibodies via an ELISA-based anti-HSV-2 IgG. We estimated marginal prevalence ratios (PR) using TMLE and compared estimates with those from propensity score full matching (PSFM) and inverse probability of treatment weighting (IPTW).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>From a total 2850 male participants included in the analytic sample, the overall weighted prevalence of HIV was 32.4% (<jats:italic>n<\/jats:italic>\u2009=\u2009941) and HSV-2 was 53.2% (<jats:italic>n<\/jats:italic>\u2009=\u20091529). TMLE estimates suggest that MMC was associated with 31% lower HIV prevalence (PR: 0.690; 95% CI: 0.614, 0.777) and 21.1% lower HSV-2 prevalence (PR: 0.789; 95% CI: 0.734, 0.848). The propensity score analyses also provided evidence of association of MMC with lower prevalence of HIV and HSV-2. For PSFM: HIV (PR: 0.689; 95% CI: 0.537, 0.885), and HSV-2 (PR: 0.832; 95% CI: 0.709, 0.975). For IPTW: HIV (PR: 0.708; 95% CI: 0.572, 0.875), and HSV-2 (PR: 0.837; 95% CI: 0.738, 0.949).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Using a TMLE approach, we present further evidence of a protective association of MMC against HIV and HSV-2 in this hyper-endemic South African setting. TMLE has the potential to enhance the evidence base for recommendations that embrace the effect of public health interventions on health or disease outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12889-021-11705-9","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T11:02:48Z","timestamp":1631098968000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Association of medical male circumcision and sexually transmitted infections in a population-based study using targeted maximum likelihood estimation"],"prefix":"10.1186","volume":"21","author":[{"given":"Lateef","family":"Amusa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Temesgen","family":"Zewotir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delia","family":"North","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayesha B. 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