J Sobngwi Tambekou, 1 D Taljaard, 2 M Nieuwoudt, 3 P Lissouba, 1 A Puren, 3 B Auvert 4. Epidemiology

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1 1 INSERM U687, Hôpital Paul Brousse, Villejuif, Frane; 2 Progressus, Johannesburg, South Afria; 3 National Institute for Communiable Diseases, Johannesburg, South Afria; 4 INSERM U687, Assistane Publique-Hôpitaux de Paris, University of Versailles, Frane Correspondene to: Dr Bertran Auvert, INSERM U687, 12 avenue Paul Vaillant- Couturier, Villejuif Cedex, Frane; bertran.auvert@uvsq.fr Aepted 28 November 2008 Published Online First 15 Deember 2008 This paper is freely available online under the BMJ Journals unloked sheme, see sti.bmj.om/info/unloked.dtl Male irumision and Neisseria gonorrhoeae, Chlamydia trahomatis and Trihomonas vaginalis: observations after a randomised ontrolled trial for HIV prevention J Sobngwi Tambekou, 1 D Taljaard, 2 M Nieuwoudt, 3 P Lissouba, 1 A Puren, 3 B Auvert 4 ABSTRACT Objetive: To assess the assoiation between male irumision and Neisseria gonorrhoeae, Chlamydia trahomatis and Trihomonas vaginalis using data from a male irumision randomised ontrolled trial. Methods: We used data olleted during the male irumision trial onduted in Orange Farm (South Afria) among men aged years. Altogether, 1767 urine samples olleted during the final follow-up visit were analysed using PCR. Prevalene of N gonorrhoeae, C trahomatis and T vaginalis was assessed as a funtion of male irumision using odds ratios (OR) given by univariate and multivariate logisti regression. Results: In an intention-to-treat analysis, prevalene of N gonorrhoeae, C trahomatis and T vaginalis among intervention and ontrol groups were 10.0% versus 10.3% (OR 0.97; p = 0.84), 2.1% versus 3.6% (OR 0.58; p = 0.065) and 1.7% versus 3.1% (OR 0.54; p = 0.062), respetively. The assoiation between T vaginalis and male irumision remained borderline when ontrolling for age, ethni group, number of lifetime partners, marital status, ondom use and HIV status (AOR 0.48; p = 0.069). In the as-treated analysis, this assoiation beame signifiant (OR 0.49, p = 0.030; AOR 0.41, p = 0.030). Conlusions: This study demonstrates for the first time that male irumision redues T vaginalis infetion among men. This finding explains why women with irumised partners are less at risk for T vaginalis infetion than other women. The protetive effet on T vaginalis is an additional argument to reommend male irumision in Afria where it is aeptable. Trial registration number: NCT Reent evidene has shown that male irumision is a promising prevention approah for sexually transmitted infetions (STIs): three randomised ontrolled trials (RCTs) 1 3 have shown that male irumision redues HIV infetion among young men in Afria. Aording to a meta-analysis published in 2006, irumised men may be at lower risk of herpes simplex virus 2 (HSV-2) infetion, hanroid and syphilis. 4 However, there are onfliting results about the assoiation of male irumision and non-ulerative STIs suh as Neisseria gonorrhoeae, Chlamydia trahomatis 5 11 and Trihomonas vaginalis infetions among men Infetion with non-ulerative STIs is major publi health issue. There are about 62 million new ases of N gonorrhoeae annually worldwide, with an estimated inidene of 17 million in sub- Saharan Afria. 15 N gonorrhoeae is asymptomati in only 10% of men but primarily asymptomati in women and its ompliations an be lethal. 15 C trahomatis worldwide inidene has been estimated at 92 million annually, with about 16 million ourring in sub-saharan Afria. 15 It is a signifiant publi health onern beause C trahomatis infetion is asymptomati in over 50% of ases among men and women 15 and it an lead to serious health ompliations if untreated. 16 Finally, T vaginalis is the most ommon non-viral STI in the world, with 174 million new ases estimated in In sub-saharan Afria, the inidene is estimated at 32 million. 15 The infetion is asymptomati in about 50% of infeted women and in over 90% of men; 15 thus, re-infetion and reexposure is problemati. 17 Furthermore, o-infetions among these three STIs are ommon The objetive of this study was to analyse the effet of male irumision on N gonorrhoeae, C trahomatis and T vaginalis prevalene using data olleted during a male irumision RCT onduted in Orange Farm, South Afria. 1 METHODS Colletion of data The tehnial details of the trial (ANRS-1265 study), inluding the desription of the population, has been published elsewhere. 1 Between February 2002 and July 2004, 3274 unirumised male volunteers, aged 18 to 24 years, signed a onsent form and were reruited, randomised into two groups and followedup. Male irumision was offered immediately after randomisation to the intervention group and after the end of the follow-up period to ontrol group partiipants. During eah follow-up visit at 3, 12 and 21 months, irumision status was assessed by a nurse through genital examination, a blood sample was taken and information about sexual behaviour was olleted. For 318 onseutive days, between 10 January 2005 and 24 November 2005, a 10 ml sample of firstvoided urine was olleted from all partiipants oming for the 21-month visit during this period. These samples were analysed to assess the assoiation between male irumision and N gonorrhoeae, C trahomatis and Tvaginalisprevalene. Laboratory methods Urine samples were frozen at 220uC immediately after olletion and kept frozen until proessing. N gonorrhoeae and C trahomatis testing was 116 Sex Transm Infet 2009;85: doi: /sti

2 performed using the COBAS Amplior detetion kit (Rohe Moleular Diagnostis, Pleasanton, California, USA). For the detetion of T vaginalis, a qualitative FRET-based real-time PCR diagnosti test (Rohe Moleular Diagnostis) was used based on previous published literature and validated using haraterised speimens PCR has been shown to identify signifiantly more trihomoniasis ases than ulture. 22 Data analysis Categorial data of the ontrol and intervention groups were ompared using x 2 or Fisher exat test when appropriate and numerial data were ompared using the Kruskal-Wallis test. N gonorrhoeae, C trahomatis and T vaginalis positive samples were analysed using intention-to-treat and as-treated analyses with univariate logisti regression. These analyses were repeated multivariately to ontrol for ethni group, eduation, age, number of lifetime partners, marital status, ondom use and HIV status. To assess whether the effet of male irumision on T vaginalis was independent of HIV infetion, whih is redued by male irumision 1 3 and assoiated with T vaginalis infetion, 23 the analysis of the assoiation between T vaginalis and male irumision was repeated a) among those who remained HIV negative during follow-up and b) exluding those who were HIV positive at reruitment. To evaluate the effet of an imbalane between the groups, analyses of signifiant results were repeated when ontrolling for the propensity sore oded in quintiles. 24 RESULTS The baseline harateristis of the partiipants who were tested for C trahomatis, N gonorrhoeae and T vaginalis by randomisation group are reported in table 1. The harateristis of those who did not attend follow-up visits during whih biologial samples were olleted but who ame for the last follow-up visit are also reported in table 1. s differed aording to their ethni distribution, the number of sex ats and HIV status. When ompared with study partiipants, those Table 1 not tested for C trahomatis, N gonorrhoeae and T vaginalis had a higher number of lifetime partners and a higher HIV prevalene. Tables 2 4 present the univariate and multivariate assoiation between male irumision and N gonorrhoeae, C trahomatis and T vaginalis, respetively. It was found that there was no effet of male irumision on N gonorrhoeae, as demonstrated by the odds ratio (OR) values lose to 1 in table 2. The borderline assoiation between male irumision and C trahomatis in the intention-to-treat analysis disappeared in the as-treated analysis. The borderline assoiation between male irumision and T vaginalis in the intention-to-treat analysis beame signifiant in the univariate and multivariate as-treated analysis. The adjusted ORs were slightly lower than the orresponding univariate ORs with values lose to 0.5. When exluding those who HIV seroonverted during followup, the OR values reported in table 4 remained almost unhanged with relative variation between 27.3% and +3.7% (results not shown). This indiates that the effet of male irumision on T vaginalis is independent of the effet of male irumision on HIV. When exluding those who were HIV positive at reruitment, the OR values and p values reported in table 4 beame slightly lower. The OR and adjusted OR (AOR) assoiated with randomisation groups were 0.45 (95% CI 0.22 to 0.89; p = 0.023) and 0.39 (95% CI 0.19 to 0.80; p = ), respetively. The OR and AOR assoiated with irumision status were 0.34 (95% CI 0.14 to 0.82; p = 0.016) and 0.39 (95% CI 0.18 to 0.76; p = 0.065), respetively. The AORs of table 4 were almost idential when the analyses were adjusted for the propensity sore in addition to the other ovariates. DISCUSSION This study demonstrates that male irumision does not have a protetive effet on C trahomatis aquisition in men, whih onurs with the findings from most studies exploring this assoiation whether assessed in ross-setional studies or in ohort studies. Only one multi-site study pooling Bakground harateristis, reported sexual behaviour and HIV prevalene at the 21-month visit Control Intervention* All partiipants tested (ontrol + intervention) Partiipants not tested for CT, NG and TV{ n = 881 n = 886 (p value) n = 1767* n = 1188 (p value) Bakground harateristis Ethni group Sotho 53.0% 54.0% (0.012) 53.5% 40.6% (,0.001) Zulu 33.52% 28.3% 30.9% 42.3% Other 13.5% 17.7% 15.6% 17.1%,21 years old 33.3% 29.1% (0.065) 31.2% 32.9% (0.33) Primary level of eduation ompleted 98.9% 98.0% (0.18) 98.4% 98.1% (0.48) Married or living as married1 4.7% 5.7% (0.45) 5.2% 7.1% (0.061) Reported sexual behaviour Mean (median) number of lifetime sex 4.2 (4.0) 4.4 (4.0) (0.55) 4.3 (4.0) 4.8 (4.0) (,0.001) partners Mean (median) number of non-spousal sex 0.88 (1.0) 0.94 (1.0) (0.48) 0.91 (1.0) 0.87 (1.0) (0.73) partners{ Mean (median) number of sex ats{ 7.4 (2.0) 9.0 (3.0) (0.045) 8.2 (3.0) 7.0 (3.0) (0.65) Consistent ondom use with non-spousal 23.4% 24.6% (0.70) 24.1% 5.2% (,0.001) sex partners{" HIV prevalene HIV positive 7.1% 4.5% (0.025) 5.8% 8.0% (0.02) *The p value orresponds to the omparison of the ontrol and intervention group; {the p value orresponds to the omparison of those tested for Neisseria gonorrhoeae (NG), Chlamydia trahomatis (CT) and Trihomonas vaginalis (TV) with those not tested; {during the past 12 months; 1at some time during the past 12 months; "among those having had sexual interourse during the past 12 months. 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3 Table 2 Assoiation between Neisseria gonorrhoeae (NG) prevalene and male irumision NG prevalene % Control 10.3% (91/881) 1 1 Intervention 10.0% (89/886) 0.97 (0.71 to 1.32; p = 0.84) 0.94 (0.69 to 1.29; p = 0.72) Unirumised 10.0% (88/878) 1 1 Cirumised 10.4% (92/887) 1.04 (0.76 to 1.41; p = 0.81) 1.02 (0.74 to 1.40; p = 0.91) *Adjusted odds ratio on ethni group, age, eduation, number of lifetime partners, marital status, ondom use and HIV status. Table 3 Assoiation between Chlamydia trahomatis (CT) prevalene and male irumision CT prevalene % Control 3.6% (32/881) 1 1 Intervention 2.1% (19/886) 0.58 (0.33 to 1.03; p = 0.065) 0.56 (0.32 to 1.00; p = 0.052) Unirumised 3.3% (29/878) 1 1 Cirumised 2.5% (22/887) 0.74 (0.42 to 1.31; p = 0.30) 0.75 (0.42 to 1.32; p = 0.31) *Adjusted odds ratio on ethni group, age, eduation, number of lifetime partners, marital status, ondom use and HIV status. Table 4 Assoiation between Trihomonas vaginalis (TV) prevalene and male irumision TV prevalene % Control 3.1% (27/881) 1 1 Intervention 1.7% (15/886) 0.54 (0.29 to 1.03; p = 0.062) 0.53 (0.28 to 1.02; p = 0.056) Unirumised 3.2% (28/878) 1 1 Cirumised 1.6% (14/887) 0.49 (0.25 to 0.93; p = 0.030) 0.47 (0.25 to 0.92; p = 0.027) *Adjusted odds ratio on ethni group, age, number of lifetime partners, marital status, ondom use and HIV status, exluding eduation beause of the limited number of ases. ross-setional data of 305 ouples from Thailand, the Philippines, Brazil, Colombia and Spain found that when ontrolling for the number of sexual partners of the ouple, male irumision was assoiated with an 82% redution in the risk of C trahomatis infetion in female partners (OR 0.18, 95% CI 0.05 to 0.58). However, C trahomatis infetion was not asertained in the men themselves in that study and the authors admit that it is possible that male irumision redues the risk of transmission of the infetion to the partner without reduing the risk of C trahomatis aquisition in the men themselves. 16 In fat, two studies seem to suggest that C trahomatis prevalene is higher among irumised men and their partners This study has some limitations. Biologial samples were not olleted throughout the follow-up period, so the C trahomatis, N gonorrhoeae and T vaginalis statuses at inlusion are unknown. As a result, some T vaginalis infetions may have predated the intervention. Thus, we report the effet of male irumision on T vaginalis prevalene and not T vaginalis inidene. Only partiipants oming for the last follow-up visit and during a speified time period were tested for C trahomatis, N gonorrhoeae and T vaginalis. This may have introdued some bias. Indeed, we found that those having undergone STIs testing were slightly different from those who had not. However, this differene was not expeted to hange the assoiation between male irumision and the C trahomatis, N gonorrhoeae and T vaginalis statuses. Lastly, the slight differene between irumised and unirumised partiipants, whih may be partly explained by a differential follow-up, may also have interfered with the result of this study. Hene, the fat that the results were not hanged when adjusting on the propensity sore is reassuring. Nevertheless, the results of this study have to be onfirmed using the data of the two other male irumision trials onduted in Kenya and Uganda. 2 3 No evidene of a protetive effet of male irumision on N gonorrhoeae infetion was found. Previous studies have suggested that results will vary aording to the population assessed: four studies among male attendees of STI linis in developed ountries found that unirumised men were up to twie as likely to develop N gonorrhoeae infetion than irumised men (OR of 1.6 to 2.0). However, none of the studies onduted in developing ountries found evidene of suh an effet. The study demonstrated a borderline protetion effet of male irumision on T vaginalis infetion by young men in the intention-to-treat analysis and a signifiant effet in the astreated analysis. The differene between the two analyses may have been aused by the high proportion of ross-over in this RCT, 1 whih diluted the effet observed in the intention-totreat analysis. The fat that the protetive effet beame slightly stronger in the multivariate analysis, whih inludes HIV status, also suggests a protetive independent effet of male irumision on T vaginalis aquisition. 118 Sex Transm Infet 2009;85: doi: /sti

4 Key messages Male irumision protets men against Trihomonas vaginalis infetion, whih is the most ommon non-viral sexually transmitted infetion in the world. T vaginalis infetion auses severe morbidity among women. Male irumision indiretly benefits women by reduing their exposure to T vaginalis. Male irumision does not provide protetion against Neisseria gonorrhoeae or Chlamydia trahomatis. This finding is noteworthy beause very few studies have investigated this assoiation in men probably due to diagnosti limitations. Nevertheless, the size of the protetive effet obtained in this study is onsistent with what has been estimated by observational studies. A ross-setional investigation onduted among men from the general population of Mwanza, Tanzania, found that male irumision status was signifiantly assoiated with T vaginalis infetion (OR 0.37, 95% CI 0.19 to 0.72) when adjusting for age. 12 In their prospetive study among US male partners of women infeted with T vaginalis, Seña and olleagues found that unirumised men were almost twie as likely to be infeted with T vaginalis (unadjusted OR 1.8, 95% CI 1.10 to 3.20). 14 The fat that N gonorrhoeae and C trahomatis are almost exlusively urethral pathogens may explain why male irumision has no protetive effet against them. In ontrast, the protetive effet against T vaginalis may indiate that T vaginalis is both a sub-preputial and a urethral pathogen. There is also evidene that male irumision redues T vaginalis aquisition by female partners. A reent randomised study onduted in Rakai, Uganda, among HIV disordant heterosexual ouples indiated that the rate of T vaginalis infetion among partners of partiipants from the intervention arms was redued by almost half (adjusted risk ratio 0.52, 95% CI 0.05 to 0.98). 13 Hene, our study illustrates why male irumision is protetive against T vaginalis infetion among women having irumised partners. Indeed, as shown in our study, male irumision redues the risk of T vaginalis infetion among men and onsequently redues the exposure of women to T vaginalis. Thus, the risk of T vaginalis infetion is lowered among women. Some studies have suggested that T vaginalis failitates the spread of HIV by up to twofold Thus, the effet of male irumision on HIV aquisition in young men may partly be due to its effet on T vaginalis. If the results of this study are onfirmed by those of the male irumision trials onduted in Uganda and Kenya, the findings of this study will reinfore the WHO-UNAIDS statement reommending the implementation of male irumision programmes in Afrian ountries with low male irumision prevalene and a high male irumision aeptability. 32 Aknowledgements: The authors would like to thank all the volunteers who agreed to take part in this study, answer the questions put to them and provide swab samples. G Sipho Phatedi for his management of the reruitment proess and Y de La Soudière for his help in the management of the data set. Dr B Gwala, Dr G Shilaluke and Dr D Zulu who performed the male irumisions for the study. G Gumede for the linial investigation and Z Nkosi for interviewing all the respondents. They would also like to thank B Klaas for the data apture, as well as M Hunter, the reruitment staff and all the assistants (C Dlamini, S Dumisi, B Masitenyane, R Matodzi, T Mbuso, A Motha, S Mpetsheni, J Nhlapo, J Ntsele, MChakela, A Tshabalala, D Mashamba, N Nhlapo) for their ooperation and support. L Short, M Mashiloane, B Miller, B Singh, S Hloma and the HIV serology laboratory of the National Institute for Communiable Epidemiology Diseases, Johannesburg, South Afria, provided tehnial assistane with the laboratory testing. Funding: This study was supported by ANRS (Frane) grant 1265, NICD (South Afria), Gates Foundation (USA) grant and INSERM (Frane). Competing interests: None. Ethis approval: The researh protool was reviewed and approved by the University of Witwatersrand Human Researh Ethis Committee (Medial) (protool study number M020104). 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