Male circumcision and risk of HIV infection: Current epidemiological data Helen Weiss London School of Hygiene & Tropical Medicine, UK

HIV seroprevalence in adults, end 2000

Systematic review, 1999 Inclusion criteria: –Studies in Africa –Female to male transmission of HIV-1 –Published papers only (up to April 1999) –28 studies identified Summary risk ratio (RR) obtained using random-effects meta analysis

Adjusted relative risk Combined Urassa-4 Seed Tyndall Simonsen Sassan-Morokro Mbugua Diallo Cameron Bwayo Urassa-3 Urassa-2 Serwadda Quigley Kelly Barongo-all Other studies High risk studies Population- based studies RR<1 reduced risk of HIV among circumcised men RR=1 (no effect)

Updated analysis - Sep 2002 Aim: To update the meta-analysis and include data from non-African countries with high HIV prevalence Inclusion criteria: –Published studies of F-M transmission in developing countries –Abstracts from XIV AIDS conference included

Studies included 11 additional studies identified –Published literature (9) –Abstracts from XIV International AIDS conference (2) –5 cohort studies –2 non-African studies Total of 38 studies, of which 22 adjusted for confounding

Study characteristics 17 population-based –12 cross-sectional, 3 cohort, 2 case-control –6 Mwanza, 4 Rakai, 3 Kenyan 18 high risk groups –STD clinic attendees, truck drivers, TB patients, discordant couples –11 cross-sectional, 5 cohort, 3 case-control –7 Nairobi studies 3 others - Volunteers, factory workers

Population-based studies - crude RRs * Additional study - not included in published meta-analysis

Population based studies - adjusted RRs * Additional study - not included in published meta-analysis

Population-based studies

High risk groups - crude RRs * Additional study - not included in published meta-analysis

High risk groups - adjusted RRs * Additional study - not included in published meta-analysis

High risk group studies

Analysis by type of study

Is the effect real? Strong, consistent effect –very unlikely to be to due to random error Significant, strong effect in cohort studies (less susceptible to bias) Effect strengthens on adjustment for confounders –effect unlikely to be due to residual confounding

Limitations Not a fully systematic review –Strength of effect may be over-estimated as studies not finding an effect are more difficult to identify –But - included studies found in recent Cochrane systematic review Observational studies only –Possibility of selection biases and residual confounding Significant heterogeneity between studies –Effect may differ in different populations

Effect of age at circumcision Many African tribes circumcise around puberty. Biologically plausible that MC has similar effect irrespective of age at circumcision Only 2 studies have examined HIV risk in relation to age at circumcision –Kelly et al; AIDS 1999; 13: –Quigley et al: AIDS 1997; 11: Conflicting and inconclusive results

Does MC affect risk of HIV transmission? Difficult to assess epidemiologically –Women may have more than one partner –More scope for misclassification Biologically less plausible than effect of acquisition of HIV

M-F transmission of HIV Uganda - cohort study of discordant couples Quinn et al; NEJM 2000; 342:921-9 –Some evidence of reduced transmission among circumcised males –RR=0.41, 95% CI Brazil - cross sectional couples study Castilho et al; XIV AIDS conf. abstr. C10907 –No effect of circumcision on HIV prevalence in female partners of 377 HIV positive men

Lack of circumcision HIV STIs

Male circumcision & other STIs

MC & cervical cancer Most common cancer in many developing countries HPV infection - major cause Geographically clusters with penile cancer –Both cancers associated with HPV infection –Lower risk of HPV infection among circumcised men –Lower risk of penile ca. among circumcised men

MC & cervical cancer Multi-country analysis of 1913 couples Castellsague et al: NEJM 2002:346: –Brazil, Colombia, Thailand, Philippines, Spain Adjusted OR = 0.72, 95% CI –In monogamous women: Adjusted OR = 0.75, 95% CI –Penile HPV infection in male partner: –Adjusted OR = 0.37 (95% CI )

Current research needs  Biological mechanism  Attitudes & feasibility of introducing MC among non-circumcising communities  Effect of age at circumcision  Effect of hygiene practices ? Classification of circumcision through physical examination rather than self-report  Data on safety of current MC practices ? Effect of MC among MSM ? Male-female transmission ? Effect of MC on other viral infections of public health importance (e.g. HPV, HSV)

Conclusions Observational evidence for a protective effect of MC on risk of HIV infection is strong and consistent BUT cannot exclude selection biases and residual confounding in observational studies RCTs will address many of these limitations  Probably not ready to actively promote MC as an HIV prevention measure

What should we do now? Disseminate current evidence Continue studies of acceptability & feasibility of MC in non-circumcising populations with high incidence of HIV Assess safety of current circumcising procedures Develop affordable services for safe voluntary MC Develop educational materials that: –emphasise that MC may reduce but not eliminate risk of HIV infection –Separate out issues of male and female circumcision

Summary of 2002 analysis All studies (n=38) –crude RR=0.52; 95% CI: 0.42 to 0.64 –adjusted RR=0.44; 95% CI: 0.37 to 0.53 Population-based studies - adjusted (n=10) –RR=0.57; 95% CI: 0.47 to 0.70 High risk groups - adjusted (n=10) –RR=0.31; 95% CI: 0.23 to 0.42