Male circumcision and risk of HIV infection: Current epidemiological data

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

2. HIV seroprevalence in adults, end 2000

4. 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

5. RR<1 reduced risk of HIV among circumcised men RR=1 (no effect) Barongo-all Kelly Population-based studies Quigley Serwadda Urassa-2 Urassa-3 Bwayo High risk studies Cameron Diallo Mbugua Sassan-Morokro Simonsen Tyndall Other studies Seed Urassa-4 Combined .1 .2 .3 .4 .5 1 2 3 4 5 Adjusted relative risk

6. 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

7. 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

8. 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

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

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

11. Population-based studies

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

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

14. High risk group studies

15. Analysis by type of study

16. 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

17. 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

18. 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; 13:399-405 • Quigley et al: AIDS 1997; 11:237-248 • Conflicting and inconclusive results

19. 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

20. 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 0.1-1.1 • 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

21. STIs Lack of circumcision HIV

22. Male circumcision & other STIs

23. 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

24. MC & cervical cancer • Multi-country analysis of 1913 couples Castellsague et al: NEJM 2002:346:1105-12 • Brazil, Colombia, Thailand, Philippines, Spain • Adjusted OR = 0.72, 95% CI 0.49-1.04 • In monogamous women: • Adjusted OR = 0.75, 95% CI 0.49-1.14 • Penile HPV infection in male partner: • Adjusted OR = 0.37 (95% CI 0.2-0.9)

25. 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)

26. 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

27. 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

28. 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