Understanding Contradictory Evidence Regarding HIV Risk Reduction among Circumcised Males in Cross-sectional Studies: The Role of Circumcision Status Misclassification and other Factors Anne Goldzier Thomas, PhD Jason Reed, MD, MPH Kelly Curran, MHS ICASA, Addis Ababa, Ethiopia December 6, 2011

Introduction MC is scaling up in 14 SSA countries following WHO/UNAIDS recommendations issued in 2007 calling for VMMC for HIV prevention WHO/UNAIDS recommendations followed results of numerous ecologic and observational studies and 3 randomized controlled trials (RCTs) proving that removal of the foreskin reduces risk of acquiring HIV RCTs are the gold standard in science for testing cause and effect; allow for control of confounding by randomization process and analytic methods

Introduction (2) Cross-sectional and observational data were never considered definitive, but provided the rationale to conduct the RCTs A vocal minority frequently attempts to discredit the protective effect of male circumcision citing exceptional cross-sectional and observational data We review criteria for evaluating cause and effect that provided equipoise for the medical male circumcision randomized clinical trials Highlight potential fallacies in correlating cross-sectional/observational data that may appear as contradictions to the RCT results

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy Bradford-Hill, Austin (1965). "The Environment and Disease: Association or Causation?". Proceedings of the Royal Society of Medicine 58: 295–300.

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy

HIV and MC Prevalence – Africa Observational Data Circumcision Prevalence < 20% Circumcision Prevalence > 80% Adapted from Halperin & Bailey, Lancet 1999; 354: 1813

Impact on HIV Incidence: Evidence from Observational Studies and RCTs Effect size .15 .2 .3 .4 .5 1 1.5 Study (95% CI) Overall 0.42 ( 0.34, 0.52) High-risk groups 0.29 ( 0.20, 0.42) General Population 0.56 ( 0.44, 0.71) South Africa 0.40 ( 0.24, 0.67) Kenya 0.41 ( 0.24, 0.70) Uganda 0.49 ( 0.28, 0.86)

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy

Consistency Is MC always found to be associated with lower HIV rates? No – MC is only shown to reduce sexual risk MC has not be shown to be protective in IDU and MSM populations Syringe exposure to HIV MC status of receptive partner will not protect from anal sex HIV exposure Cross-sectional and observational associations may be biased/confounded Circumcised and uncircumcised men may be different in ways related to HIV risk which are not measured or controlled for in the study methods Sex during healing period Traditional MC Not following post MC care instructions

Consistency (2) Traditional MC Definition of MC and initiation Incomplete removal of foreskin MC status classification errors – self report in population-based surveys MC is usually over-reported in self-report Defining circumcision is nuanced when foreskin cutting is performed for traditional reasons In some countries, there may be a bias against being uncircumcised when the majority is circumcised Secrecy Men may become circumcised after being infected with HIV Covered in Temporal Relationship slide Circumcision may increase the risk for HIV exposure

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy

Specificity Does MC reduce risk of any other sexually transmitted infections? Men Human papilloma virus Herpes simplex virus type II Genital ulcer disease Female partners Cervical cancer Bacterial vaginosis Trichomonas vaginalis

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy

Temporal Relationship Cross-sectional data do not allow for evaluation of temporal relationships Men may become circumcised after being infected with HIV Cross-sectional data do not distinguish the timing of two events to determine cause and effect Medical circumcision in non-circumcising countries/areas is often performed as a result of frequent STIs, which may be correlated with increased HIV Growing population of HIV+ children Circumcision may increase the risk for HIV exposure Traditional circumcision ceremonies may not use sterile instruments/reuse cutting blades Cultural practices that believe healing if promoted by early sexual intercourse post-circumcision

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy

Adjusted Incidence Rate Ratio Biological Gradient Is there a dose-response relationship? Yes - foreskin size is associated with HIV risk Foreskin Size HIV Incidence per 100 PY Adjusted Incidence Rate Ratio <= 26.3 cm 0.80 py 2.37 26.4 – 35.0 cm 0.92 py 35.2 -45.5 cm 0.90 py > 45.6 cm 2.48 py Kigozi, G., M. Wawer, et al. (2009). AIDS 23(16): 2209-2213.

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy

Biologic Plausibility Foreskin size - area Microbial environment Epithelial layer depth Langerhan’s Cells and CD4+ HIV target cells Tissue structure Ref: Dinh MH, et al. Am J Rep Immun 65 (2011) 279-283

Hill’s Criteria for Causal Evidence Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment (reversibility) Analogy

Coherence Is this association coherent with HIV natural history? Yes – HIV is acquired sexually Yes – HIV is higher among men with STI and MC reduces STI Yes – Men who are not circumcised may have trauma to the foreskin which promotes HIV entry

DHS MC – HIV Association HIV Prevalence Risk Ratio Statistical Significance Circumcised Not Burkina Faso 1.8 2.9 0.62 NS Cameroon 4.1 1.1 3.73 + Cote d’Ivoire 2.8 3.8 0.74 Ethiopia 0.9 0.82 Ghana 1.6 1.4 1.14 Kenya 3.0 12.6 0.24 - Lesotho 22.8 15.2 1.50 Malawi 13.0 10.0 1.39 Niger 1.0 Rwanda 3.5 2.1 1.67 Tanzania 6.5 5.6 1.16 Uganda 0.68 Zimbabwe 16.6 14.2 0.95 Garenne, M. (2008). African Journal of Aids Research 7(1): 1-8

Conclusions Male circumcision denialism continues to undermine efforts to scale up this important HIV prevention modality While there are certainly other evidence-based HIV prevention modalities that are also important such as PMTCT, and use of condoms, and treatment as prevention, MC has the potential to prevent 3.4 million HIV infections and to save $16.5 billion USD in treatment costs We need to pivot away from spending scarce time and financial resources questioning whether MC will protect lives and move in earnest towards putting our full effort to make this prevention modality the desirable social norm and readily available

Thank You!