1. 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

2. 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

3. 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

4. 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.

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

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

7. 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)

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

9. 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

10. 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

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

12. 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

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

14. 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

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

16. 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 cm
0.90 py
> 45.6 cm
2.48 py
Kigozi, G., M. Wawer, et al. (2009). AIDS 23(16):

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

18. 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)

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

20. 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

21. 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

22. 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

23. Thank You!