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Estimated Protection Too Conservative

Posted by plosmedicine on 30 Mar 2009 at 23:48 GMT

Author: James Shelton
Position: Senior Medical Scientist
Institution: US Agency for International Development
E-mail: JShelton@USAID.Gov
Submitted Date: November 07, 2005
Published Date: November 11, 2005
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The randomized study by Auvert et al on male circumcision to prevent HIV infection is clearly a landmark study, which supports compelling observational evidence of strong protection.1 However, I believe the highlighted degree of protection of 60% from the "intent to treat" analysis is probably too conservative. Deep in the article we learn that the "per protocol" analysis, which addressed the 10.3% of men allocated to the non-circumcision group who nevertheless decided to be circumcised outside the study, found a relative risk of 0.24% - or a protective effect of 76%.

Some might argue that the "intent to treat" analysis is more "scientific" and reduces the impact of some selection or behavioral bias in those who opted for circumcision notwithstanding their allocation to the control arm. For example it could be that men allocated to the non-circumcision group who were predisposed to less risky behavior but wanted to be super safe, might have chosen to be circumcised. In the opposite direction, those who were indulging most in risky behavior might have chosen to be circumcised to reduce their risk.

In my view, however, if we are interested in the true biologic effect, it is not very scientific to bias toward the analysis with a 10% contamination of that biological effect. In this study we are fortunate enough to have quite rich reported behavioral data. More analysis of the "per protocol" analysis should have been presented including the behavior of the crossovers. It is reasonably likely that any difference in the behavior of the crossovers would have little impact since in the "intent to treat" analysis, adjustment for the increase in riskier behavior in the treatment group had little effect on the overall result.

The paper should have had prominent presentation of both analyses. In either case the protection is quite substantial. But from an epidemiologic and personal perspective, what amounts to a failure rate of 40% versus 24% could be quite important.

1. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africe: a systematic review and meta-analysis. AIDS 2000; 14:2361-2370.

No competing interests declared.