Trials of Circumcision to Prevent HIV Infection May Overstate Effect When Stopped Early

The Lancet, Volume 368: Page 1236, 7 October 2007.

Cautious optimism for new HIV/AIDS prevention strategies

The 2006 International AIDS Conference, showcased in the special (Lancet)^Red issue, was filled with promises for effective prevention strategies. Media attention and plenary speeches suggested that effective strategies, notably male circumcision and pre-exposure prophylaxis (PREP), are imminent.¹ Instead we advise cautious optimism.

The inferences drawn from the only completed randomised controlled trial (RCT) of circumcision could be weak because the trial stopped early.² In a systematic review of RCTs stopped early for benefit,³ such RCTs were found to overestimate treatment effects. When trials with events fewer than the median number (n=66) were compared with those with event numbers above the median, the odds ratio for a magnitude of effect greater than the median was 28 (95% CI 11–73). The circumcision trial recorded 69 events, and is therefore atrisk of serious effect overestimation.

We therefore advocate an impartial meta-analysis of individual patients’ data from this and other trials underway before further feasibility studies are done.

Although the rationale for PREP is exciting, researchers have leapt from small (n=6–18) and inconsistent nonrandomised monkey studies into multicentred trials.⁴ The first PREP trial results were provided at the conference,⁵ but had an insufficient number of infections to provide any inferences about effectiveness (two of363 vs six of 368).

New interventions are required to slow the HIV/AIDS pandemic. Disappointments stemming from media hype and misinterpretation of early trials can make policy and recruitment of appropriate trial populations difficult. If we are to alter the epidemic’s progress, we should be methodologically rigorous, and cautiously optimistic about the potential for new interventions.

We declare that we have no conflict of interest.

*Edward Mills, Nandi Siegfried
emills@cihhrs.org

Centre for International Health and Human Rights Studies, 1255 Sheppard Avenue East, Toronto, Ontario M2K 1E2, Canada (EM); and Clinical Trial Service Unit, Department of Medicine, University of Oxford, Oxford, UK (NS)

References

Saletan W. When cutting isn’t cruel. Washington Post Aug 20, 2006: B02.
Siegfried N. Does male circumcision prevent HIV infection? PLoS Med 2005; 2: e393. [Full Text]
Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005; 294: 2203–09. [Abstract]
Mills EJ, Singh S, Singh JA, Orbinski JJ, Warren M, Upshur RE. Designing research in vulnerable populations: lessons from HIV prevention trials that stopped early. BMJ 2005; 331: 1403–06. [Full Text]
Peterson L, Taylor D, Clarke EEK, et al. Findings from a double-blind, randomized, placebocontrolled trial of tenofovir disoproxil fumarate (TDF) for prevention of HIV infection in women. XVI International AIDS Conference; Toronto, Canada; Aug 17, 2006.

Citation:

Mills J, Siegfried N. Cautious optimism for new HIV/AIDS prevention strategies. Lancet 2006;368:1236.

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