Circumcision and HIV
Two out of three key trials registered late
Does circumcision of adult men reduce HIV transmission? Initial scepticism, surely the foreskin reduces friction between penis and vagina, and prevents abrasions and blood transfer, and conflicting observational data, were eventually overcome by three randomised trials, one each from South Africa (click here), Kenya (click here) and Uganda (click here). In each trial men were randomly allocated to immediate circumcision or to wait for two years. All three trials showed about half the number of new HIV infections in the immediate circumcision group. The relevant Cochrane review (click here) summarises them as follows:
“The resultant incidence risk ratio (IRR) was 0.50 at 12 months with a 95% confidence interval (CI) of 0.34 to 0.72; and 0.46 at 21 or 24 months (95% CI: 0.34 to 0.62). These IRRs can be interpreted as a relative risk reduction of acquiring HIV of 50% at 12 months and 54% at 21 or 24 months following circumcision.”
The Cochrane reviewers judged “the potential for significant biases affecting the trial results [as] low to moderate”. Referring to selective reporting they wrote “All three trials clearly stated in their protocols that the primary outcome was HIV incidence. The risk of bias due to incomplete outcome reporting is therefore low in all three trials.”
The trial protocols have not been published so we have to trust that the Cochrane reviewers interpreted them correctly. But if they relied on trial registration documents (click here, for South Africa, here for Kenya and here for Uganda) they would have been misled. They they all indicate more of less the same primary outcomes and planned sample sizes as in the respective papers. But according to the date of first entry, only the Kenyan trial was prospectively registered. The South African trial was registered a year and a half after recruitment ended and seven days before the results were published! The Ugandan one a month after recruitment ended,and a month before publication.
| Recruitment period | Date of 1st publication of results | 1st trial registration date | Registry planned sample size | Primary outcome in registry | Primary outcome in paper | |
| South Africa | July 2002 – Feb 2004 | 26 July 2005 | July 19 2005 | 3274 planned.
3274 in paper |
HIV infection at 3, 12 and 21 months | All HIV infections at 3, 12 and 21 months |
| Kenya | Feb 2002 – Dec 12 2006 | 24 Feb 2007 | April 23 2003 | Initially 3,000. Altered to 2887 in registry.
2784 in paper |
HIV incidence at 2 years
Complications of circumcision |
HIV incidence after three interim analyses |
| Uganda | August 2002 – Dec 2006 | 24 Feb 2007 | Jan 23 2007 | 5,000 planned
4996 in paper. |
HIV acquisition no time point specified | HIV incidence |
It looks like PLOS One and The Lancet wanted to publish sexy high impact trials, found they weren’t registered, so got the authors to do it retrospectively, and hoped no-one would notice! All three trials were funded by the public sector.
Jim Thornton
Trackbacks
- Male genital mutilation « Ripe-tomato.org
- Cock-ups happen « Ripe-tomato.org
- Newborn Research « Ripe-tomato.org
- Boston/Botswana circumcision trial – 2 | Ripe-tomato.org
- Denied, withheld, and uncollected evidence and unethical research cloud what really happened during three key trials of circumcision to protect men | Don't Get Stuck With HIV
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I’ve only just seen this. Other critiques of the studies are collected here http://www.circumstitions.com/HIV-SA.html and here http://www.circumstitions.com/HIV-SA-garenne.html
Thanks.I’d not seen that.You make good points. I agree with most.
But the quality of the three adult circumcision trials was pretty high. I may grumble at the lack of registration, and your point about the effect sizes probably being overestimated by stopping early, is good.
We can argue forever about whether the benefit was caused by the co-intervention of wearing a condom, or how the meme “circumcision protects against AIDS” will play out in practice. But if adult males want to get their foreskins chopped off, that’s their business. I’m just annoyed if my tax pays for it, and even more annoyed if it funds chopping kids’ foreskins off.
All agreed. I think the high dropout rate relative to the infection rate is another cause for serious concern – especially since dropouts might well be tied to HIV+ status in the circumcised men (encouraged to find out their own status at nearby clinics), but to cold feet in the control groups (while it was too late for that in the experimental groups).
And as others have pointed out, with contacts not traced, we have no assurance that all or even any HIV was (hetero)sexually transmitted. Granting for the moment that these intact men were more susceptible to penile infections, that would make them more susceptible to iatrogenic (doctor-caused) infection. Amateur street corner “needle men” with hypotermics of quack nostrums are a likely risk.
You say “the quality of the three adult circumcision trials was pretty high”. I would like to comment on the lack of transparency on these trials.
Not only were these trials registered late, but there is no publicly available audit trail: Nobody outside the closed group of researchers/reviewers/DMC conducting the studies has seen the protocol or the data. I personally requested the protocol and details of the ethical approval of the South-African study from Witwatersrand Univeristy – they said that they were “confidential”. I have spoken to other researchers who have requested the data, one said “they are keeping their data very close to their chest”. I am aware of an FOI request seeking this information from the US NIH – no reply was received.
As such we have no knowledge of any a-priori determination of the statistical methods. We do not know the criteria for early termination or the membership of the Data Monitoring Committee. The South-African trial was criticised in respect of its randomisation procedures.
The authors of these studies were on record as advocating circumcision before they performed these trials. One said that it was his mission in life to “promote” circumcision. Another has described in print how he sought to build the body of evidence for circumcision over a number of years.
As such I suggest it seems reasonable to ask whether there was any selection bias or whether they had a peek at their data before deciding on early termination. If the evidence is as strong as the authors claim, surely they would not oppose full disclosure of the trial data and documentation?