HIV Treatment Bulletin - Vol. 6, No. 9, September 2005
Polly Clayden, HIV i-Base

Previous observational data from over 30 published studies, the earliest dating from 1986, have suggested that men who have been circumcised are at a reduced risk from female-to-male sexual HIV transmission, but up until now this has not been supported by evidence from a prospective randomised trial.

In an oral session Bertran Auvert presented compelling results from the Orange Farm Trial (ANRS 1265) - a randomised intervention trial to assess the effect of male circumcision on HIV incidence among young men in an urban setting close to Johannesburg (‘there are no oranges, there is no farm’). This is an area of high HIV prevalence (31.6%) and largely heterosexual transmission. In an earlier study to determine acceptability, 70% of uncircumcised young men said that they would be circumcised if it could prevent HIV. The local prevalence of male circumcision was 20%.

Participants (n=3,273) were between 18-24 years of age, willing to be circumcised, in good health, and were willing to accept the randomisation and to give informed consent. The trial was designed so participants were randomised directly after screening. Circumcision in the intervention group was performed by medical doctors immediately, using the forceps guided method, with local anaesthetic and post-operative analgesia. In the control group, circumcision was deferred until after the 21-month visit. Both groups had scheduled clinic visits at 3, 12 and 21 months. Approximately 90% of young men in the overall study were sexually active.

After an interim analysis showed a highly significant statistical difference in outcome between the two arms (p<0.0095), the trial was stopped by the study’s Data and Safety Monitoring Board. Circumcision was then proposed to the men in the control group. There were 4664 person years of follow up, with a mean of 17.9 months (IQR 12.7-21.0 months). In the intervention group 4.8% (68/1427) were not circumcised and in the control group 8.4% (92/110) were circumcised. 7.9% of the intervention group and 9.7% of the control group were lost to follow up.

The investigators reported 69 infections overall: 18 in the intervention group (2, 7 and 9 at months 3, 12 and 21 respectively) and 51 in the control group (11, 22 and 36 at months 3, 12 and 21 respectively). The incidence rates were 0.77 (0.49-1.23) and 2.2 (1.7-2.9) per year in the intervention and control arms respectively.

With an unadjusted RR=0.35 (95% CI 0.20-0.60, p=0.00013), the intervention offered 65% protection (95%CI 40-80%). The RR did not vary significantly (RR=0.34, protection 66%) even after controlling for other factors, including condom use and sexual behaviour . Analysis per protocol (ie ignoring the effect of the crossover between the intervention and control arms) the authors reported an unadjusted RR=0.25 and 75% protection.

There was a very low complication rate (3.8%, mainly relating to pain, but with no reports of permanent damage and no deaths. Out of 60/1582 complications pain (n=13), swelling (n=10), excessive bleeding (n=9) and problems with appearance (n=9) were the most frequently reported.

Dr Auvert explained that this is the, “First RCT demonstrating a strong protective effect of safe male circumcision on HIV acquisition by males.” He added that the results were consistent with the expectations of the study but acknowledged that the results were not predictive of the long-term protective effect of circumcision on HIV acquisition. He posed the question whether this strategy should be considered as a public health intervention.

Comment

The primary mechanisms for protection conferred by male circumcision were proposed in a study presented at last years Bangkok conference and reported in the HTB coverage from that meeting. [2] These include the high density of CD4-receptor rich langerhans cells near to the surface of the inner foreskin and thicker keratinisation that occurs after circumcision. Additionally the foreskin may provide a humid area to trap HIV allowing for a longer period for transmembrane entry.

There still remains a very low awareness of these mechanisms of infection in prevention interventions and literature, which still misleadingly and implausibly tend to refer to abrasions and cuts rather than the porous nature of membranes, particularly on the glans and foreskin, but also other sexual mucosa.

The protective value of circumcision in this study relates to the context of >30% HIV prevalence in a heterosexual setting for young men. This setting also probably explains the high level of acceptance of circumcision as an intervention. It is not possible to draw conclusions from this study about the effectiveness in other settings, or level of protection in other populations, such as MSM.

It is also important that the circumcision in the study was performed in a medical setting and resulted in no death or serious complications. Monitoring of the safety aspects outside a clinical trial, and appropriate training for practitioners performing circumcision, will also be important if this intervention becomes widely adopted.

The press conference for this study, which can be viewed online, also highlighted the importance of waiting for results from three trials that are already underway in Uganda and Kenya. [3]

References:

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