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Circumcision-for-HIV prevention trial stopped early due to clear efficacy
Study results led to widespread recommendations for male circumcision to reduce HIV transmission.
LOS ANGELES — Findings that male circumcision reduced the risk of HIV transmission by more than 50% in circumcision trials in Uganda and Kenya have led to new world and national health policies.
Data from the trials, which were recently closed due to clear efficacy, were presented at a WHO meeting in Montreux, Switzerland, in March. Based on the results, public health experts at the WHO meeting recommended that male circumcision be recognized as an additional important intervention to reduce the risk of HIV transmission.
Circumcision practice implications as they relate to HIV prevention in the United States are on the agenda of a CDC meeting scheduled for April 27.
Trial results
Ronald H. Gray, MD, MSc, a professor at Johns Hopkins University Bloomberg School of Public Health in Baltimore, and his colleagues presented results from two trials at the WHO meeting and at the 14th Conference on Retroviruses and Opportunistic Infections, held here, and the results were also published in Lancet. Efficacy, social acceptability and the number of HIV transmissions averted by male circumcisions were illustrated in his presentations.
In a randomized trial in the Rakai District of southwestern Uganda, 4,996 HIV–negative men aged 15 to 49 years who agreed to receive HIV testing results and counseling were enrolled in the study. Men who were ineligible for the NIH trial because they were living with HIV were enrolled in a parallel Gates Foundation-sponsored trial.
Participants were randomly assigned to receive immediate circumcision (n=2,474) or into a delayed intervention arm (n=2,522), in which men would undergo circumcisions after two years follow up. Enrollment characteristics, behaviors and number of reported sex partners were balanced between the two arms. Ninety-one percent of men received circumcision within two weeks of enrollment. Follow-ups were held at week four and at six, 12 and 24 months to assess prevention, collect samples and test for HIV and STDs. Retention rates were around 90% in both arms.
In the intent-to-treat analysis, the cumulative HIV incidence over 24 months was 0.66 per 100 person years in the circumcised arm and 1.33 per 100 person years in the control arm with an incidence ratio of 0.49 (95% CI, 0.28-0.84, P=.0057).
Serious adverse events of circumcision, which was a sleeve procedure, were reported in five participants and resolved.
Trial closed
The primary endpoints of the study were HIV incidence and surgery safety, and the secondary endpoints were STD symptoms, STDs, risk behavior and acceptability.
Using incident data compared in each arm, researchers determined a minimum efficacy of 51% for HIV transmission aversion by male circumcision. The estimate is conservative because of the early trial closure, researchers said. Overall efficacy estimates were similar to those from trials in Kenya and South Africa.
Researchers also found that the efficacy of circumcision may be greater in subgroups at high risk, such as those with multiple partners and non-marital partners, suggesting greater protection in the most highly exposed.
The trial was stopped on Dec. 12, 2006, at an unscheduled interim analysis when circumcision was found to provide significant protection. The NIH Data Safety Monitoring Board monitored the trial.
“As a consequence of the early closure of the trial, we had only accrued 73% of the total information we hoped to get,” Gray said. “Forty-four percent of the men had completed the second year of follow-up, so the trial was closed quite prematurely.”
STDs and circumcision
Researchers also looked at STD symptoms in the cohort, particularly genital ulcer disease. Circumcision reduced rates of genital ulcer disease by 47% but had no impact on urethral symptoms. The effects of circumcision on urethral infection are unclear.
The period prevalence of genital ulcer disease was 3.1% in the circumcised arm and 5.8% in uncircumcised arm with a prevalence rate ratio of 0.53 (95% CI, 0.43-0.64).
“This suggests that circumcision is potentially protective against infections that are acquired cutaneously through the skin rather than through infections of the urethral mucosa,” Gray said.
Researchers found that the overall impact of circumcision reduced HIV acquisition regardless of whether a man had a genital ulcer. Circumcision blunted the increase of risk associated with symptomatic genital ulcers and reduced HIV risk irrespective of genital ulcer disease, but effects were more pronounced in men with genital ulcer disease. Preliminary estimates suggest that the reduction of genital ulcer disease episodes in circumcised men accounted for about 7.5% of the total reduction in HIV incidence attributable to circumcision.
“It is complicated, but we are sorting it out,” Gray said.
Culture acceptance
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Numerous social science studies to assess cultural and religious acceptability were conducted before the trials began. Circumcision was not traditional in the area prior to the study.
“We were surprised that enrollment went well, and we found a lot of positive attitudes even independent of the possible HIV effect,” Gray said.
Religion did not play a large role in willingness to participate. Before the trial, 60% of men said they were willing to be circumcised, according to Gray.
“We asked Christian men if the procedure would change their religious identity, and many said ‘Christ was circumcised, so I don’t think it would matter,’” Gray said.
The community at large viewed circumcision as an improvement in personal hygiene, and women were more enthusiastic about it than men. Some men tried to enroll in the study a second time under false names. “These were mainly men who had been randomized to the control group and wanted to improve their chances of getting circumcised, so I think they were motivated,” Gray said.
Post-circumcision risk
Researchers warned that circumcision is not a stand-alone measure for HIV and STD transmission prevention. The trial included free condoms and safe sex counseling. Researchers feared that circumcision could give men a false sense of protection, leading them to risky behavior.
There was no evidence of behavioral disinhibition among circumcised men in the trial, but researchers attributed this to the level of risk prevention education included in the program.
“The important thing for future programs is to maintain the level of intensity of health education to prevent disinhibition,” Gray said.
Newborn circumcision
Deciding ages for circumcision is a complex issue, but researchers said newborn circumcision is optimal. “It is simpler, safer and cheaper,” Gray said.
The problem with promoting infant circumcision only, however, is that decades need to pass before infections are averted, he said.
For optimal HIV transmission prevention via circumcision, men from all age groups should be considered, researchers said. “I’d like to see a start of neonatal circumcision now and see a long-term benefit but also do the adolescent and adult surgeries now,” Gray said. – by Kirsten H. Ellis
For more information:
- Gray R, Kigozi G, Serwadda D, et al. Randomized trial of male circumcision for HIV prevention in Rakai, Uganda. Presented at: the 14th Conference on Retroviruses and Opportunistic Infections; Feb. 25-28, 2007; Los Angeles.
- Gray R, Kigozi G, Serwadda D, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: A randomized trial. Lancet. 2007;369:617-619.
- Wawer M, Gray R, Kigozi G, et al. The effects of male circumcision on genital ulcer disease and urethral symptoms, and on HIV acquisition: An RCT in Rakai, Uganda. Presented at: the 14th Conference on Retroviruses and Opportunistic Infections; Feb. 25-28, 2007; Los Angeles.