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Long-term Benefits of Circumcision for HIV Prevention

Adult male circumcision continued to offer men a high degree of protection against HIV infection after nearly 5 years, according to long-term follow-up data from a study in Uganda presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) last week in Boston. A related study found that elective adult circumcision reduced the occurrence of genital ulcers by about half, though it had no significant effect on genital herpes.

During 2005-2006 evidence from 3 large randomized trials conducted in South Africa, Kenya, and Uganda, showed that elective adult male circumcision reduced the risk of HIV acquisition by 50% to 60% over the short-term.

In all these studies, men interested in circumcision were randomly assigned to undergo the procedure immediately or after a waiting period. All participants also received regular HIV prevention counseling and free condoms.

The U.S. National Institutes of Health, which sponsored the trials in Kisumu, Kenya, and Rakai, Uganda, halted the studies in December 2006 after an interim analysis at 24 weeks showed that circumcision reduced the risk of HIV infection by more than half.

At this year's CROI, Xiangrong Kong from Johns Hopkins University's Bloomberg School of Public Health presented findings from extended follow-up of men in the Rakai trial.

This study enrolled 4996 HIV negative men aged 15 to 49. After the trial was halted, men in the control group were offered circumcision as well, and participants in both the immediate and delayed circumcision groups received ongoing post-trial surveillance for up to 5 years.

Results

• Over 5 years of follow-up, about 80% of men in the initial control group opted to undergo circumcision.
• After nearly 5 years of surveillance, incidence rates were 0.50 per 100 person-years among all circumcised men versus 1.93 per 100 person-years among uncircumcised men, a 73% reduction.
• An analysis restricted to original control arm participants who were circumcised after the randomized trial phase showed a 67% risk reduction.
• Men in the original control arm who opted for circumcision were similar to those who declined with regard to age, education, marital status, number of sex partners, condom use, and alcohol use with sex.
• Overall, during post-trial follow-up the 2 groups together reported:
  • No change in the number of non-marital sex partners;
  • 10% decrease in alcohol use with sex;
  • 6% decrease in any condom use;
  • 4% decrease consistent condom use.
• However, these risk behavior changes did not differ significantly between circumcised and uncircumcised men.

Based on these findings, the investigators concluded, "[t]he effectiveness of male circumcision during a post-trial observational study was comparable to the efficacy of circumcision for HIV prevention during a randomized trial."

"Post-trial male circumcision acceptance was high among controls, with no evidence of self-selection," they continued. "Condom use declined in controls both opting for and declining male circumcision, however, the changes were similar between groups and there was no evidence of risk compensation associated with circumcision."

Genital Ulcer Disease

In the second presentation, Supriya Mehta from the University of Illinois at Chicago described further findings from the Kisumu, Kenya, circumcision trial, which enrolled 2784 men aged 18 to 24 years.

In this analysis the researchers focused on sexually transmitted infections other than HIV, looking at genital ulcer disease (GUD) overall, and at specific causes of GUD including herpes simplex virus type 2 (HSV-2), syphilis, and chancroid. In several prior studies the presence of genital ulcers has been shown to increase the risk of both acquiring and transmitting HIV.

Results

• Over a 24-months follow-up period, circumcision reduced the risk of HIV infection by 62%.
• Overall GUD incidence fell by 48% among circumcised men compared with uncircumcised men (2.7 vs 5.2 per 100 person-years, respectively).
• HSV-2 incidence did not differ significantly however, with rates of 5.8 per 100 person-years among circumcised men versus 6.1 per 100 person-years among uncircumcised men, a reduction of only 6%.
• Incidence of syphilis was 23% higher among circumcised men, but this difference also did not reach statistically significance.
• Among men newly infected with HSV-2, circumcision conferred a stronger protective effect against GUD, reducing the risk by 67%.
• After controlling for circumcision status, HIV incidence was 3 times higher among men with incident HSV-2 infection, and almost 6 times higher among men with GUD.
• About two-thirds of GUD cases -- 63% among circumcised men and 68% among uncircumcised men -- were not due to HSV-2, and about 40% had no identifiable infectious cause.
• About one-third of new HIV infections occurred among men who were both HSV-2 negative and had no GUD.

"Circumcision halved the risk of GUD among our trial participants, but was not protective against HSV-2 incidence, even though one-third of genital ulcers were herpetic," the investigators concluded.

They also found that "efficacy of [medical male circumcision] against HIV acquisition was not altered by baseline or incident HSV-2 or GUD."

"In our population, the protective effect of [medical male circumcision] against HIV acquisition may be mediated by GUD itself, rather than by HSV-2," they suggested. "Determining the causes of clinically detected GUD is necessary to effectively treat and prevent GUD and reduce associated HIV risk, and to understand how circumcision may confer protection."

At a press conference discussing the findings, Mehta suggested that some cases identified as GUD might actually have been due to physical trauma to the penis, which was about 30% less likely among circumcised compared with uncircumcised men.

The researchers were unable to explain, however, why their results differed from those of the South Africa and Uganda trials, which found that circumcision was associated with HSV-2 incidence reductions of about 30% and 40%, respectively.

Investigator affiliations:

Abstract 36: Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; Rakai Health Science Program, Entebbe, Uganda; Makerere University, Kampala, Uganda.

Abstract 147LB: University of Illinois at Chicago, Chicago, IL; RTI Internationall, Research Triangle Park, NC; University of Nairobi, Kenya; University of Manitoba, Winnipeg, Canada; Impact Research and Development Org, Kisumu, Kenya.

3/11/11

References

X Kong, G Kigozi, V Ssempija, and others. Longer-term Effects of Male Circumcision on HIV Incidence and Risk Behaviors during Post-trial Surveillance in Rakai, Uganda. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 36.

S Mehta, C Parker, J Ndinya-Achola, and others. MMC Is Not Protective against HSV-2 Incidence but Halves the Risk of GUD Incidence: Results from the Randomized Trial of MMC to Reduce HIV in Kisumu, Kenya. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 147LB.