Doubts on Circumcision and HIV Risk Disappear

CHICAGO, Feb. 23 -- The verdict on male circumcision and HIV transmission has been validated. It cuts the risk of HIV infection by more than 50%.

Now the question is how to implement what some experts called "the most compelling evidence-based prevention strategy" since it was discovered that anti-retroviral drugs could interrupt mother-to child transmission of HIV.

The publication of two large African studies in the Feb. 24 issue of The Lancet brings to three the major trials that have found male circumcision helps prevent HIV.

All three were halted early after data monitoring committees found a significant benefit for the circumcised men.

• Circumcision Halves Risk of Heterosexual HIV Transmission;
• Male Circumcision Equal to Vaccine in Preventing HIV Infection

Although there had been questions about the methods used in the first study -- of 3,274 men in South Africa -- the latest trials confirm the early results:

• In 2,784 men ages 18 to 24 in Kisumu, Kenya, researchers found the two-year HIV incidence was 2.1% in the circumcised men and 4.2% among controls - a difference that was statistically significant at P=0.0065.
• The risk reduction in the Kenyan trial was 53%.
• In 4,996 men ages 15 to 49 in the rural Rakai district of Uganda, researchers found a two-year HIV incidence of 0.66 cases per 100 person-years in circumcised men and 1.33 cases per 100 person-years among controls, which was significant at P=0.006.
• The risk reduction in Uganda was 51%.

The South African study, by comparison, showed a risk reduction of 60%.

The mechanism of the protection appears to relate to exposure of HIV target cells, according to Robert Bailey, Ph.D., of the University of Chicago, and colleagues, who led the Kenyan trial.

They wrote, "the inner mucosal surface of the human foreskin, exposed upon erection, has nine times higher density of HIV target cells (Langerhans' cells, CD4+ T cells, and macrophages) than does cervical tissue. In addition, by contrast with the foreskin's inner surface, HIV target cells on the outer surface and the glans are protected by a layer of squamous epithelial cells."

Dr. Bailey and colleagues added, "We now have very concrete evidence that a relatively simple surgical procedure can have a very large impact on HIV. This is really the first good news we've had in quite a long time. If we can reduce the risk of infection by such a substantial amount then we can save a lot of lives."

But outside experts cautioned that the finding must be put into practice with care, both practically and ethically.

"Otherwise, a historic opportunity to save lives could be squandered," said Marie-Louise Newell, Ph.D., of the United Kingdom's Medical Research Council and Till Brnighausen, M.D., of Harvard Medical School.

In a commentary accompanying the two studies, Drs. Newell and Brnighausen noted that while acceptance of circumcision appeared to be high in both studies, other communities may be less open.

Also, the number of health-care workers able to do circumcisions in adults safely is likely to be limited in many areas, they said.

On the public health front, the challenge will be to get across the message that circumcision reduces the risk but does not prevent HIV infection, so that condom use remains essential.

And finally, they argued, the ethics of widespread circumcision need to be addressed. "Is it ethical to circumcise everybody even if many will not benefit from the intervention," they asked - for instance, those who don't engage in risky sexual behavior or are already HIV-positive?

On the other hand, they noted, a simple calculation of the risk reduction rates, applied to a high-risk area such as South Africa's KwaZulu-Natal province - where few of the 2.5 million men are circumcised - shows that if the procedure were implemented, it would prevent about 35,000 new HIV infections in 2007 alone.

According to Thomas Coates, Ph.D., of the University of California at Los Angeles, and colleagues, it remains unclear if circumcision will reduce the risk of an HIV-positive man transmitting the virus to his female partners or if, conversely, it might increase the risk by "behavioral dis-inhibition."

In a viewpoint article, they cautioned that because all three studies reported much the same results, "pressure will begin mounting for broad implementation of male circumcision."

Such a strategy should not be attempted willy-nilly, they said, but only after widespread discussion and planning, in order to ensure that this "most compelling evidence-based prevention strategy (is) affordable and safely available" to all who need it.

The Kisumu trial found that 22 men in the intervention group and 47 in the control group had tested positive for HIV when the study was stopped Dec. 12, 2006.

Adverse events related to the procedure were few -- 21 events in 1.5% of the circumcised men -- and resolved quickly. The researchers saw no evidence of behavioral change after the surgery.

"We do know that some circumcised men become infected with HIV," Dr. Bailey said. "But we did find that the circumcised men in our study did not increase their risk behaviors after circumcision."

In both trials, all participants were given counseling about safe sex and had access to condoms.

In the Rakai trial, led by Ronald H Gray, M.D., of Johns Hopkins Bloomberg School of Public Health, 22 men in the intervention group and 45 in the control group had contracted HIV when the study was halted in December.

Adverse events were slightly higher -- occurring in 84 circumcisions, or 3.6% -- and all resolved with treatment. Behaviors were much the same in both groups during follow-up, the researchers said.