HIV This Week

Kigozi G, Gray RH, Wawer MJ, Serwadda D, Makumbi F, Watya S, Nalugoda F, Kiwanuka N, Moulton LH, Chen MZ, Sewankambo NK, Wabwire-Mangen F, Bacon MC, Ridzon R, Opendi P, Sempijja V, Settuba A, Buwembo D, Kiggundu V, Anyokorit M, Nkale J, Kighoma N, Charvat B. The Safety of Adult Male Circumcision in HIV-Infected and Uninfected Men in Rakai, Uganda. PLoS Med. 2008;5(6):e116.

The objective of the study was to compare rates of adverse events related to male circumcision in HIV-positive and HIV-negative men in order to provide guidance for male circumcision programmes that may provide services to HIV-infected and uninfected men. A total of 2,326 HIV-negative and 420 HIV-positive men (World Health Organization stage I or II and CD4 counts > 350 cells/mm(3)) were circumcised in two separate but procedurally identical trials of male circumcision for HIV and/or sexually transmitted infection prevention in rural Rakai, Uganda. Participants were followed at 1-2 days and 5-9 days, and at 4-6 weeks, to assess surgery-related adverse events, wound healing, and resumption of intercourse. Adverse event risks and wound healing were compared in HIV-positive and HIV-negative men. Adjusted odds ratios were estimated by multiple logistic regression, adjusting for baseline characteristics and postoperative resumption of sex. At enrolment, HIV-positive men were older, more likely to be married, reported more sexual partners, less condom use, and higher rates of sexually transmitted disease symptoms than HIV-negative men. Risks of moderate or severe adverse events were 3.1/100 and 3.5/100 in HIV-positive and HIV-negative participants, respectively (Adjusted odds ratio 0.91, 95% confidence interval [CI] 0.47-1.74). Infections were the most common adverse events (2.6/100 in HIV-positive versus 3.0/100 in HIV-negative men). Risks of other complications were similar in the two groups. The proportion with completed healing by 6 weeks post surgery was 92.7% in HIV-positive men and 95.8% in HIV-negative men (p = 0.007). Adverse events were more common in men who resumed intercourse before wound healing compared to those who waited (Adjusted odds ratio 1.56, 95% CI 1.05-2.33). In conclusion, the overall safety of male circumcision was comparable in asymptomatic HIV-positive and HIV-negative men, although healing was somewhat slower among the HIV infected. All men should be strongly counselled to refrain from intercourse until full wound healing is achieved. Trial registration: http://www.ClinicalTrials.gov; for HIV-negative men, and for HIV-positive men.

Editors’ note: The finding that there is no difference in the risk of adverse events for asymptomatic HIV-positive and HIV-negative men is encouraging because HIV testing is not mandatory for circumcision. HIV testing is a key voluntary component of a comprehensive service but all men who are in good health may undergo circumcision whether they decide to be tested or not. They should all be advised that early resumption of sexual intercourse has been shown to delay wound healing. As well, preliminary data from other studies and common sense concur that sex before complete wound healing may increase their risk of acquiring HIV, rather than protecting them, and may increase their risk of transmitting HIV to a sexual partner if they already have HIV infection.

With the growing incidence of HIV, there is a desperate need to develop simple, cheap, and effective new ways of preventing HIV infection. Male circumcision reduces the risk of infection by about 60%, probably because of the removal of the Langerhans cells which are abundant in the inner foreskin and are the primary route by which HIV enters the penis. Langerhans cells form a vital part of the body’s natural defence against HIV and only cause infection when they are exposed to high levels of HIV virions. Rather than removing this natural defence mechanism by circumcision, it may be better to enhance it by thickening the layer of keratin overlying the Langerhans cells, thereby reducing the viral load to which they are exposed. Pask and colleagues investigated the ability of topically administered oestrogen to induce keratinization of the epithelium of the inner foreskin. Histochemically, the whole of the foreskin is richly supplied with oestrogen receptors. The epithelium of the inner foreskin, like the vagina, responds within 24 hours to the topical administration of oestriol by keratinization, and the response persists for at least 5 days after the cessation of the treatment. Oestriol, a cheap, readily available natural oestrogen metabolite, rapidly keratinizes the inner foreskin, the site of HIV entry into the penis. This thickening of the overlying protective layer of keratin should reduce the exposure of the underlying Langerhans cells to HIV virions. This simple treatment could become an adjunct or alternative to surgical circumcision for reducing the incidence of HIV infection in men

Editors’ note: Langerhans cells are no more abundant in the inner foreskin than they are in the outer foreskin or shaft of the penis, but the thinner protective keratin layer of the inner foreskin makes them more accessible for HIV. The abstract does not describe the methodology. Two sexually inactive uncircumcised men applied oestrogen cream to the inner foreskin daily for 14 days before undergoing circumcision. Contact smears taken daily and surgical tissue sections were examined. Keratinisation increased for these two men but this does not translate into protection against HIV. Clinical trials to evaluate efficacy would be required before conclusions could be drawn about whether oestrogen cream plays any role in HIV prevention for insertive men.