Non-randomised studies of circumcision

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Daniel Halperin of the Harvard Center for Population and Development Studies has been one of the foremost advocates for male circumcision as an HIV-prevention measure. In a 1999 essay in The Lancet,1 he noted that the countries in Africa where less than 20% of the male population is circumcised form a broad swathe extending from the Central African Republic and southern Sudan in the north, through the former British colonies of east Africa, and down to Botswana, Zimbabwe, and Swaziland. These coincide, in the main, with the countries with highest HIV prevalence.

In countries where less than 20% of the male population is circumcised, HIV prevalence in 1999 ranged from 25% in Zimbabwe to around 12% in Rwanda. In countries where male circumcision was over 20%, HIV prevalence ranged from 7.6% on Congo (Brazzaville) to 2% in west African countries like Guinea and Benin.

The same pattern is observed regarding HIV prevalence and circumcision in Asia, though with HIV prevalences an order of magnitude lower. Countries where less than 20% of the male population is circumcised range from Cambodia (HIV prevalence 2.4%) to China (0.1%). Countries with more than 20% of men circumcised range from the Philippines (0.1%) down to Bangladesh (0.03%) and HIV in these countries tends to be concentrated among sex workers and injecting drug users. There is very little overlap between the countries. The near 100% circumcision rate in Muslim countries may contribute to the very low HIV prevalence in Middle Eastern countries.

Circumcision may not be the whole explanation for these differences; Halperin makes the case that countries with low circumcision rates also tend to have cultures where people have high levels of non-commercial concurrent sexual partnerships. These two factors taken together, he says, are in themselves sufficient to explain differences in HIV prevalence.

Differences in circumcision and HIV rates may also be observed locally and within populations. Kenya is a well-studied case. The general HIV prevalence in 1999 in Kenya was estimated as 11%. But prevalence in circumcised men was about 3%. In a study of Nyanza province on the shores of Lake Victoria, prevalence in circumcised men was 2%, but in uncircumcised men it was 21%.

Most ethnic groups in Kenya practise circumcision; the main tribe that does not are the Luo people, who live in the east of the country and are concentrated in Nyanza. In a paper for the World Bank,2 Beegle and Özler found that HIV prevalence in Luo men aged 15 to 49 in Nyanza was 20.4% and amongst non-Luo men it was 0.8%. In women aged 15 to 49 it was 25.6% and 7.0% amongst Luo and non-Luo women respectively.

Non-randomised trials had already found a significant protective effect. In one of the earliest studies from Rakai, Uganda,3 Thomas Quinn of Johns Hopkins University found that 40 of 137 uncircumcised male partners of HIV-positive women became infected by their partner. In contrast, there were no infections among 50 circumcised men with HIV-positive partners.

Not all studies have shown such a dramatic protective effect but there are virtually none that have shown no effect. In a United States Agency for International Development (USAID) meeting in 2002, Helen Weiss of the London School of Hygiene and Tropical Medicine provided a meta-analysis of 16 different circumcision studies which taken together demonstrated a protective effect identical to that seen in the Orange Farm RCT - just over 70%.4 Individual study effects ranged from over 95% to around 30%. Only one study had findings that were not statistically significant.

Studies in high-income countries

Would circumcising men benefit some populations in developed countries or countries without generalised epidemics? In many countries with highly focal epidemics, the answer is probably not if most infections are among injecting drug users or gay men (see below for the evidence on gay men).

However, circumcision might help to reduce HIV incidence and prevalence if there is significant heterosexual transmission amongst certain population groups – say, between female sex workers and their clients, or amongst specific high-risk ethnic or cultural minorities.

One review of evidence from the USA,5 where HIV disproportionately affects the black and, to a lesser extent, the Latino population, suggests that circumcision could cut the risk of heterosexual HIV transmission in black and Hispanic men.

Based on the African data, the authors from the Centers for Disease Control and Prevention (CDC) said that: "it is likely that circumcision will decrease the probability of a man acquiring HIV via penile–vaginal sex with an HIV-infected woman in the US."  Nonetheless, because there are many differences between the underlying HIV epidemics in Africa and the US, the impact of adult male circumcision on HIV-transmission rates in the US was hard to predict.

Adult male circumcision would most likely have the largest impact in populations where circumcision has been rare. Although circumcision is already very common in the US, circumcision rates have traditionally been lower among Hispanic men in the United States, where only 42% of Mexican-American men are circumcised, compared with 88% of non-Hispanic white men and 73% of non-Hispanic black men.

The authors highlight findings from a study of men attending a Baltimore STI clinic (Warner 2006), which found that while circumcision was not associated with a protective effect throughout the whole clinic population, it was associated with a reduced risk of infection among men known to have had unprotected sexual intercourse with HIV-positive female partners.6

The researchers looked at a population of African-American men attending sexual-health clinics in Baltimore, Maryland, between 1993 and 2000. They identified 394 visits that were made because the men had been notified that they had been exposed to HIV after penile-vaginal contact with a woman with diagnosed HIV infection. This enabled the investigators to look at the efficacy of circumcision as a method of HIV prevention in men known to have had exposure to HIV.

Among the 394 men who attended the clinic because of known HIV exposure, circumcision was associated with a significant 51% reduction in HIV prevalence (10 vs 22%).

“The around 50% reduction in prevalence observed among men with known HIV exposure is of comparable magnitude to the risk reported across the three African trials (range, 48% to 60%),” commented the investigators.

However, the CDC were cautious in their recommendations. ‘Some sexually active men may consider circumcision as an additional HIV-prevention measure, but should do so only in consultation with their physician or healthcare provider, and with a clear understanding of the costs and risks of circumcision,’ they said.

Men who choose to be circumcised should be counselled about the importance of waiting until wound healing is complete before having sexual intercourse.


Randomised controlled trials of circumcision as a preventive measure

Because of the accumulating evidence that circumcision might protect against HIV infection, three randomised controlled trials (RCTs) of circumcision in (largely young) HIV-negative adult males were initiated in three different countries in Africa.

In each case, the trial was stopped early because the results were so conclusive – demonstrating that circumcision has anything between a 50 and a 75% protective effect against HIV infection in men – that it was considered unethical not to offer circumcision to the control group in advance of the planned trial end date.

The scientific evidence for circumcision’s efficacy in preventing HIV was sufficiently convincing for the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) to recommend in March 2007 that male circumcision should be scaled up in 13 African countries where HIV prevalence was over 15% and where there were low levels of circumcision. These were Botswana, Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, South Africa, Swaziland, Tanzania, Uganda, Zambia and Zimbabwe.

The trials were:

  • A trial7 conducted by the French research organisation Institut National de la Santé et de la Recherche Medicalé (INSERM) in the peri-urban township of Orange Farm in South Africa. This randomised 3273 men aged between 16 and 24 to be circumcised at the start of the trial or to be offered circumcision at the end of it 21 months later. This study’s findings were initially announced in July 2005 and published in PLoS Medicine in November 2005.
  • A trial8 conducted by the University of Illinois and supported by the US National Institute of Allergies and Infectious Diseases (NIAID) in the city of Kisumu, Kenya. Kisumu was chosen because it is the largest city predominantly inhabited by the traditionally uncircumcised Luo people. This randomised 2784 men aged between 18 and 24 to circumcision or delayed circumcision, with a follow-up time of 24 months. The study population had a higher HIV incidence than the other studies and so could be smaller. This study was reported in January 2007 and published the following month in The Lancet.  
  • A trial9 also supported by NIAID and conducted by Johns Hopkins University in collaboration with Makerere University in Rakai Province, Uganda. This randomised 4996 men to circumcision or delayed circumcision and recruited the wider age range of 15 to 49, also over two years. This study also reported in January 2007 and the paper was published in the same issue of The Lancet as the Kisumu study.;

The HIV infection rates and seroconversion rates, and the degrees of protection seen, were as follows:

  • In Orange Farm there were 51 seroconversions in the control arm (annual HIV incidence 2.2%) and 18 in the intervention arm (incidence 0.77%). This indicated that circumcision had an efficacy of 60% as an HIV-prevention method.

  • In Kisumu, 47 infections in the control arm and 22 in the intervention arm were initially reported, implying an efficacy of 53%. However, at a 42-month follow-up,10 it was discovered that a number of HIV infections had been undetected at baseline, and the true figures were 18 infections in circumcised and 45 in uncircumcised men. This increased the efficacy to 60%.

  • In Rakai there were 45 infections in the control arm (incidence 1.33%) and 22 in the intervention arm (incidence 0.66%), yielding an intent-to-treat efficacy of 51%.

As-treated analyses yield higher efficacies

All these analyses are on an ‘intent-to-treat’ basis, i.e., results are classified according to the arm to which participants were originally randomised. However, there were significant ‘crossovers’ in all these trials: some participants who were originally randomised to be circumcised never were, but some members of the control group were circumcised in traditional or medical settings outside the trial. In the Orange Farm trial the majority of the crossovers were controls who got circumcised, whereas in the other two trials the majority of crossovers were intervention-arm participants who never got circumcised.

‘As-treated’ or ‘per-protocol’ analysis, in which HIV incidence and relative risk was classified according to actual circumcision status, resulted in even higher efficacies being reported for circumcision in each trial. In as-treated analyses, the efficacy seen in the Orange Farm study rose to 76%, and in Rakai to 60%.

In the Kisumu trial, as already noted, the as-treated analysis takes account of the fact that one participant in the control group and three in the intervention group were subsequently found to have been HIV-positive at baseline. However, in this trial there were also some infections diagnosed in the first month after their operation in the circumcision group, including three men who denied having sex in this month. If these early infections are assumed to have actually taken place before circumcision, this yields an efficacy of 68%.

Long-term follow-up

Long-term follow-up findings from the Kisumu Study were presented at the Mexico City International AIDS Conference in 2008.

Lead investigator Robert C. Bailey reported that the protective effect of circumcision against HIV infection remained unchanged for at least 42 months after the operation. Indeed, he had revised his estimate of its effect upwards from between 53 and 59% to 65 and 70%.

There is, of course, no reason to think that the protective effect of circumcision against HIV should be anything other than lifelong. There had, however, been concerns that all three RCTs of circumcision had been stopped before they reached full term, Bailey noted, and sceptics questioned whether there was any evidence that the effect persisted beyond the two-year span of the trials.

After the end of the RCT, men in the control group could be circumcised, and 42% of them chose to do so. When asked why more did not choose circumcision knowing the result, Bailey commented that it was partly because this was a highly mobile population of young men and that many had moved away to Nairobi and Mombasa.

By month 42, 1545 (55%) of the original trial group was still available for follow-up, evenly split between those who had originally been in the circumcision arm and those who had been controls.

During the next 18 months there were five more infections in the circumcised men and 17 more in men who remained uncircumcised. This gave an infection rate of 2.6% in circumcised men and 7.4% in uncircumcised men, raising the protective effect further to 70%.

When only men who had originally been randomised to circumcision were counted, this fell slightly. At present, the HIV-incidence rate among men randomised to circumcision has been calculated as 0.77% a year, and among uncircumcised men 2.37% a year, giving a protective effect of 65%.

Trial participants are being followed up until September 2009, providing five years of data.

Premature resumption of sex

Although circumcision protects against HIV once the penis has healed, men may actually be more vulnerable to HIV in the immediate post-circumcision period, before the operation wound has healed properly. One priority of researchers was, therefore, to find out whether trial subjects did resume sex before the recommended healing period of one month.

An analysis of all three circumcision RCTs published in AIDS in 200911 found that there were few HIV infections as a consequence of early resumption of sexual activity after circumcision. However, the writers caution that their data “do not preclude the possibility” that men who have sex in the first few weeks after circumcision have an increased risk of infection with HIV.

Only 4% of men in the Kisumu study and 5% of men in the Rakai study reported the resumption of sexual activity within 30 days of circumcision, whereas early sexual intercourse was reported by over a fifth (23%) of men in the Orange Farm trial.

At the six-month follow-up visit, 0.4% of men in the Kisumu study who did not report early sex had become infected with HIV compared to 2% of individuals who did resume sexual activity early. Similarly, in the Rakai study a higher HIV prevalence was found amongst men who resumed sexual activity early compared to those who did not (2 vs 1%).

Analysis showed that the early resumption of sexual activity increased the risk of infection at six months (odds ratio [OR] = 2.00; 95% CI 0.32-13.6), but this was not statistically significant. However, the investigators caution that the low numbers of HIV infections meant that there was “insufficient power to detect meaningful associations”.

Similar rates of HIV seroconversions were seen in men in the Rakai study who had early sex after incomplete wound healing and those who had early intercourse with complete wound healing (0.6 vs 0.7%).

The investigators also suggest “enhanced counselling should include active involvement of female partners where possible and intense counselling for married men who are more likely to resume sex early.”

Adverse events

In contrast to some other studies reporting high rates of post-operative adverse events (AEs - see below), the three RCTs reported low rates of AEs. The Orange Farm trial reported 60 AEs in the first month after circumcision (3.8%) of which the most common were pain (n=13), swelling or haematoma (bleeding under the skin –n=10), excessive external bleeding (n=9) and infections (n=3). At the end of the trial the reported rate of long-term adverse events, which included things like chronic pain, sexual dysfunction and dissatisfaction with the appearance of the penis, was 1%.

In the Kisumu study the number of adverse events definitely or probably related to surgery was 23 (1.7%).  These included seven cases of wound disruption or delayed healing, five of external bleeding and five infections.

The Rakai study gave less information on adverse events but found a higher rate of 8% in the first month after surgery, of which only 3% were classed as worse than mild. The rate of severe AEs was 0.2%: five events. These comprised one infection, two haematomas, one reopened wound caused by heavy lifting, and one severe herpes infection that could have been set off by the surgery, but was not at the wound site.

It is important to note that a rate of adverse events an order of magnitude higher than those seen in the RCTs has been observed in unregulated medical and traditional settings in Africa – see Rolling out circumcision for more details.

Sexual function and sexual pleasure

Opponents of circumcision believe that one of its adverse effects is to reduce sexual pleasure. Some studies in both developed countries and Africa have shown a higher rate of sexual dysfunction in older circumcised men compared with uncircumcised men.

One study12 stimulated circumcised and uncircumcised men’s penises with a fine probe and mapped the relative sensitivity of different areas. They found that uncircumcised men had significantly lower pressure thresholds, i.e., were sensitive to a much lighter touch.

They found, furthermore, that: “The transitional region from the external to the internal prepuce is the most sensitive region of the uncircumcised penis and more sensitive than the most sensitive region of the circumcised penis.” In other words, that parts of the foreskin are more sensitive than the glans and that circumcision “ablates the most sensitive parts of the penis.”

However, an older study13 of 123 men who had been circumcised as adults for medical reasons found that most men were happy they had been circumcised, although results on sexual satisfaction are mixed. Two-thirds (64%) were circumcised because of a tight foreskin (phimosis). Adult circumcision resulted in worsened erectile function (p = 0.01) and decreased penile sensitivity (p = 0.08), but there was no change in sexual activity (p = 0.22) and there was improved satisfaction (p = 0.04). Of the men, 50% reported benefits and 38% reported harm. Overall, 62% of men were satisfied with having been circumcised.

In Kenya, John Krieger studied the effects of circumcision on sexual function and sexual pleasure in a substudy of 2784 participants in the RCT of circumcision at Kisumu.14 In terms of ejaculation problems (too soon or too late), difficulty achieving erections, and pain or lack of pleasure during sex, he found absolutely no difference between circumcised men and uncircumcised controls twelve months after circumcision.

The number of men reporting sexual problems declined rapidly from baseline to twelve months in both circumcised and uncircumcised men: 7 to 8% of men at baseline reported erectile dysfunction, but only 1 to 2% at 12 months, regardless of circumcision status.

This unexplained finding may be due to men wishing to please investigators, or a result of ‘regression to the mean’ (whereby minorities in surveys tend to join the majority as time goes on) but, commented Kreiger, “it shows the value of having a control group” as without one it would have seemed that circumcision improved sexual function.


References

  1. Halperin D, Bailey R Male circumcision and HIV infection: 10 years and counting. The Lancet 354:1813-15, 1999
  2. Beegle K, Özler B Young Women, Rich(er) Men, and the spread of HIV. Development Research Group, The World Bank, unpublished paper, 2007
  3. Quinn TC et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 342(13): 921-929, 2000
  4. Weiss H Male circumcision and risk of HIV infection: Current epidemiological data. USAID meeting, 18 September 2002: Male Circumcision: Current Epidemiological and Field Evidence - Program and Policy Implications for HIV Prevention and Reproductive Health, 2002
  5. Sullivan PS et al. Male circumcision for the prevention of HIV transmission: What the new data mean for HIV prevention in the United States. PLoS Med 4(7):e223, 2007
  6. Warner L et al. Male circumcision and risk of HIV infection among heterosexual African-American men attending Baltimore sexually transmitted disease clinics. J Infect Dis 199(1): 59-65, 2009
  7. Auvert B et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2(11):e298, 2005
  8. Bailey RC et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. The Lancet 369: 643-56, 2007
  9. Gray RH et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. The Lancet 369(9562):657-66, 2007
  10. Bailey RC, Egesah O, Rosenberg S Male circumcision for HIV prevention: a prospective study of complications in clinical and traditional settings in Bungoma, Kenya. Bulletin of the World Health Organization 86(9):669-677, 2008
  11. Mehta SD et al. Does sex in the early period after circumcision increase HIV-seroconversion risk? Pooled analysis of adult male circumcision clinical trials. AIDS 23(12):1557-1564, 2009
  12. Sorrells ML et al. Fine-touch pressure thresholds in the adult penis. British Journal of Urology, 99, 864-869, 2007
  13. Fink KS et al. Adult circumcision outcomes study: effect on erectile function, penile sensitivity, sexual activity and satisfaction. Journal of Urology 167(5):2113-2116, 2002
  14. Krieger JN et al. Adult male circumcision: effects on sexual function and sexual satisfaction. Seventeenth International AIDS Conference, Mexico City, abstract TUAC0305, 2005
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