Infected cells, such as peripheral blood mononuclear cells in vaginal fluids or semen, can adhere to mucosal surfaces or can migrate through abrasions, so serving as a continuing source of budding virions [277]. Although minor trauma to mucosal tissues can occur during a sexual encounter to permit entry and inflammation can increase the risk of infection, this is not a requirement for infection to occur [277]. Wetness under the foreskin is an indicator of poor hygiene and is associated with a 40% increase in risk of HIV infection [403]. A wet penis may enhance attachment of infectious virions for longer, reduce healing after trauma, or may lead to balanitis under the foreskin and consequent micro-ulcerations [403].
The foreskin is thus the weak point that allows HIV to infect men during heterosexual intercourse with an infected partner. A circumcised man with a HEALTHY penis is thus very unlikely to get infected. However, ulcerations (from herpes, syphilis, etc) or abrasions on the penis will allow infection and a circumcised man with these will continue to be at risk of HIV, as well as some other STIs. In one study, individuals with HSV-2 have twice the risk of acquiring HIV than those without, and those infected with both viruses are more likely to transmit HIV than if they just have HIV [545]. In another the risk was increased 3-5 fold [574]. Giving co-infected patients acyclovir has therefore been suggested. Of course condom use is strongly advocated in attempting to lower transmission. Condoms, when ALWAYS used, reduce HIV infection by 80–90% [229]. Condom use remains low, however [177]. In one study, 78% had never used them [651]. Another, in Australia, found 25% never used them, with only 25% always using them [282]. Moreover, condoms are not a panacea, and a man with a foreskin can still be infected by HIV-laden fluids coming into contact with the inner foreskin, for example during foreplay, prior to application of the condom preceding vaginal penetration. A condom can, moreover, break!
Epidemiological research
In a 1998 joint WHO/UNAIDS report the percent of 15-49 year-olds infected with HIV in different regions was as follows: Sub-Saharan Africa 8.6%, Caribbean and Latin America 0.6%, South and SE Asia 0.6%, ‘Western’ countries 0.4%, Eastern Europe and Central Asia 0.2%, North Africa and Middle East 0.1%, East Asia and Pacific 0.1% [202]. These proportions have now increased. In a 2006 report, UNAIDS figures show that HIV prevalence in adults in 29 developing countries (not including Sub-Saharan Africa) with primarily heterosexual transmission was 0.76% for 11 with low (<20%) rates of circumcision and 0.09% for 17 with high rates of circumcision (>80%) [[158]], i.e., was 8-fold higher in those with low circumcision rate. The difference was highly significant (P <0.001). Heterosexual transmission is the primary mode of infection in Africa, the Middle East, the Caribbean and South and South-East Asia. This included predominantly Christian countries that practice circumcision such as the Philippines, Benin, Ghana, Equatorial Guinea and Gabon. Data for Sub-Saharan Africa appears in a later section. What follows summarizes data for various countries, both developing and developed.
In developing countries the rate of female-to-male HIV transmission was 341 times higher than in developed countries [401]. (This compared with a male-to-female rate 2.9-fold higher in developing countries.) Among couples in the West, female-to-male transmission was 11% [354]. For male-to-female it was 23%. In Africa, however, female-to-male was 73% [246] and male-to-female was 60% [246, 326]. In another study, in rural Uganda, female-to-male transmission (12 per 100 person years) was identical to male-to-female transmission [450]. After consideration of all of the factors, lack of circumcision was highlighted as a major driving force behind the AIDS epidemic [401].
United States of America:
In the USA over 1 million have been diagnosed with AIDS. At the end of 2005 the CDC estimated that 438,000 Americans were living with HIV/AIDS [www.avert.org/statsum] or 0.4% of the population [361a]. Of these, 77% are men, with 15% of men who were diagnosed with HIV infection in 2005 having contracted it from heterosexual intercourse [585]. For homosexual sex it was 59%. Of women, 65% were infected during heterosexual contact. There were 1,411 children aged under 13 years; most had acquired the virus from their mothers.
The number of diagnoses increased annually to 2005, reaching 45,669 in that year, with 17,011 deaths. In total 550,394 have died since the beginning of the epidemic, most prior to age 45. Heterosexual acquisition has grown by 42%. The incidence figures may, however, be underestimates, the true numbers likely being twice these.
In the USA an early overall estimate of risk of HIV infection per heterosexual exposure, when HIV status is unknown, is less than 1 in 100,000 [93, 422].
An association of higher incidence of HIV with being uncircumcised in the USA was first noted in 1989 [620]. A study of heterosexual couples in Miami found a higher incidence of HIV in men who were uncircumcised. A study in New York City found that risk ratio for HIV infection in heterosexual men as a result of being uncircumcised was 4.1, rate being 2.1% versus 0.6% for uncircumcised men as compared circumcised men [567]. Another US study that looked at heterosexual sex found a risk ratio of 2.9 [289]. (See also review [380]).
In homosexual men a study in Seattle found a 2.2-times higher HIV-positivity in the 15% who were uncircumcised [309]. The other, involving 3257 homosexual men in 6 US cities studied from 1995-1997, identified various risk factors, lack of circumcision once again being found to double the risk of acquiring HIV [85]. A failed HIV vaccine trial stopped in 2007 noted that ‘infected men were less likely to be circumcised’ [186]. No association between circumcision status and either HIV or syphilis infection in homosexual men, was seen in a San Francisco study, although the authors noted that a large proportion of gay men practice both insertive and receptive anal intercourse [369]. The latter would obviate the possibility of seeing an association with circumcision status.
Similarly, no association was seen in a Sydney study of homosexual men, but the authors noted that it was too small and had too many confounding factors to be capable of yielding a valid conclusion [224]. Even after increasing the size of this cohort, no association with circumcision status has been noted [568]. The numbers were still low, however, including only 9 seroconversions amongst gay men who reported no receptive anal intercourse. Consequently the confidence intervals of the data were extremely wide.
Interestingly, per-contact risk of infection from receptive oral sex is claimed to be comparable to that of insertive anal sex [85, 105, 594]. This is not, however, generally accepted as yet.
A position paper in 2007 stated “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 USA” and that “some sexually active men may consider circumcision as an additional HIV prevention measure” [554]. This was in addition to condoms of course, although in the USA condoms were never used during heterosexual sex with a non-primary partner in the case of 16% of men and 24% of women [488].
The Report warned, however, that any reduction in reimbursement by public and private medical insurance for circumcision, and any decline in rate of circumcision, could reverse the benefit that the USA has enjoyed to date because of its high rate of circumcision [554].
United Kingdom:
In the United Kingdom and several other Western European countries, most infections are from heterosexual contact. The incidence in the UK is 0.2% of the population [www.avert.org/aids-uk].
Australia:
In Australia there were 23,360 diagnoses of HIV and 10,028 of AIDS up until the end of 2006, with 6,685 deaths [www.avert.org/ausstatg]. AIDS incidence is the same as the UK (1.3 per 100,000) and lower than the USA (14 per 100,000). In Australia, 64-68% of HIV is in men who have sex with men (MSM)); 19% are from heterosexual sex, 4-8% injecting drug users, and 9% other. HIV rate is highest in New South Wales (214 per 100,000 people), followed by Victoria (110 per 100,000), ACT (87), Qld (73), NT (73), WA (69), SA (66) and Tas (24).
Europe and Russia:
In Europe generally (13 centres from 9 countries) rate is higher than in the USA: 3 in 10,000 [156]. (And circumcision rate is very low in Europe.) In Russia, heterosexual transmission grew from 5% of all infections in 2001 to 20% in 2005 [www.avert.org/ecstatee].
Asia:
In Asia, rate of HIV is low where circumcision is high: e.g., Philippines (0.06% of adults are HIV-positive), Bangladesh (0.03%) and Indonesia (0.05%). In contrast the rate is 10-50 times higher in countries with a large proportion of uncircumcised males: e.g., Thailand (2.2%), India (1.8%) and Cambodia (2.4%) [227]. Large increases in infections are expected in such Asian countries over time [227]. More details for each region follow:
China:
In 2000 there was an outbreak of HIV in central China arising from use of contaminated needles to buy and on-sell blood from people there. China is the biggest country in Asia (1.3 billion). It has at least 650,000 cases. By 2010 HIV cases could reach 10 million [www.avert.org/aidschina]. Approx. 10% of infections are from heterosexual contact. The leadership of this, the biggest country in the world, is well placed by its political ideology to reduce such a disaster by institution of a circumcision policy.
India:
HIV was first reported in India in 1986 and is now widespread. An early report said 5.1 million were infected (1% of the adult population [205] or 0.5% of the total population [www.avert.org/aidsindia]). However, this was revised downwards in 2007 to 2.5 million (0.4% of adults) [119]. Nevertheless the figure could be up to 6 million [119]. Hindu men, who, unlike Muslim men, are virtually all uncircumcised and thus are at increased risk. A prospective study published in the Lancet in 2004 of 2,298 men initially not infected with HIV men found that circumcision was strongly protective against HIV-1 infection with a 6.7-fold reduction in adjusted relative risk (0.14; P = 0.0089) [464]. The data led them to conclude that biological rather than behavioural differences were responsible and that the foreskin has an important role in sexual transmission of HIV. Most infections in India are from heterosexual sex.
A study published in 2007 found lower HIV incidence in Muslim men (circumcised) compared with Hindu men (uncircumcised), 1.0% versus 4.4%, respectively (odds ratio 0.42), despite Muslim men having more sex partners and vistits to commercial sex workers [562a]. This finding was not influenced by concurrent infection with other STIs.
Thailand:
In Thailand, a country with low circumcision rates, 1.4% of adults are infected, mostly via heterosexual sex, with 3 times more men than women infected. A study of young military conscripts in Northern Thailand, where the men were having regular contact with female sex workers, the rate was 1 in 18 to 1 in 32 [353].
Central Asia and Eastern Europe:
Central Asia, as well as Eastern Europe, are experiencing an alarming increase in HIV infections, with a 46% rise in the number of people living with HIV between 2001 and 2003 [442].
Middle East:
Muslim nations such as Egypt, Iran, Pakistan, Bangladesh and Indonesia there is a very low prevalence of HIV infections [529]. In Kuwait, a study published in 2007 of 1068 male and 28 female patients presenting for a range of STIs, over 99% of which were acquired heterosexually, found no HIV or syphilis [10].
Comoros (Indian Ocean)
This population has a high circumcision rate and only 1 of 3990 individuals was infected with HIV [135]. Only 1 sex worker was HIV positive. Syphilis was also rare, but STIs not associated with circumcision status were prevalent.
South America:
Three-quarters of HIV infections in Rio de Janeiro State have been attributed to unprotected heterosexual intercourse [171]. Over 90% were uncircumcised.
Africa:
Sub-Saharan Africa has 63% of the world’s AIDS cases. Strikingly, in 4 southern African countries adult HIV prevalence exceeds 20%, the rate in Swaziland being 33%. South Africa with 5.5 million people infected has more than any country in the world. HIV rates differ in different regions as a function of circumcision practise. Modelling has established that varying rates of circumcision have played a major role in explaining the strikingly different HIV epidemics I different parts of Sub-Saharan Africa [413].
Based on data from Kenya, if one partner is HIV positive and otherwise healthy then a single act of unprotected vaginal sex carries a 1 in 300 risk for a woman and as low as a 1 in 1000 risk for a man [93]. (The rates are very much higher for unprotected anal sex and intravenous injection.) This data did not take into account circumcision status. In Kenyan truck drivers female-to-male infectivity per sex act was 1 in 78 for uncircumcised and 1 in 200 for circumcised men [51]. In Nairobi the rate is 1 in 1000 in the absence [240] and 1 in 6 in the presence [95] of genital ulcers.
UNAIDS data for 2004 show the prevalence of HIV in 38 Sub-Saharan African countries was 16% for the 8 countries with low (<20%) circumcision rates and 3% for the 22 with high (>80%) circumcision rates [158]. This was independent of Muslim and Christian religion.
Sub-Saharan Africa would appear to be where HIV first appeared in the human species. This region has 75% of HIV infections in the world [581]. Of 44 sub-Saharan countries, in only 4 is the prevalence less than 1%. In 7 of the 16 in which it is greater than 10%, more than 20% of the population is infected. In South Africa 25% of adults are infected and in Botswana 40%. Mortality in those infected is elevated 50–500% [www.who.int/emc-hiv]. Sexual transmission continues to be by far the major mode of spread of HIV in Africa [494]. Being in a stable sexual relationship with an HIV-infected person is a major risk factor for HIV infection [345]. Naturally most of these infections involved uncircumcised men. The male, who is more likely to be promiscuous than the female, is the major source of infection in the majority of women, who only have that one partner [185]. They may then pass on the virus to their children during pregnancy and breastfeeding. Men should therefore be the target for intervention strategies aimed at combating the disease.
There have now been over 40 studies of the role of circumcision in HIV incidence. One of the earliest key studies of the risk of HIV infection imposed by having a foreskin was that by Cameron, Plummer and associates published as a large article in Lancet in 1989 [95]. It was conducted in Nairobi. Rather than look at the existing infection rate in each group, these workers followed HIV negative men until they became infected. The men were visiting prostitutes, numbering approx. 1000, amongst whom there had been an explosive increase in the incidence of HIV from 4% in 1981 to 85% in 1986. These men were thus at high risk of exposure to HIV, as well as other STIs. From March to December 1987, 422 men were enrolled into the study. Of these, 51% had presented with genital ulcer disease (89% chancroid, 4% syphilis, 5% herpes) and the other 49% with urethritis (68% being gonorrhea). 12% were initially positive for HIV-1. Amongst the whole group, 27% were not circumcised. The men were followed up each 2 weeks for 3 months and then monthly until March 1988. During this time 8% of 293 men seroconverted (i.e., 24 men), the mean time being 8 weeks. These displayed greater prostitute contact per month (risk ratio = 3), more presented with genital ulcers (risk ratio = 8; P < 0.001) and more were uncircumcised (risk ratio = 10; P < 0.001). Logistic regression analysis indicated that the risk of seroconversion was independently associated with being uncircumcised (risk ratio = 8.2; P < 0.0001), genital ulcers (risk ratio = 4.7; P = 0.02) and regular prostitute contact (risk ratio = 3.2; P = 0.02). The cumulative frequency of seroconversion was 18% and was only 2% for men with no risk factors, compared to 53% for men with both risk factors. Only one circumcised man with no ulcer seroconverted. Thus 98% of seroconversion was associated with either or both cofactors. In 65% there appeared to be additive synergy, the reason being that ulcers increase infectivity for HIV. This involves increased viral shedding in the female genital tract of women with ulcers, where HIV-1 has been isolated from surface ulcers in the genital tract of HIV-1 infected women.
In this African study the rate of transmission of HIV following a single exposure was 13% (i.e., very much higher than in the USA). It was suggested that concomitant STIs, particularly chancroid [93], may be a big risk factor, but there could be other explanations as well. In uncircumcised males the highly vascular frenulum is particularly susceptible to tearing or other damage during intercourse, and is also a frequent site of lesions produced by other STIs [556]. The risk of HIV infection is thus further reduced by circumcision, which therefore reduces the synergy that normally exists between HIV and other STIs [556]. Prevalence of HIV was lower in circumcised men in Uganda, but rate of other STIs was similar between circumcised and uncircumcised men, pointing to the preputial mucosa as an important target tissue for HIV, but not other STIs [214].
An earlier study in Nairobi was the first to notice that among 340 men being treated for STIs there was a 3-fold higher rate of positivity for HIV if they had genital ulcers or were uncircumcised (11% of these men had HIV) [532]. Subsequently another report showed that amongst 409 African ethnic groups spread over 37 countries the geographical distribution of circumcision practices indicated a correlation of lack of circumcision and high incidence of AIDS [73]. In 1990 Moses in the International Journal of Epidemiology reported that amongst 700 African societies involving 140 locations and 41 countries there was a considerably lower incidence of HIV in those localities where circumcision was practiced [377, 378]. Truck drivers, who generally exhibit more frequent prostitute contact, have shown a higher rate of HIV if uncircumcised [455].
Interestingly, in a West African setting, men who were circumcised but had residual foreskin were more likely to be HIV-2 positive than those in whom circumcision was complete [436].
Of 33 cross-sectional studies to the mid 1990s, 22 reported statistically significant association, e.g. [139, 145, 256, 269, 532, 582], by uni-variate and multi-variate analysis, between the presence of the foreskin and HIV infection (4 of these 33 were from the USA). Five reported a trend (including 1 of the studies in the USA) [378, 379]. Of the 6 that saw no difference 4 were from Rwanda and 2 from Tanzania. In an editorial review in 1994 of 26 studies it was pointed out that more work was needed in order to reduce potential biases in some of the previous data [139]. Studies since then that did control for such potential confounding factors, have confirmed that there was indeed a significantly lower HIV prevalence among circumcised men [328, 582]. Hazard rate ratio for being uncircumcised in one of these was 4.0 [328].
Many of the earlier studies have now been re-evaluated and those that were negative are now consistent with the majority of studies, i.e., ALL studies show lower HIV in circumcised populations. In this large systematic meta-analysis published in 2000 [610], 27 studies were examined, with 21 showing reduced risk in circumcised men. In 15 that were adjusted for potential confounding factors the association with circumcision was 0.42 (i.e., rate in uncircumcised was 2.4 fold higher). The difference was highest in men at high risk, circumcised being 0.27 vs uncircumcised (i.e., was 3.7 fold higher for the uncircumcised). The authors concluded that safe services for circumcision should be provided as an AIDS prevention strategy in parts of Africa where men are not traditionally circumcised. Moreover, in tribes that do perform ritual circumcision, a study suggested transfer of HIV in infected blood contaminating the instruments used [76]. Thus traditional circumcision needs to be made safer. Some of these infections may, however, have been from false reporting of sexual activity / 'virgin status' [2a, 618a].
The case-control studies have continued since then. A Kenyan study found HIV incidence of 8% in men overall, but 29% in uncircumcised men, and 17% in women [490]. A South African study found lower HIV in circumcised Xhosa men [270]. It found 3.6% had had sex with another man, mostly as a result of having been coerced, and was a one-off event. A study in 2006 in which circumcision reduced HIV incidence 8-fold found an unexpected association with hygiene [364]. Subpreputial wetness, an indicator of inferior hygiene, is associated with slightly higher HIV infection (prevalence relative risk = 1.4) [403].
In addition to the many case-control studies there have been a number of prospective studies, including ones in Kenya and Tanzania, reporting statistically significant association with lack of circumcision. The increased risk in the significant studies ranged from 1.5 to 9.6. Later adjustment of the data for other factors showed all studies were significant in demonstrating higher HIV in uncircumcised men [610]. Women are at higher risk if their partner is uncircumcised. A study in Dar es Salaam, Tanzania, where most men are circumcised, noted that married women, with one sex partner, had a 4-fold higher relative risk of HIV if their husband was uncircumcised [284]. In most of these studies circumcision status was self-reported. However, physical examination in one study showed that 33% of men who said they were circumcised were in fact not circumcised [397]. Amongst Muslims, 26% were not circumcised. In the meta-analysis by Weiss et al. [610], only one study actually verified the circumcision status by physical examination [582]. Agreement between self-reported and actual circumcision status was only about 81% in a study in a small geographic area of Kenya [83]. This study also found many had only a partial circumcision due to enormous variation in operative technique used. Moreover, clinical reports of circumcision status can also be inaccurate, especially if the clinician was a woman, as reported in a US study of White, Black and Hispanic males that showed a disagreement of 16% [151].
A study of racially mixed adolescent males (mean age 15) in Houston, Texas found that only 69% of those who were circumcised knew this, with 7% thinking they weren’t and 23% unsure [469]. Thus the residual HIV infection amongst so-called circumcised groups could quite likely be to a large extent from this residue of uncircumcised men, i.e., the estimated protective effect from being circumcised could really be far greater than the statistics above.
The conclusive findings emerging from the large number of studies have, moreover, led various workers to propose that circumcision be used as an important intervention strategy in order to reduce AIDS [93, 181, 187, 227, 256, 298, 350, 378, 380]. Such advice has been taken up, with newspaper advertisements from clinics in Tanzania, western Kenya, Rwanda, Uganda and other parts of Africa offering this service to protect against AIDS [227]. Young men are opting for circumcision and tribal elders are changing the edicts of their culture by now allowing circumcision in order to prevent AIDS [227, 397]. In traditionally noncircumcising cultures, circumcision rate has increased to 23% overall with a mean age of having it done of 17.4 years, and the rate is even higher (57%) in those who had at least 8 years of education [397]. Health was cited as the reason.
Willingness to get circumcised is high. The work in Tanzania [397], as well as in all other studies such as in Kenya [55], Botswana [293] and South Africa [318, 454], show the majority of population groups are willing to accept circumcision to reduce HIV.
A review of 13 studies from 9 countries that examined acceptability found a median of 65% of men (range 29-87%) were willing to become circumcised and 69% of women (range 47-79%) favored circumcision for their partners [618]. Furthermore, 79% (50-90%) of men and 81% (70-90%) of women were willing to get their sons circumcised.
After 30 days 99% of men in a Kenyan study reported being very satisfied with the procedure, as were their partners (92%), and 96% had resumed general activities within the first week [310, 311]. None of the men and only 0.3% of partners were very dissatisfied with the outcome. By 3 days 83% of those with regular employment had resumed working, and by 1 week this was 93%, rising to 99% by one month [311]. By one month 10%, and by 3 months 65%, reported having had sex [311].
Similar findings have been obtained in Zimbabwe [230]. In the South African RCT 98.5% of men questioned 3 months after their circumcision were ‘very satisfied’ with the result [43] and in the Kenyan RCT 99.5% were ‘very satisfied’ [56].
Thus circumcision can be readily and successfully adapted into a culture. However, this must be accompanied by education that makes it clear that circumcision reduces, but does not eliminate the risk. Moreover, although earlier studies also appeared to show that circumcision is most effective as a preventative measure against HIV infection if it is performed prior to puberty [294], more recent work suggests a benefit at any age [7]. In the Kenyan study cost of supplies, obtained locally, equated to US$20, and charge for the procedure was US$13 in a government hospital and US$77 in a private hospital [310]. Rigorous counselling against sexual activity until the wound healed was stressed.
The possibility of an absolute protective effect of circumcision in an otherwise healthy penis was suggested by a large study published in the prestigious New England Journal of Medicine in 2000 [450]. This involved 415 heterosexual couples in which only one partner (228 men and 187 women) was HIV-positive. It followed them prospectively for 30 months. The incidence of seroconversion was 17 per 100 person-years among the 137 uncircumcised male partners. However, among the 50 circumcised men with a HIV-infected female partner, not one seroconverted, i.e., none became infected, even though they were having regular unprotected sex with an infected woman. The effect was apparent in circumcised non-Muslim men as well as Muslims (who wash after intercourse), suggesting behaviors arising from religion were not involved [215]. Moreover, the protection was seen only when circumcision had been performed prior to puberty [215]. A commentary to this article highlighted the need to explore circumcision in reducing the spread of AIDS [120].
A study reported in 2004 in which fastidious matching of uncircumcised and circumcised groups was carried out has continued to show a higher rate of HIV infection in uncircumcised men [7]. The study involved 845 Luo men in a single ethnic community in rural Kenya in which circumcision was dictated by their particular African-instituted Christian religious denomination, and involved 9 churches of each persuasion. In an accompanying Commentary on this article it was mentioned that ‘careful (even obsessive) statistical analysis has zealously controlled for every possible confounder’, meaning that ‘the quality of the science informing the debate has just moved up a notch’ [187].
Frequency of sexual intercourse has also been excluded. In a study of 188 circumcised and 177 uncircumcised men in Mbale, Uganda, non-Muslim circumcised men engaged in more risk-taking behaviors, such as drinking alcohol in conjunction with sex, sex with women on the first day of meeting, sex in exchange for money or gifts, pain on urination, penile discharge, earlier sexual debut (16 vs 17), more extramarital sex partners in the previous year (1.1 vs 0.6), and more nonwet sex [52]. (The latter, which is also practiced in Haiti, the Dominican Republic and to a certain extent in the USA, in an uncircumcised man can cause bleeding of the foreskin and frenulum, so increasing infection risk [228].) Muslims had a lower risk profile regarding all of these factors, except for being less likely to have used a condom ever or during the previous sexual encounter (odds ratio 0.3). This highlights the fact that the foreskin itself confers an increased risk of HIV infection. Research has also shown that differences in biological factors such as circumcision and STIs are more important than behavior in risk of HIV infection, with more people who considered themselves to be at low risk being infected with HIV [273].
Overall, rough estimates are that circumcision has prevented more than 10 million HIV infections so far in Africa and Asia [183]. Worldwide this figure will obviously be greater.
An extensive Cochrane review [530] examined 37 observational studies, and noted that these varied in quality and potential confounding variables, so making a meta-analysis inappropriate. It stated that although most studies show a protective effect of circumcision results of randomized controlled trials were needed. An earlier evaluation of the evidence by others had also advocated randomized controlled trials to cement the strong suggestive evidence [54].
The 3 randomized controlled trials (RCTs) in Africa:
Three randomized controlled trials were begun in the early 2000s. The results for one of these were reported in 2005 [43]. This involved 3,274 uncircumcised men aged 18-24 in the Orange Farm area, a semi-urban region near Johannesburg in South Africa. The men were randomized into a control or intervention (circumcision) group and the intention was for evaluation at clinic visits at 3, 12 and 21 months. So striking was the benefit of circumcision that at 18 months the Data and Safety Monitoring Board stopped the trial early so that the control group could be offered circumcision without delay. Protection was 60% (or 61%, after controlling for behavioural factors such as sexual activity, which was higher in the intervention group). Thus circumcision “prevented 6 out of 10 potential infections”. In fact their per-protocol analysis (which corrects for the dilutional effect of cross-overs, so treating men who were actually circumcised as circumcised and men who were uncircumcised as uncircumcised, and is thus more meaningful) showed a protective effect of 76%. It was concluded that “circumcision provides a degree of protection against acquiring HIV infection equivalent to what a vaccine of high efficacy would have achieved” and “may provide an important way of reducing the spread of HIV infection”.
Moreover, 99% of the men were “very satisfied” with their circumcision.
The findings were consistent with the data from meta-analysis of observational studies above, but showed a higher protective effect.
The authors suggested that “if women are aware of the protective effect of male circumcision, this awareness could, in turn, have an impact on prevalence of male circumcision by encouraging males to become circumcised”. Also, circumcision “could be incorporated rapidly into the national plans of countries where most males are not circumcised” (just as the example of South Korea where circumcision has risen from virtually zero 50 years ago to 85% today [297]).
The authors further stated that circumcision “is an inexpensive means of prevention, performed only once, and … over a wide age range, from childhood to adulthood” and “the number of HIV infections that could be avoided … is high”. Nevertheless, circumcision must be promoted as part of a package that includes safe-sex (condoms) and fidelity. Compare this with messages regarding prevention of cardiovascular disease, type 2 diabetes, cancer, etc, namely, stay slim AND don’t smoke AND control blood pressure AND eat healthy food AND don’t drink alcohol to excess, etc (i.e, not any of these alone). The study’s findings were widely reported, including in two Science commentaries [116, 117].
The two other randomized controlled trials in Kenya and Uganda that were to be completed in 2007 and 2008 were similarly stopped early (in Dec 2006) by the monitoring committee because the preventative effect was so striking. The findings were published in the esteemed medical journal the Lancet in Feb 2007 [56, 216]. Circumcisions in the Kenyan trial were performed between Feb 2002 and Mar 2004 [310]. Each study involved 2,784 and 4,996 uncircumcised men aged 18-24 and 15-40, respectively [56, 216]. In each study half as many of the circumcised men became infected as the uncircumcised. The more relevant ‘as-treated’ protective effect of circumcision was 60%. Extensive data analyses dismissed a plethora of other, potentially confounding, factors as contributing to the much higher HIV incidence in the uncircumcised group in each of the studies. Only 1.5% [56] and 3.6% [216] experienced an adverse event related to their circumcision, and these resolved quickly. There was moreover no behavioural risk compensation after circumcision [56, 216].
Exploding the myth that circumcision is extremely painful, the Kisumu study found that at 3 days follow-up, 48% reported NO pain, 52% very mild pain, NONE moderate or severe pain, and by 8 days, 89% no pain, 11% mild [56]. Moreover, 99.5% of the men were 'very satisfied' with their circumcision and 0.5% were 'somewhat satisfied'. None were 'dissatisfied'.
The protective effect was greater than that reported conservatively in the abstract. For a start, it seemed that 3 of the men in the circumcised group were likely to have been HIV positive before the operation (since they tested positive at month 1 but had not had sex during this period, in accordance with study directions), and there was one HIV-positive man who disobeyed instructions and did have sex during the first month. After excluding these subjects, 2-year HIV incidence was 1.6% for the circ group vs. 4.2% for the control group = a 68% protective effect [56].
In the Introduction of this paper the authors point out the fact that currently available prevention measures (barriers, etc) "have often been unsuccessful in restricting the spread of HIV", as well as the to futility of relying on a HIV vaccine, stating “there is little promise that an effective vaccine will be available within the next 15 years [56]. They also noted that “although the availability of antiviral therapy for individuals infected with HIV is increasing worldwide, many more new infections are occurring for every additional person on such treatment.” Antiviral treatment is horrendously expensive, whereas prevention is much more desirable, and circumcision is cheaper.
The data show that there was low condom use by each group, even when condoms were provided free to all participants. The low rate is very similar to what we see in developed countries. Those engaged in risky sex are prevalent in the same age bracket as ones who drive recklessly, binge drink, etc, etc. ... i.e., those in the age bracket where the 3 'I's apply ... 'immune, infertile, immortal'! Circumcision is a one-off and does not have to be 'applied', is not inconvenient (except for a few weeks of no sex after having it done), and reduces a plethora of other problems.
The new data (much as previous data) showed that circumcision reduces HIV infection irrespective of number of partners (where there was NO risk compensation, ie, the circumcised men did NOT immediately go out and have more risky sex thinking that circumcision was a panacea for preventing HIV infection). In the South African randomized controlled trial the men who had a circumcision DID exhibit increased sexual activity, but this did not increase their infection. In fact the per-protocol protection was 76%! This is enormous in public health terms.
As well, these new data also showed circumcision conferred a cumulative efficacy of 48% in reduction of genital ulcer disease in the circumcised group [216], as reported previously in observational studies.
Gray and co-workers state (p 665, col 2, para 3): "neonatal circumcision or circumcision of younger boys will provide a simpler, safer, and cheaper option ..." [216]. Here they refer to HIV benefits only, neglecting to mention the 11-fold reduction in UTIs in first year of life, as well as phimosis that affects 10% of uncircumcised boys, and the other problem, diseases and infections throughout the life of the male and his sexual partners such as cervical cancer, chlamydia, etc.
For a circumcision efficacy of 50% when HIV incidence is 1.3 per 100 person-years in uncircumcised men (as in Rakai) 35 surgeries would be needed to prevent one HIV infection over 10 years, if all underwent circumcision [216]. For South Africa (3.8 per 100 person-years HIV incidence) far fewer circumcisions would be needed to prevent one HIV infection. In South Africa STIs account for over 26% of all deaths and over 5 million DALYs in 2000, more than 98% of this burden was due to HIV/AIDS. A model that incorporates backward bifurcation showed, using partial data from South Africa, that male circumcision at a 60% efficacy level could prevent 220,000 cases of HIV and 8,200 deaths in South Africa within a year [443a]. It also showed that male circumcison by itself could significantly reduce, but not eliminate, HIV burden in a community. Disease elimination was, however, feasible when combined with anti-retrovirals and, to a lesser extent, condoms [443a]. Another study estimated, based on a 50% protection against HIV infection by circumcision, an increase in the rate of circumcision to 100% from the current 10% in Ndola, Zambia would reduce the prevalence of HIV in adults from 27% down to 7% [116]. Thus the effect could be quite striking.
(ie, 'A model that incorporates backward bifurcation showed, using partial data from South Africa, that male circumcision at a 60% efficacy level could prevent 220,000 cases of HIV and 8,200 deaths in South Africa within a year [443a]. It also showed that male circumcison by itself could significantly reduce, but not eliminate, HIV burden in a community. Disease elimination was, however, feasible when combined with anti-retrovirals and, to a lesser extent, condoms [443a].)
A joint analysis in 2006 by the World Health Organization in Geneva, UNAIDS and other experts around the world found that in Sub-Saharan Africa circumcision could avert 2 million new infections and 0.3 million deaths over the subsequent 10 years, and in the 10 years after that a further 4 million new infections and 3 million deaths, a quarter of this being in South Africa [625]. It equated circumcision with condom use or a vaccine.
Another reputable analysis, based on the South African trial data, found that 1000 circumcisions would prevent 308 HIV infections over 10 years at a cost of $181 per HIV infection averted (net savings $2.4 million) [276].
Estimates of the economic and human resources required for 14 Sub-Saharan countries where circumcision is <80% and HIV >5%, and assuming >85% of men get circumcised show an initial 5-year cost of $922M (private) / $397 (public) [44]. 1912 circumcisers would be needed, i.e, 0.23 per 10,000 adults. In years 6-10 the number needed would reduce to 504 and cost to $208M/$84M. They reported that 5-8 circumcisions would be needed to prevent one HIV infection, and concluded that, although expensive, the roll-out of circumcision would be cost-effective overall and sustainable, and would have important benefits to public health.
Mathematical modeling has predicted that with 80% circumcision uptake, a 45-67% reduction in prevalence would be achieved in both men and women within a decade in African countries with high HIV prevalence, and with a 50% uptake, HIV would be reduced 25-41% [383]. Further modeling has predicted that for a 60% efficacy, 19 surgeries prevent 1 HIV infection in both sexes at a cost per infection averted of $1269 [217]. Circumcision therefore appeared to provide a cost-effective prevention strategy. Indeed, the reduction predicted would be sufficient to ‘abort the epidemic’ [217]. A modeling study in Sydney predicted that by 2020 complete male circumcision in an average country could reduce HIV prevalence from 8.3% to 5.3%, and incidence from 13.5 seroconversions per thousand to 7.3 per thousand [339]. They reported that for Zimbabwe a HIV rate of 25% for no circumcision would be reduced to 13% for 100% circumcision.
These studies lead to the conclusion that "circumcision must now be deemed to be a proven intervention for reducing the risk of heterosexually acquired HIV infection in adult men" [216]. Dr Kevin de Cock, Head of the WHO's HIV/AIDS department has called the studies an "extraordinary development" and circumcision a "potent intervention in HIV prevention" [http://www.iht.com/bin/print.php?id=4728041]. As stated earlier, on March 28 2007, the World Health Organization endorsed circumcision for prevention of HIV infection [621]. ‘Global expansion of male circumcision programs [is a] vital tool for control of HIV infection [484].
Rapidity of spread
The sorts of health problems faced by the 'third-world', coupled with a lack of circumcision may account for the rapid spread of HIV through Asia [617]. The reason for the big difference in apparent rate of transmission of HIV in Africa and Asia, where heterosexual exposure has led to a rapid spread through these populations and is the main method of transmission, compared with the very slow rate of penetration into the heterosexual community in the USA and Australia, could be related at least in part to a difference in the type of HIV-1 itself [314]. In 1995 an article in Nature Medicine discussed findings concerning marked differences in the properties of different HIV-1 subtypes in different geographical locations [414]. A class of HIV-1 termed 'clade E' is prevalent in Asia and differs from the 'clade B' found in developed countries in being more highly capable of infecting Langerhans cells found in the foreskin, so accounting for its ready transmission across mucosal membranes. The Langerhans cells are part of the immune system and in turn carry the HIV to the T-cells, whose numbers are then severely depleted by the virus as a key feature of AIDS. The arrival of the Asian strain in Australia was reported in Nov 1995 and has the potential to utilize the uncircumcised male as a vehicle. More vigorous promotion of circumcision is needed to help curtail infections.
Risk compensation
A worry of AIDS experts is that knowing that circumcision is protective against HIV infection many will be less concerned about engaging in risky behavior [100]. This is known as ‘risk compensation’ and was referred to above. Thus circumcision should be promoted as part of a package of protections. Encouragingly, at stated earlier, risk compensation was not a concern in the RCTs testing circumcision for HIV prevention [56, 216]. In a Kenyan study men were less likely to engage in risky behaviours during the first year after being circumcised and thereafter there was no difference compared with uncircumcised men [8]. However, in the South African RCT the men who received a circumcision had more sexual encounters, with all 5 sexual behavior factors being significantly higher in this group [43]. Despite this, their HIV acquisition was no greater (in fact less) than in the other two trials. Men in the circumcised arm of the Uganda RCT were less likely to use condoms in the first 6 months after circumcision, but thereafter all risk behaviors were similar in the two groups [216].
Ethical and other challenges:
Various obstacles have been recognized that could impede the full roll-out of circumcision [463]. These include cost, supply of sufficient competent circumcisers, circumcision training, adequacey of clinics and resources, best age, risk compensation, conflict between individuals within families and society who want it done or who don’t want it done, prioritization of individuals in the face of limited resources, education to ensure circumcision is not seen as a panacea, and ethical issues in relation to culture, such as obstacles to changing the culture, as well as the need to alter certain practices in cultures that do circumcise so as to make the procedure safer [463]. Ensuring safe circumcisions will require all stakeholders to work together [365].
The challenges seem minor, however, when compared to the perceived benefit. Many concerns have little validity. For example, as far as acceptability is concerned, the WHO produced another report in 2007 that showed that most cultures are neutral on circumcision [646]. Those generally opposed include Indians of Hindu or Seikh faiths, since being uncircumcised distinguishes them from Muslims where they live. To increase the speed of the roll-out of circumcision paramedical as well as traditional and religious figures may be enlisted and trained [220]. A voucher system for circumcision has been suggested [220]. The Bill & Melinda Gates Foundation has provided substantial donations to circumcision for HIV/AIDS prevention but more is needed, as are doctors from other parts of the world so that they can supplement the efforts already underway in Africa.
Increased uptake of circumcision might result in stigmatisation of uncircumcised men as being less ‘safe’ [288].
Condoms:
Sexual transmission of HIV and other STIs should be reduced by use of barrier protection such as condoms. A feared AIDS epidemic resulted in media campaigns starting in the 1980s aimed at increased condom use. In a 1996 survey of American college students only 60% had used condoms in the previous 6 months and less than 50% definitely intended to use them in the next month [67]. Amongst a general US population sample, 62% of adults in 1996 reported using condoms at previous intercourse outside of an ongoing relationship [25]. A report in 2006 found that in the USA 16% of men and 24% of women never used condoms during heterosexual sex with a non-primary partner [488]. Another US survey of women attending STI clinics in Baltimore, consistent condom use was stated as 25%, with 48% saying there had been no condom use in the previous 14 days [267]. However, testing for male DNA in the vagina showed that this was present in all, albeit higher in the no condom-use group [267]. A review in the Lancet in 2000 reported condom use was 55% [155]. Amongst younger people, an Australian study found only 25% always used condoms, with 25% never having used them [282]. In Mexico condom use was 51% in young men and 23% when reported by young women [92]. Consistent condom use was, moreover, only 30% [92]. In Mexican public school students, average age of sexual debut was 14 years, and of the 13,293 subjects in this study, 46% had an intermediate and 37% a high HIV/AIDS knowledge [564]. Males with high knowledge were more likely to use condoms (odds ratio 1.4), whereas females in this category were less likely (odds ratio 0.7) [564].
Thus at least half of the sexually-active population of western countries are not using condoms. Indeed, the message of condom campaigns can easily be forgotten, especially in the young, in whom passion will over-ride compliance on occasions. Young people represent the most sexually promiscuous, at-risk group. They are at an age when risk-taking behaviour is prevalent (cf. smoking in young people vis-a-vis the anti-smoking campaign, dangerous driving, alcohol and drug taking, stunts, etc). In the case of HIV too, this will have tragic consequences. Many young people do not use condoms and openly scoff at the idea, despite the health warnings. Indeed it may be a sign of machismo to the young adult. It is well-known that the three "I"s are represented in their behavior of being "infertile", "immortal", and "immune" . Thus education is only part of the answer and where an additional simple procedure is available to reduce the risk, then logic dictates that it should be used. The result will be many lives saved.
Even when used, the method of condom use is often incorrect. Condoms may break during intercourse. There can also be strong cultural and esthetic objections to their use. Also, application of a condom to a circumcised penis is easier than to a penis with a foreskin.
In the prospective study referred to earlier of circumcised and uncircumcised men whose female partner was infected, condoms were made available continuously [450]. However, in discussing this study it was pointed out that 89% of the men never used condoms and condom use did not appear to influence the overall rate of transmission of HIV [556]. Only circumcision status did. A review of 10 studies from Africa found that overall there was no association between condom use and reduced HIV infection, with one study showing a positive association between use of a condom and HIV infection [534]! Circumcision removes the tissue that is the entry point for HIV. Unless a condom is used during all sex play then the risk remains of contact between the inner lining of the foreskin and HIV-laden secretions, sperm (in the case of homosexual sex), cells or tissues of an infected sex partner.
Thus condom use is far from a panacea for HIV prevention, since exposure of the vulnerable foreskin to infected biological fluids could take place during foreplay prior to application of the condom.
Diaphragms, used commonly by women as a contraceptive, provide no protection against HIV infection [423].
‘Docking’
Homosexual men who engage in a form of mutual masturbation [527], also known as ‘docking’, a sexual practice that requires the foreskin, are placing themselves at risk, often not knowing of the danger this puts them in if their partner is infected.
Circumcision status and risk to women
If a man is HIV-positive, whether he is circumcised or not makes little difference to whether a women he has sex with will become infected [578]. The only exception was women from high-risk settings (hazards ratio = 0.16).
Recommendation to US President, and NIH position
A 100-page document prepared in 2005 by the ‘Presidential Advisory Council for HIV/AIDS’ entitled “Achieving an HIV-free Generation: Recommendations for a New American HIV Strategy” argues the case for circumcision in HIV prevention. This official advice was adopted by a 16:2 vote (with 1 abstention) by the Council and presented to the President and Secretary Leavitt. The effort was praised by Carol Thompson from the White House. The National Institutes of Health have reacted similarly in realizing that they must develop policy that accords with the research findings.
Circumcision could extinguish the HIV epidemic:
Analysis of the dynamics of the epidemic suggests that heterosexual transmission of HIV probably peaked during the 1990s [526]. Given its effectiveness, circumcision, if implemented widely, has the potential to drive the prevalence of HIV virtually to extinction [217]. In fact, a ‘parachute approach’ to evidence-based medicine has been suggested, where, in the case of HIV, in the face of good evidence and enormous potential benefits, large scale circumcision could have been started in the early 1990s when the link was already clear, rather than wait until 2007 after the findings from the 3 RCTs [446]. In the intervening period millions of lives would have been saved.
Heterosexual transmission was the initial, and remains the major, mode of transmission worldwide, lack of circumcision is a major contributing factor to the AIDS epidemic. Even though other modes of transmission are prevalent in developed countries, heterosexual transmission remains and may be especially relevant for men who visit counties with high HIV. Moreover, in some studies [215, 294], but not in a more recent one [7], the effectiveness of circumcision in AIDS risk reduction was greater when performed prior to puberty.
‘ABC’
Thus, to the old ‘ABC’ (abstinence, behavior and condoms) one can now invoke an ABC that goes ‘antivirals, barriers and CIRCUMCISION.
Call for action:
Some quotes from an article by Harvard expert Daniel Halperin and associates [301a] are pertinent: “Male circumcision is the only modality for prevention of HIV transmission that has been proven to work by the highest standards of scientific evidence”. Particularly in regions of high HIV prevalence “the majority of uncircumcised men want the procedure performed, and generally an even higher proportion of women in those regions would prefer to have a circumcised partner”. Professional, governmental and advocacy communities have been criticized for the “glacially slow introduction of male circumcision”. “If this were an actual vaccine, packaged with a pharmaceutical company logo and shiny labelling, few people would be deliberating … There would instead be massive mobilization.” “Unfortunately, in these times of profit-driven healthcare, no single entity stands to earn large sums of money from male circumcision. The procedure is not patented, owned or trademarked.” “Male circumcision works: it is as least as good as the HIV vaccine we have been waiting for, praying for and hoping to see in our lifetimes.”
And this from the Institute of Catholic Bioethics: “Mandating neonatal male circumcision is an effective therapy that has minimal risks, is cost efficient and will save human lives. To deny individuals access to this effective thereapy is to deny them the dignity and respect all persons deserve. Neonatal male circumcision is medically necessary and ethically imperative” [115a]
Footnote: The author of this website chaired the Circumcision session at the 4th International AIDS Society Conference in July 2007.
