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HIV infection is via the foreskin
Over 25 million people have died from AIDS. To date 60 million have been infected with HIV (15,000 each day, i.e., one every 6 seconds; 4.3 million in 2003) and 40 million are currently living with HIV, leading to >15 million children being orphaned [www.unaids.org][105, 274]. By 2050 there could be one billion infected ! Half of HIV cases are men, most of whom have been infected through their penises , the foreskin having been implicated as early as 1986 . Over 80% of these infections have arisen from vaginal intercourse .
How then does HIV enter a man's body in this way? Epidemiological data from more than 40 studies (discussed below) shows that HIV is much more common in uncircumcised, as opposed to circumcised, heterosexual men . A wealth of evidence indicates that male circumcision protects against HIV infection, as acknowledged in the major journals Science [67, 68, 170] and Nature , and its promotion in HIV prevention is advocated .
During heterosexual intercourse the foreskin is pulled back down the shaft of the penis, meaning that the whole of its inner surface is exposed to vaginal secretions . An early suggestion that attempted to explain the higher HIV infection in uncircumcised men was that the foreskin could physically trap HIV-infected vaginal secretions and provide a more hospitable environment for the infectious inoculum . Initial thoughts were that the port of entry could potentially be the glans, sub-prepuce and/or urethra. It was suggested that in a circumcised penis the drier, more keratinized skin covering the penis may prevent entry. However, subsequent studies showed that the glans of the circumcised and uncircumcised penis were in fact identical in histological appearance, having exactly the same amount of protective keratin . In contrast, the inner lining of the foreskin is a mucosal epithelium and lacks a protective keratin layer . The foreskin's inner epithelium thus resembles histologically the lining of the nasal passages and vagina. All such mucosal epithelia are major targets for infection by micro-organisms (colds, flu, STIs, etc). Added to this is the fact that the uncircumcised penis is more susceptible to minor trauma and ulcerative disease, and the preputial sac could harbor pathogenic organisms in a pool of smegma . The mucosal inner lining of the adult foreskin is rich in Langerhans cells and other immune-system cells (22.4, 11.5 and 2.4% of total cell population is represented by CD4+ T cells, Langerhans cells and macrophages) . (This contrasts with the neonate, where the foreskin is deficient in such cells , the proportion being instead 4.9, 6.2 and 0.3%, respectively ). The respective percentages for immune-system cells in the cervical mucosa are: 6.2, 1.5 and 1.4% . In the external layer of the foreskin, which is like the rest of the penis, the proportions are very much lower: 2.1, 1.3 and 0.7%, respectively . Although the urethra is also a mucosal surface, Langerhans cells are rarer, and it is not regarded as a common site of HIV infection.
The counterintuitive observation that HIV risk is actually lower in circumcised men who have more frequent exposure than it is in circumcised men with less frequent exposure, has led to the hypothesis that repeated contact of the small area of exposed urethral mucosa with subinfectious inoculums may induce an immune response having a protective effect over and above that afforded by removal of the vulnerable foreskin . The small area exposed may mean that the infectious inoculum per act of intercourse may be less likely to overwhelm the effects of partial protection as compared with the mucosal area exposed in a foreskin or vagina . This hypothesis remains to be tested. Mucosal alloimmunization has also been suggested as a protective factor against HIV .
The immune cells of the inner lining of the foreskin help fight bacteria and viruses that accumulate under it. However, in the case of HIV, they act as a `Trojan horse', serving as portals for uptake of HIV into the body, where HIV entry generally requires CD4 receptors and cofactors such as chemokine receptors CCR5 and CXCR4 present in high density on the surface of Langerhans cells . Moreover, the selective entry of HIV via the inner foreskin has been shown by direct experimentation [28, 38, 267]. Punch biopsies were taken from fresh foreskin obtained immediately after circumcision of the adult male. Cultures were made of cells from the external surface (which resembles the rest of the penis) and from the inner mucosal surface of the foreskin. Live HIV tagged with a fluorescent marker was then applied. Within minutes the HIV entered the Langerhans cells [see picture above - obtained, with permission, from  (similar images can be seen in ). No uptake occurred for cultured epithelium of the keratinized outer surface of the foreskin, i.e., the part that resembles the skin of the circumcised penis. The mean number of HIV copies per 1000 cells (determined by quantitative PCR) one day after infection was 301 for the mucosal inner foreskin, but was undetectable in the outer, external, foreskin . For cervical biopsies mean HIV copy number was 30, showing that the mucosal inner foreskin is 10-times more susceptible to HIV infection than the cervix . The HIV receptor CCR5 was, moreover especially prevalent on foreskin tissue cells . This biological work thus nicely confirms the epidemiological evidence to be discussed below. It is furthermore supported by experiments in which SIV (the monkey equivalent of HIV) has been applied to foreskin of monkeys, that then became infected . The monkey work also showed infected Langerhans cells. Antigen presenting cells in the mucosa of the inner foreskin  are a primary target for HIV infection in men .
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. 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 . Giving co-infected patients acyclovir has therefore been suggested.
Risk per exposure
In the USA the overall estimated risk of HIV infection per heterosexual exposure, when HIV status is unknown, is less than 1 in 100,000 [55, 263].
In Europe (13 centres from 9 countries) rate is higher than in the USA : 3 in 10,000. (And circumcision rate is much lower in Europe .)
An overview of all of these various studies found that in developing countries the rate of female-to-male HIV transmission was 341 times higher than in developed countries . (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% . For male-to-female it was 23%. In Africa , however, female-to-male was 73%  and male-to-female was 60% [157, 206]. In another study, in rural Uganda , female-to-male transmission (12 per 100 person years) was identical to male-to-female transmission . After consideration of all of the factors, lack of circumcision was highlighted as a major driving force behind the AIDS epidemic .
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 . 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 .
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 . It was conducted in Nairobi .
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) . 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 . 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 [235, 236]. 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 . Of 33 cross-sectional studies to the mid 1990s, 22 reported statistically significant association, e.g. [84, 86, 163, 169, 330, 362], 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 ) [233, 236]. 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 . 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 [208, 362]. Hazard rate ratio for being uncircumcised in one of these was 4.0 . 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 , 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.
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 .
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 [55, 109, 113, 143, 163, 185, 221, 234, 236]. 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 . 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 [143, 245]. 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 . Health was cited as the reason. This work in Tanzania , as well as all other studies such as in Kenya , Botswana  and South Africa [199, 283], show the majority of population groups would be willing to accept circumcision to reduce HIV.
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 .
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 . 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' .
Overall, rough estimates are that circumcision has prevented more than 10 million HIV infections so far in Africa and Asia . Worldwide this figure will obviously be greater.
An extensive Cochrane review  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 .
The 3 randomized controlled trials in Africa :
Three randomized controlled trials were begun in recent years. The results from the first of these were reported in 2005. This study 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% 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. 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). 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". The study's findings were widely reported, including in two Science commentaries . The 2 other randomized controlled trials in Kisumu, Kenya and Rakai, Uganda, that were to be completed in 2007 and 2008, were similarly stopped early (in Dec 2006) by the monitoring committees because the preventative effect was so striking. The findings were published in the esteemed medical journal, the Lancet in Feb 2007 [33a, 135a]. They involved 2784 and 4996 uncircumcised men aged 18-24 and 15-49 years, respectively [33a, 135a]. In each study the as-treated protective effect of circumcision was 60%. Only 1.5% [33a] and 3.6% [135a] experienced an adverse event related to circumcision, and these resolved quickly. There was, moreover, no behavioural risk compensation after circumcision [33a, 135a]. 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 [33a]. Moreover, 99.5% of the men were 'very satisfied' with their circumcision and 0.5% were 'somewhat satisfied'. None were 'dissatisfied'.
In the Introduction of this paper the authors point to the fact that currently available prevention measures (barriers, etc) "have often been unsuccessful in restricting the spread of HIV", as well as the to the futility of relying on a HIV vaccine, stating "there is little promise that an effective vaccine will be available within the next 15 years" [33a]. They also note that "although the availability of antiretroviral therapy for individuals infected with HIV is increasing worldwide, many more new infections are occurring for every additional person started on such treatment." Antiviral treatment is horrendously expensive, whereas prevention is much more desirable, and circumcision is cheaper.
Extensive data analyses dismissed a plethora of other, potentially confounding, factors as contributing to the much higher HIV incidence in he uncircumcised group in each study.
The new data also showed circumcision conferred a cumulative efficacy of 48% in reduction of genital ulcer disease in the circumcised group [135a], as seen in observational studies.
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 [135a]. For South Africa (3.8 per 100 person-years HIV incidence) far fewer circumcisions would be needed to prevent one HIV infection.
It was also stated that "neonatal circumcision or circumcision of younger boys will provide a simpler, safer, and cheaper option ..." [135a].
It has been estimated that even if circumcision were to offer only 50% protection, 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% . Thus the effect could be quite striking.
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 [385a]. 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) [171a].
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" [135a]. 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].
HIV was first reported in India in 1986 and is now widespread. With 5.1 million infected (1% of the adult population . Hindu men, who are not circumcised, 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) . 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. India, 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 .
Like Africa there are regional and ethnic differences in circumcision practice. Just as in Africa , HIV prevalence follows the foreskin. Rate is low where circumcision is high: e.g., Philippines (0.06% of adults), Bangladesh (0.03%) and Indonesia (0.05%). In contrast the rate is 10-50 times higher in countries where most males are uncircumcised: e.g., Thailand (2.2%), India (1.8%) and Cambodia (2.4%) . Large increases in infections are expected in such Asian countries over time . Moreover the outbreak of HIV in central China in 2000 arising from use of contaminated needles to buy and on-sell blood from people there allowed entry of HIV which could then spread via heterosexual transmission. 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.
Studies in the USA have not been as conclusive. Some studies have shown a higher incidence in uncircumcised men . In an early study in New York City , however, no significant correlation was found, but the patients were mainly intravenous drug users and homosexuals, so that any existing effect may have been obscured. Male-male sex accounts for the largest number of HIV infections in the USA . In two US studies lack of circumcision was associated with a 2-fold increased risk of HIV infection. One, in Seattle , found that homosexual men were 2.2-times as likely to be HIV positive if uncircumcised. No association was found in a Sydney study, but the authors noted that it was too small and had too many confounding factors to be capable of yielding a valid conclusion. 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 was 2.1% vs 0.6% for uncircumcised vs circumcised. Another US study found a risk ratio of 2.9 . (See also review ).
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 . 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 . In 1995 an article in Nature Medicine discussed findings concerning marked differences in the properties of different HIV-1 subtypes in different geographical locations . 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.
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.