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HIV Infection Is Via The Foreskin
by Professor Brian J. Morris, University of Sydney (Australia)

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 [142]! Half of HIV cases are men, most of whom have been infected through their penises [190], the foreskin having been implicated as early as 1986 [108]. Over 80% of these infections have arisen from vaginal intercourse [171].

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 [111]. A wealth of evidence indicates that male circumcision protects against HIV infection, as acknowledged in the major journals Science [67, 68, 170] and Nature [380], and its promotion in HIV prevention is advocated [95].

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 [345]. 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 [57]. It was also suggested that the increased surface area, traumatic physical disruption during intercourse and inflammation of the glans penis (balanitis) could aid in recruitment of target cells for HIV-1. 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 [345]. In contrast, the inner lining of the foreskin is a mucosal epithelium and lacks a protective keratin layer [28] (see picture below taken, with permission, from [28]). 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 [8]. 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) [267]. (This contrasts with the neonate, where the foreskin is deficient in such cells [376], the proportion being instead 4.9, 6.2 and 0.3%, respectively [267]). The respective percentages for immune-system cells in the cervical mucosa are: 6.2, 1.5 and 1.4% [267]. 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 [267]. 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 [374]. 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 [374]. This hypothesis remains to be tested. Mucosal alloimmunization has also been suggested as a protective factor against HIV [271].

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 [8]. 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 [28] (similar images can be seen in [267]). 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 [267]. 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 [267]. The HIV receptor CCR5 was, moreover especially prevalent on foreskin tissue cells [267]. 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 [232]. The monkey work also showed infected Langerhans cells. Antigen presenting cells in the mucosa of the inner foreskin [164] are a primary target for HIV infection in men [345].

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 [341]. 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% [146]. Condom use remains low, however [105]. 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!

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 [94]. (And circumcision rate is much lower in Europe.)

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 [55]. (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 [27]. In Nairobi the rate is 1 in 1000 in the absence [153] and 1 in 6 in the presence [57] of genital ulcers.

In Asia, a study of young military conscripts in Northern Thailand, a country with low circumcision rates, and where the men were having regular contact with female sex workers the rate was 1 in 18 to 1 in 32 [224].

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 [248]. (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% [225]. For male-to-female it was 23%. In Africa, however, female-to-male was 73% [157] 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 [281]. After consideration of all of the factors, lack of circumcision was highlighted as a major driving force behind the AIDS epidemic [248].

Epidemiological research

Africa:


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 [361]. 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 [308]. Being in a stable sexual relationship with an HIV-infected person is a major risk factor for HIV infection [217]. 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 [112]. 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 [57]. 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 [55], 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 [345]. The risk of HIV infection is thus further reduced by circumcision, which therefore reduces the synergy that normally exists between HIV and other STIs [345]. 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 [134]. 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) [330]. 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 [43]. 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]. Truck drivers, who generally exhibit more frequent prostitute contact, have shown a higher rate of HIV if uncircumcised [284]. 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 [270]. 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 [84]. 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 [208]. 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 [379], 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 [379]. 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 [176]. 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 [245]. Amongst Muslims, 26% were not circumcised. In the meta-analysis by Weiss et al. [379], only one study actually verified the circumcision status by physical examination [362]. Agreement between self-reported and actual circumcision status was only about 81% in a study in a small geographic area of Kenya [49]. 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% [89].

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 [294]. 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 [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 [143]. 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 [245]. Health was cited as the reason. This work in Tanzania [245], as well as all other studies such as in Kenya [29], Botswana [182] and South Africa [199, 283], show the majority of population groups would be willing to accept circumcision to reduce HIV. After 30 days 99% of men in a Kenyan study reported being very satisfied with the procedure, as were their partners, and 96% had resumed general activities within the first week [194]. Similar findings have been obtained in Zimbabwe [145]. 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 [183], more recent work suggests a benefit at any age [6]. 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 [194]. 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 [281]. 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 [135]. Moreover, the protection was seen only when circumcision had been performed prior to puberty [135]. A commentary to this article highlighted the need to explore circumcision in reducing the spread of AIDS [69].

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 [6]. 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' [113].

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 [30]. (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 [144].) 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.

Overall, rough estimates are that circumcision has prevented more than 10 million HIV infections so far in Africa and Asia [111]. Worldwide this figure will obviously be greater.

An extensive Cochrane review [329] 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 [31].

Three randomized controlled trials were begun in recent years. The results for one of these were reported in 2005 [22]. 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). 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 [67, 68].

Two other randomized controlled trials are in progress in Kenya and Uganda, with projected completion in 2007 and 2008. The circumcisions in the Kenyan trial were performed between Feb 2002 and Mar 2004 [194]. Interestingly, the cross-overs in these has been lower (namely 5%, as opposed to 10% in the South African trial, in the case of those randomized to the control group who ended up getting circumcised), so the results of these other trials could make a bigger impact than those from the South African trial.

Even if circumcision were to offer only 50% protection, it has been estimated that 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% [67]. Thus the effect could be quite striking.

India:

HIV was first reported in India in 1986 and is now widespread. With 5.1 million infected (1% of the adult population [128]. 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) [291]. 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 [274].

Asia:

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%) [143]. Large increases in infections are expected in such Asian countries over time [143]. 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.

USA:

Studies in the USA have not been as conclusive. Some studies have shown a higher incidence in uncircumcised men [384]. 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 [193]. The other, involving 3257 homosexual men in 6 US cities studied from 1995-1997, identified various risk factors, lack of circumcision being found to double the risk of acquiring HIV [50]. 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 [140]. Interestingly, per-contact risk of infection from receptive oral sex is comparable to that of insertive anal sex [50, 62, 368]. 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 [353]. Rate was 2.1% vs 0.6% for uncircumcised vs circumcised. Another US study found a risk ratio of 2.9 [179]. (See also review [234]).

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 [383]. 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 [195]. In 1995 an article in Nature Medicine discussed findings concerning marked differences in the properties of different HIV-1 subtypes in different geographical locations [257]. 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.

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 [40]. Amongst a general US population sample, 62% of adults in 1996 reported using condoms at previous intercourse outside of an ongoing relationship [15]. In a review in the Lancet condom use was similarly reported as 55% [93]. Studies in Mexico found condom use to be 51% in young men and 23% in young women. Consistent condom use was, moreover, only 30% [54]. In public school students, average age of sexual debut was 14 years. Of the 13,293 subjects in this study, 46% had an intermediate and 37% a high HIV/AIDS knowledge [351]. 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) [351].

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 [281]. 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 [345]. 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 [332]! 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. Homosexual men who engage in mutual masturbation [328], 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. 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 [135, 183], but not in a more recent one [6], the effectiveness of circumcision in AIDS risk reduction was greater when performed prior to puberty.

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.
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