Circumcision and HIV
||This article is written like a personal reflection or opinion essay rather than an encyclopedic description of the subject. (January 2013)|
Over forty epidemiological studies have been conducted to investigate the relationship between male circumcision and HIV infection. Reviews of these studies have reached differing conclusions about whether circumcision could be used as a method for the prevention of HIV/AIDS.
Experimental evidence was needed to establish a causal relationship between lack of circumcision and HIV, so three randomized controlled trials were commissioned as a means to reduce the effect of any confounding factors. Trials took place in South Africa, Kenya and Uganda. All three trials were stopped early by their monitoring boards on ethical grounds, because those in the circumcised group had a lower rate of HIV contraction than the control group. The results showed that circumcision reduced vaginal-to-penile transmission of HIV by 60%, 53%, and 51%, respectively. A meta-analysis of the African randomised controlled trials found that the risk in circumcised males was 0.44 times that in uncircumcised males, and reported that 72 circumcisions would need to be performed to prevent one HIV infection. The authors also stated that using circumcision as a means to reduce HIV infection would, on a national level, require consistently safe sexual practices to maintain the protective benefit.
As a result of these findings, the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) stated that male circumcision is an efficacious intervention for HIV prevention but should be carried out by well trained medical professionals and under conditions of informed consent (parents consent for their infant boys). Both the WHO and CDC indicate that circumcision may not reduce HIV transmission from men to women, and that data is lacking for the transmission rate of men who engage in anal sex with a female partner. The joint WHO/UNAIDS recommendation also notes that circumcision only provides partial protection from HIV and should never replace known methods of HIV prevention. A newer study, published in PLOS in January, 2010, points out that gross changes in the penis's microbiome occurs following circumcision, and this may play a role in protection from HIV and other sexually transmitted diseases. A 2001 report of a study, which "was published as an abstract and presented at a conference", in MedPage Today, states that the "benefit of male circumcision for HIV prevention persists, even long after the procedure". However, they also insist that "these data and conclusions should be considered to be preliminary until published in a peer-reviewed journal."
Some earlier reports had expressed the position that circumcision has little to no effect on HIV transmission among heterosexual couples. Furthermore, some have challenged the validity of the African randomized controlled trials, prompting a number of researchers to question the effectiveness of circumcision as an HIV prevention strategy.
Earliest appearance in the literature
According to Alcena, it was he who first hypothesised that low rates of circumcision in Africa were partly responsible for the continent's high rate of HIV infection. He did this via a letter to the New York State Journal of Medicine in August 1986. He also alleges that the late Aaron J. Fink stole his idea when Fink published a letter to The New England Journal of Medicine entitled A possible explanation for heterosexual male infection with AIDS, in October 1986.
In 1989 Cameron found uncircumcised men 8.2 times more likely to have HIV. Since then over 40 epidemiological studies have been conducted to investigate the relationship between circumcision and HIV infection.
In 1994, de Vincenzi and Mertens surveyed previous studies that had links between circumcision status and HIV; they surveyed 23 in total. They criticised the Cameron study saying that it may have suffered from selection bias.
In 1995 Ntozi noted: "There are now two schools of thought about the link between lack of circumcision and HIV infection in Africa. One school is that of Bongaarts et al. (1989), Moses et al. (n.d.) and Caldwell and Caldwell (1994) who use geographical distribution evidence to argue that the association between lack of circumcision and a high level of HIV infection in Africa is so convincing that the likelihood of a link should be recognized and taken into account where possible in the battle against AIDS. Moses et al. (n.d.) have gone further to recommend circumcision interventions for Africa. In contrast, De Vincenzi and Mertens (1994) argue that the evidence for an association, at least from small-scale surveys, is doubtful and hence not conclusive enough to qualify circumcision as an intervention.
Van Howe conducted a meta-analysis in 1999 and found circumcised men at a greater risk for HIV infection. He further speculated that circumcision may be responsible for the increased number of partners, and therefore, the increased risk. Van Howe's work was reviewed by O'Farrell and Egger (2000) who said Van Howe used an inappropriate method for combining studies, stating that re-analysis of the same data revealed that the presence of the foreskin was associated with increased risk of HIV infection (fixed effects OR 1.43, 95%CI 1.32 to 1.54; random effects OR 1.67, 1.25 to 2.24). Moses et al. (1999) also criticised Van Howe's paper, stating that his results were a case of "Simpson's paradox, which is a type of confounding that can occur in epidemiological analyses when data from different strata with widely divergent exposure levels are combined, resulting in a combined measure of association that is not consistent with the results for each of the individual strata." They concluded that, contrary to Van Howe's assertion, the evidence that lack of circumcision increases the risk of HIV "appears compelling".
Weiss, Quigley and Hayes carried out a meta-analysis on circumcision and HIV in 2000 and found as follows: "Male circumcision is associated with a significantly reduced risk of HIV infection among men in sub-Saharan Africa, particularly those at high risk of HIV. These results suggest that consideration should be given to the acceptability and feasibility of providing safe services for male circumcision as an additional HIV prevention strategy in areas of Africa where men are not traditionally circumcised."
The USAID document summarised research as of September 2002. It states:
- A systematic review and meta-analysis of 28 published studies by the London School of Hygiene and Tropical Medicine, published in the journal AIDS in 2000, found that circumcised men are less than half as likely to be infected by HIV as uncircumcised men. A subanalysis of 10 African studies found a 71 percent reduction among higher-risk men. A September 2002 update considered the results of these 28 studies plus an additional 10 studies and, after controlling for various potentially confounding religious, cultural, behavioral, and other factors, had similarly robust findings. Recent laboratory studies in Chicago found HIV uptake in the inner foreskin tissue to be up to nine times more efficient than in a control sample of cervical tissue.
Siegried et al. (2003) surveyed 35 observational studies relating to HIV and circumcision: 16 conducted in the general population and 19 in high-risk populations. They state:
- We found insufficient evidence to support an interventional effect of male circumcision on HIV acquisition in heterosexual men. The results from existing observational studies show a strong epidemiological association between male circumcision and prevention of HIV, especially among high-risk groups. However, observational studies are inherently limited by confounding which is unlikely to be fully adjusted for. In the light of forthcoming results from RCTs, the value of IPD analysis of the included studies is doubtful. The results of these trials will need to be carefully considered before circumcision is implemented as a public health intervention for prevention of sexually transmitted HIV.
In 2005, Siegfried et al. published a review including 37 observational studies. Most studies indicated an association between lack of circumcision and increased risk of HIV, but the quality of evidence was judged insufficient to warrant implementation of circumcision as a public health measure. The authors stated that the results of the three randomised controlled trials then underway would therefore provide essential evidence about the effects of circumcision as an HIV intervention.
Kiwanuka et al.'s (1996) study on the relationship between religion and HIV in rural Uganda was presented at the 1996 10th International AIDS Conference He said that: "Lower rates of HIV infection among Pentecostals appear to be associated with less alcohol consumption, sexual abstinence and fewer sexual partners, whereas the low HIV prevalence in Muslims appears to be associated with low reported alcohol consumption and male circumcision." Muslims, despite having the lowest rate of sexual abstinence and the highest rate of having two or more sexual partners, had the lowest level of HIV infection compared with the other religious groups in the study (Catholics, Protestants, and Pentecostals). The factor in common between the Muslims (14.5% seropositive) and the Pentecostals (14.6% seropositive) was the lower alcohol consumption rate in these two groups than amongst Protestants (19.2%) and Catholics (19.9%).
Kelly et al. (1999) investigated the age of male circumcision and risk of prevalent HIV infection in rural Uganda and found that circumcision before the age of 12 resulted in a reduction to 0.39 of the odds of being infected. The degree of protection varied with the age at which circumcision was performed. Those circumcised at between 13 and 20 years had an odds ratio of 0.46, and those circumcised after the age of 20 at an odds ratio of 0.78. They concluded: "Prepubertal circumcision is associated with reduced HIV risk, whereas circumcision after age 20 years is not significantly protective against HIV-1 infection."
Buvé and colleagues (1999) investigated the reasons why the HIV prevalence rate among pregnant women in many large towns in Central, East and southern Africa was higher (>30%) than in the cities and towns of most of West Africa (<10%). Between June 1997 and March 1998 surveys were carried out and blood samples were taken in 4 sites. Kisumu (Kenya) and Ndola (Zambia), in Central/East Africa, were selected as the towns with high HIV prevalence, while the low-prevalence towns in West Africa were Cotonou (Benin) and Yaoundé (Cameroon). "In conclusion, differences in the rate of HIV spread between the East African and West African cities studied cannot be explained away by differences in sexual behaviour alone. In fact, behavioural differences seem to be outweighed by differences in HIV transmission probability."
Bailey et al. (1999) interviewed 188 circumcised and 177 uncircumcised consenting Ugandan men in one of four native languages during April and May, 1997. Non-Muslim circumcised men were found to have a higher risk profile than uncircumcised men. Muslims generally had a lower risk profile than other circumcised men except they were less likely to have ever used a condom or to have used a condom during the last sex encounter. Bailey et al. concluded that "these results suggest that differences between circumcised and uncircumcised men in their sex practices and hygienic behaviors do not account for the higher risk of HIV infection found among uncircumcised men. Further consideration should be given to male circumcision as a prevention strategy in areas of high prevalence of HIV and other sexually transmitted diseases. Studies of the feasibility and acceptability of male circumcision in traditionally non-circumcising societies are warranted."
Bonner (2001) reserved caution over using circumcision to prevent HIV: "Until we know why and how circumcision is protective, exactly what the relationship is between circumcision status and other STIs, and whether the effect seen in high-risk populations is generalisable to other groups, the wisest course is to recommend risk reduction strategies of proven efficacy, such as condom use."
At the 14th International AIDS conference in 2002, Changedia and Gilada reported that "Though circumcision offers protection in acquisition of HIV infection, our findings reveal that it does not reduce transmission of HIV in conjugal settings." Hunter et al. (1994), however, report that "Women whose husband or usual sex partner was uncircumcised had a threefold increase in risk of HIV, and this risk was present in almost all strata of potential confounding factors." Fonck et al. (2000) reported that "Partners of circumcised men had less-prevalent HIV infection."
The prevalence of circumcision varies across Africa. Studies have been conducted to assess the acceptability of promoting circumcision in place where they traditionally do not circumcise. In 2007, country consultations and planning to scale up male circumcision programmes took place in Botswana, Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, South Africa, Swaziland, Uganda, Tanzania, Zambia and Zimbabwe. Kebaabetswe et al. carried out interviews in nine geographically representative locations to determine the acceptability of male circumcision as well as the preferred age and setting for male circumcision in Botswana. Their conclusion was "Male circumcision appears to be highly acceptable in Botswana. The option for safe circumcision should be made available to parents in Botswana for their male children. Circumcision might also be an acceptable option for adults and adolescents, if its efficacy as an HIV prevention strategy among sexually active people is supported by clinical trials." Boyle criticised Kebaabetswe et al.'s proposal to introduce infant circumcision to Botswana saying that: "The proposal by Kebaabetswe and colleagues for the introduction of circumcision into Botswana is seriously flawed, and is irresponsible in failing to place the emphasis on safe sex practices. As described here, there are many medical, sexual, psychological, social, human rights, ethical, and legal aspects that must be considered. Reliance on circumcision to prevent HIV transmission is wishful fantasy, and can only result in a calamitous worsening of the HIV-AIDS epidemic."
Bailey et al. looked at the possible adverse effects of introducing male circumcision on a public health scale and the post operative satisfaction levels of 380 circumcisions on 18-24 year old consenting men. As to satisfaction; "At 30 days post-surgery, 99.3% of men reported being very satisfied and 0.7% somewhat satisfied with circumcision. None were dissatisfied." And with regard to adverse effects; "All were mild or moderate and resolved within hours or several days of detection." Their findings were presented at the 15th International AIDS Conference held in Bangkok in 2004.
At the 15th International AIDS Conference in 2004, Connolly et al. presented their report detailing the effects of circumcision in South Africa. They reported that, among racial groups, "circumcised Blacks showed similar rates of HIV as uncircumcised Blacks, (OR: 0.8, p = 0.4) however other racial groups showed a strong protective effect, (OR: 0.3, p = 0.01)." They added "When the data are further stratified by age of circumcision, there is a slight protective effect between early circumcision and HIV among Blacks, OR: 0.7, p = 0.4." They conclude that "in general, circumcision offers slight protection." At the same conference, Thomas et al. (2004) reported that "male circumcision is not associated with HIV or STI prevention in a U.S. Navy population."
Reynolds et al. (2004) found that male circumcision was strongly protective against HIV-1 infection with circumcised men being almost seven times less at risk of HIV infection than uncircumcised men. They further state that: "The specificity of this relation suggests a biological rather than behavioural explanation for the protective effect of male circumcision against HIV-1."
Baeten et al. (2005) found that uncircumcised men were at a greater than twofold increased risk of acquiring HIV per sex act when compared with circumcised men. They conclude as follows:
- "Moreover, our results strengthen the substantial body of evidence suggesting that variation in the prevalence of male circumcision may be a principal contributor to the spread of HIV-1 in Africa."
At the 2006 Conference on Retroviruses and Opportunistic Infections Quinn et al. presented their study, conducted in Rakai, Uganda, which observed a 30% reduction in male-to-female HIV transmission, suggesting some protective effect for the female partner.
Newell and Bärnighausen (2007) also stated there was "firm evidence that the risk of acquiring HIV is halved by male circumcision."
Mishra et al. (2006) used data collected from the Demographic and Health Surveys and found that HIV prevalence was "considerably higher in urban areas and for women, especially at younger ages. Adults in wealthier households, in polygamous unions, being widowed/divorced/separated, having multiple sex partners, and having reported STIs had higher HIV rates than other adults. No consistent relationship between male circumcision and HIV risk was observed in most countries."
Way et al. (2006) also used data from Demographic and Health Surveys in Burkina Faso, Cameroon, Ghana, Kenya, Lesotho, and Malawi and from AIDS Indicator Surveys in Tanzania and Uganda to conduct his study. They found that "With age, education, wealth status, and a number of sexual and other behavioral risk factors controlled statistically, in only one of the eight countries were circumcised men at a significant advantage. In the other seven countries, the association between circumcision and HIV status was not statistically significant for the male population as a whole."
Garenne (2006) has doubts about circumcision's value in reducing HIV, and Talbott (2007), in a controversial paper stated that cross country regression data pointed to prostitution as the key factor in the AIDS epidemic rather than circumcision. World Health Organization AIDS Prevention Team official Tim Farley disagreed with the findings of the paper, while Chris Surridge, PLoS One's managing editor, defended its publication. In 1999 the American Medical Association had stated, "behavioral factors are far more important in preventing these infections than the presence or absence of a foreskin."
If proper hygienic procedures are not adhered to, the circumcision operation itself can spread HIV. Brewer et al. (2007) report, "[circumcised] male and female virgins were substantially more likely to be HIV infected than uncircumcised virgins. Among adolescents, regardless of sexual experience, circumcision was just as strongly associated with prevalent HIV infection. However, uncircumcised adults were more likely to be HIV positive than circumcised adults." They concluded: "HIV transmission may occur through circumcision-related blood exposures in eastern and southern Africa."
Van Howe et al. criticise the drive to promote circumcision in Africa, asking "Why are circumcision proponents expending so much time and energy promoting mass circumcision to North Americans when their supposed aim is to prevent HIV in Africa? The circumcision rate is declining in the US, especially on the west coast; the two North American national paediatric organisations have elected not to endorse the practice, and the practice’s legality has been questioned in both the medical and legal literature. ‘Playing the HIV card’ misdirects the fear understandably generated in North Americans by the HIV/AIDS pandemic into a concrete action: the perpetuation of the outdated practice of neonatal circumcision."
Connolly et al. (2008) found that "circumcision had no protective effect in the prevention of HIV transmission. This is a concern, and has implications for the possible adoption of the mass male circumcision strategy both as a public health policy and an HIV prevention strategy."
Sidler et al. (2008) say that using neonatal non-therapeutic circumcision to combat the HIV crisis in Africa is neither medically nor ethically justifiable. Furthermore, promoting circumcision might worsen the problem by creating a false sense of security and therefore undermining safe sex practices. Education, female economic independence, safe sex practices and consistent condom use are proven effective measures against HIV transmission.
Boiley et al. (2008) found that the protection of circumcision against STI contributes little to the overall effect of circumcision on HIV.
Men who have sex with men (MSM)
Millett et al. (2007) found no association in three major US cities between circumcision and HIV infection among Latino and black men who have sex with men (MSM) . They conclude as follows: "In these cross-sectional data, there was no evidence that being circumcised was protective against HIV infection among black MSM or Latino MSM."
Lagarde (2003) stated that "More than 70% of the non-circumcised men (NCM) stated that they would want to be circumcised if MC were proved to protect against sexually transmitted diseases (STD)." Lagarde cautioned that "Our results strongly suggest that interventions including MC should carefully address the false sense of security that it may provide."
A 2008 meta-analysis of 15 observational studies, including 53,567 gay and bisexual men from the United States, Britain, Canada, Australia, India, Taiwan, Peru and the Netherlands (52% circumcised), found that the rate of HIV infection was non-significantly lower among men who were circumcised compared with those who were uncircumcised. For men who engaged primarily in insertive anal sex, a protective effect was observed, but it too was not statistically significant. Observational studies included in the meta-analysis that were conducted prior to the introduction of highly active antiretroviral therapy in 1996 demonstrated a statistically significant protective effect for circumcised MSM against HIV infection. In response to the meta-analysis by Millett et al., Vermund and Qian note that "circumcision would likely be insufficiently efficient to be universally effective in reducing HIV risk, and will have to be combined with other prevention modalities to have a substantial and sustained prevention effect."
Randomized controlled trials
Africa has a higher rate of adult HIV infection than anywhere else in the world. Three randomized controlled trials were commissioned in Africa to investigate whether circumcision could lower the rate of HIV contraction.
The first study to be published was named ANRS-1265. It was funded by the French government’s research agency, Agence Nationale de Recherches sur la SIDA (ANRS) and carried out in Orange Farm, Gauteng in South Africa. The purpose was to test the effect of adult male circumcision on HIV acquisition. The principal investigator was Dr. Bertran Auvert of Versailles University. The study enrolled 3,274 men aged 18–24. The participants were split into two equal groups. One group was circumcised straight away; the other group, serving as a control, was to be circumcised 21 months later. 146 of the original participants were found to have HIV at the start of the trial - to avoid stigmatization, they were not excluded. It was planned that all the men would visit the research clinic four times during this 21-month period, and that they would be tested for HIV each time. They were instructed not to have sex for six weeks after the operation, and asked at each clinic visit to provide detailed information about their sexual activity. The circumcision procedure used was the forceps-guided method, carried out by three local general practitioners in their surgical offices. After 17 months, 20 men had contracted HIV in the circumcised group and 49 in the control group. The trial was halted on ethical grounds. The results of the trial were published in November 2005.
The authors said, “Male circumcision provides a degree of protection against acquiring HIV infection, equivalent to what a vaccine of high efficacy would have achieved. Male circumcision may provide an important way of reducing the spread of HIV infection in sub-Saharan Africa.”
Williams et al.(2006) looked at the potential impact of circumcision on HIV in Africa, based upon the South African RCT, saying that that male circumcision (MC) could substantially reduce the burden of HIV in Africa, particularly in southern Africa where the existing prevalence of male circumcision is low and the existing prevalence of HIV is high. More specifically it predicted that if full coverage with MC was achieved in sub-Saharan Africa over the next ten years, MC could prevent approximately 2.0 (1.1 to 3.8) million new HIV infections over that ten-year period and a further 3.7 million in the ten years after that.
The above conclusions drawn from the Orange Farm study have been criticised by Michel Garenne (2006) of the Institut Pasteur. In his critique, published in the PLOS Medicine, he concludes that: "'male circumcision should be regarded as an important public health intervention for preventing the spread of HIV' appears overstated. Even though large-scale male circumcision could avert a number of HIV infections, theoretical calculations and empirical evidence show that it is unlikely to have a major public health impact, apart from the fact that achieving universal male circumcision is likely to be more difficult than universal vaccination coverage or universal contraceptive use."
Mills and Siegfried (2006) point out that trials that are stopped early tend to overestimate treatment effects. They argued that a meta-analysis should be done before further feasibility studies are done.
The NIAID, part of the NIH, supported two further trials, conducted in Kenya and in Uganda. The primary objectives of these studies were to determine whether adult male circumcision can be administered safely, and whether it would reduce the risk of acquiring HIV infection through heterosexual contact. After an initial HIV screening and a medical exam, eligible men were randomly assigned either to receive circumcision immediately or to wait two years before circumcision. All participants were closely followed for two years to collect information about their health, sexual activity, and their and their partners’ attitudes about circumcision; to counsel participants in HIV prevention and safe sex practices; and to check the HIV status of the volunteer. Participants in the Kenyan study were scheduled for six visits over the two-year follow-up, compared with four visits for the Ugandan trial participants. In addition to the study visits, men enrolled in the Kenyan trial were encouraged to receive all of their outpatient health care at the study clinics, which enabled researchers to collect information on the safety of the procedure and the number of other sexually transmitted diseases the men had during follow-up.
The Kenyan trial, also known as the UNIM trial (Universities of Nairobi, Illinois and Manitoba trial), began in February 2002, in Kisumu, Kenya. It was a collaborative effort between US, Canadian and Kenyan researchers, led by Dr. Robert Bailey, of the University of Illinois. Also involved were Stephen Moses, University of Manitoba, Jeckoniah Ndinya-Achola, University of Nairobi, and Kwango Agot, UNIM. The trial was funded by the NIAID and the Canadian Institutes of Health Research. This trial enrolled 2,784 men between 18 and 24 years old. The participants were assessed by HIV testing, medical examinations, and behavioural interviews during follow-ups at 1, 3, 6, 12, 18, and 24 months. The circumcision procedure used in the Ugandan trial is known as the sleeve method and takes about 30 minutes. The Ugandan trial used cauterization of the blood vessels to control bleeding and stitches to close the wound. 22 men in the intervention group and 47 in the control group had tested positive for HIV when the study was stopped on ethical grounds.
The Ugandan trial began August, 2003 in Rakai, Uganda, with 4,996 men aged between 15 and 49 years old. It was led by Ronald Gray and Maria Wawer of Johns Hopkins Bloomberg School of Public Health and David Serwadda and Nelson Sewankambo of Makerere University in Kampala, Uganda. The circumcision procedure used in the Kenyan trial was the foreskin clamp method. The Kenyan trial procedure took about 25 minutes and used stitches to control bleeding and improve wound closure. Trained and certified physicians performed the circumcisions in well-equipped operating rooms. Post-operative follow-up visits were scheduled at 24–48 hours, 5–9 days, and 4–6 weeks. HIV testing, physical examination, and interviews were repeated at 4–6 weeks, 6-, 12-, and 24-month follow-up visits. After 24 months, 964 of the original 2387 men of the circumcised men had been retained of whom 22 had contracted HIV. 980 of the 2430 uncircumcised men had been retained of whom 45 had contracted HIV.
- Male circumcision should now be recognized as an efficacious intervention for HIV prevention.
- Promoting male circumcision should be recognized as an additional, important strategy for the prevention of heterosexually acquired HIV infection in men.
Kim Dickson, coordinator of the working group that authored the report, commented:
- Male circumcision "would have greatest impact" in countries where the HIV infection rate among heterosexual males is greater than 15 percent and fewer than 20 percent of males are circumcised.
- WHO further recommends that the procedure must be done by a trained physician.
- Protection is incomplete and men must continue to use condoms and have fewer partners.
- Newly circumcised men should abstain from sex for at least six weeks.
The World Health Organization (WHO) said: “Although these results demonstrate that male circumcision reduces the risk of men becoming infected with HIV, the UN agencies emphasize that it does not provide complete protection against HIV infection. Circumcised men can still become infected with the virus and, if HIV-positive, can infect their sexual partners. Male circumcision should never replace other known effective prevention methods and should always be considered as part of a comprehensive prevention package, which includes correct and consistent use of male or female condoms, reduction in the number of sexual partners, delaying the onset of sexual relations, and HIV testing and counselling.”
Others have also expressed concern that some may mistakenly believe they will be fully protected against HIV through circumcision and see circumcision as a safe alternative to other forms of protection, such as condoms.
Dowsett et al. urged caution over using circumcision as a HIV prevention strategy saying that there were still questions that needed to be answered: "We need to investigate the effects of those other social and contextual factors that will be in play in real world settings – because the effectiveness of male circumcision will not be generated by the efficacy of the surgery alone." He contrasts the preventative effect of circumcision taken from the RCT's (55%) with the preventative effect of condoms (80-90%). He criticises the fact that the trials were not double-blinded - the participants knew their circumcision status and so this could have affected how the men responded behaviourally, psychologically and sexually. He criticised the randomisation measures used in the trial: sexual practices (number of partners, condom use) and sexual health measures (presence of STIs), saying that "Effective measures were not used, and differences related to sexual subjectivity, such as sexual network participation, pleasure preferences, body image, sexual history effects (e.g. abuse), partner preferences (younger, older, peers, groups) and so on were never assessed or analysed." He also asks how the extensive counselling and education might have influenced the participants' sexual activity. He adds that "all participants were subject to regular monitoring (e.g. behaviour surveys, clinical check-ups), which clearly might have enhanced compliance with suggested safety regimes and lowered risk-taking during the follow-up period. Such compliance cannot be guaranteed in real world settings." He also said the trials were subject to the Hawthorne effect.
An interim analysis from the Rakai Health Sciences Program in Uganda suggested that newly circumcised HIV positive men may be more likely to spread HIV to their female partners if they have sexual intercourse before the wound is fully healed. “Because the total number of men who resumed sex before certified wound healing is so small, the finding of increased transmission after surgery may have occurred by chance alone. However, we need to err on the side of caution to protect women in the context of any future male circumcision programme,” said Maria Wawer, the study's principal investigator.
Kalichman et al. (2007) argue that any protective effects circumcision could offer would be partially offset by increased HIV risk behavior, or “risk compensation" including reduction in condom use or increased numbers of sex partners. They note that circumcised men in the South African trial had 18% more sexual contacts than uncircumcised men at follow-up. They also said that because participants were given ongoing risk-reduction counseling and free condoms, it "reduced the utility of these trials for estimating the potential behavioral impact of male circumcision when implemented in a natural setting." They also criticised current models for failing to account for increased HIV risk behaviour. Increased HIV risk behaviour would mean more women would be infected which would consequently increase the risk of men. It would also mean that non-HIV STI's, which have been associated with increased HIV risk, would increase. Green et al. (2008) also disagree with using circumcision to prevent HIV, citing similar reasons.
Published meta-analyses, using data from the RCTs, have estimated the summary relative risk at 0.42 (95% CI 0.31-0.57), 0.44 (0.33-0.60) and 0.43 (0.32-0.59). (rate of HIV infection in circumcised divided by rate in uncircumcised men). Weiss et al. report that meta-analysis of "as-treated" figures from RCTs reveals a stronger protective effect (0.35; 95% CI 0.24-0.54) than if "intention-to-treat" figures are used. Byakika-Tusiime also estimated a summary relative risk of 0.39 (0.27-0.56) for observational studies, and 0.42 (0.33-0.53) overall (including both observational and RCT data). Weiss et al. report that the estimated relative risk using RCT data was "identical" to that found in observational studies (0.42). Byakika-Tusiime states that available evidence satisfies six of Hill's criteria, and concludes that the results of her analysis "provide unequivocal evidence that circumcision plays a causal role in reducing the risk of HIV infection among men." Mills et al. conclude that circumcision is an "effective strategy for reducing new male HIV infections", but caution that consistently safe sexual practices will be required to maintain the protective effect at the population level. Weiss et al. conclude that the evidence from the trials is conclusive, but that challenges to implementation remain, and will need to be faced.
Estimated impact of circumcision programs
Modelling of the population-level impact of circumcision has shown mixed results. Podder et al. found that although circumcision would not eliminate HIV, it would "significantly reduce" the HIV burden in a population, stating that reduction was more effective when circumcision was combined with anti-retroviral drugs than with condoms. Disease elimination was considered feasible when all interventions were combined. Hallet et al. predicted "dramatic" reductions in HIV if circumcision were scaled up alongside behaviour change programmes.
Studies of the cost-effectiveness of circumcision programmes have been similarly mixed. Kahn et al. studied sub-Saharan African settings with a high or moderate HIV prevalence, reporting that adult circumcision is "likely to be a cost-effective HIV prevention strategy" even when deployed among only a small fraction of the population. The authors concluded that circumcision "generates large net savings after adjustment for averted HIV medical costs". White et al. concluded that circumcision "is a cost-saving intervention in a wide range of scenarios of HIV and initial circumcision prevalence but the United Nations Joint Programme on HIV/AIDS/WHO recommended target age group should be widened to include older HIV-uninfected men and counselling should be targeted at both newly and already circumcised men to minimize risk compensation". The UNAIDS/WHO/SACEMA Expert Group on Modelling the Impact and Cost of Male Circumcision for HIV Prevention found "large benefits" of circumcision in settings with high HIV prevalence and low circumcision prevalence. The Group estimated "one HIV infection being averted for every five to 15 male circumcisions performed, and costs to avert one HIV infection ranging from US$150 to US$900 using a 10-y time horizon". McAllister et al. estimated that consistent condom use is 95 times more cost effective than circumcision at reducing the rate of HIV in sub-Saharan Africa; the World Health Organisation states that circumcision is "highly cost-effective" in comparison to other HIV interventions when data from the South African trial are used, but less cost-effective when data from the Ugandan trial are used.
Langerhans cells and HIV transmission
Langerhans cells are part of the human immune system. Three studies identified high concentrations of Langerhans and other "HIV target" cells in the foreskin and Szabo and Short suggested that the Langerhans cells in the foreskin may provide an entry point for viral infection. McCoombe, Cameron, and Short also found that the keratin is thinnest on the foreskin and frenulum. Van Howe, Cold and Storms criticised Szabo and Short's suggestion as "pure speculation". Fleiss, Hodges and Van Howe had previously stated a belief that the prepuce has an immunological function. Waskett criticised their specific hypothesis on technical grounds. A study published in 2007 by de Witte and others said that langerin, produced by Langerhans cells, is a natural barrier to HIV-1 transmission by Langerhans cells.
Dowsett (2007) questioned why it was just males that were being encouraged to circumcise: "Langerhans cells occur in the clitoris, the labia and in other parts of both male and female genitals, and no one is talking of removing these in the name of HIV prevention."
- Szabo, R.; R.V. Short (June 2000). "How does male circumcision protect against HIV infection?". BMJ 320 (7249): 1592–1594. doi:10.1136/bmj.320.7249.1592. PMC 1127372. PMID 10845974.
- Van Howe, R.S. (January 1999). "Circumcision and HIV infection: review of the literature and meta-analysis". International Journal of STD's and AIDS 10: 8–16. doi:10.1258/0956462991913015. Retrieved 2008-09-23. "Thirty-five articles and a number of abstracts have been published in the medical literature looking at the relationship between male circumcision and HIV infection. Study designs have included geographical analysis, studies of high-risk patients, partner studies and random population surveys. Most of the studies have been conducted in Africa. A meta-analysis was performed on the 29 published articles where data were available. When the raw data are combined, a man with a circumcised penis is at greater risk of acquiring and transmitting HIV than a man with a non-circumcised penis (odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01-1.12). Based on the studies published to date, recommending routine circumcision as a prophylactic measure to prevent HIV infection in Africa, or elsewhere, is scientifically unfounded."
- O'Farrell, R.S.; M. Egger (March 2000). "Circumcision in men and the prevention of HIV infection: a 'meta-analysis' revisited". International Journal of STD's and AIDS 11 (3): 137–142. doi:10.1258/0956462001915480. PMID 10726934. "The results from this re-analysis thus support the contention that male circumcision may offer protection against HIV infection, particularly in high-risk groups where genital ulcers and other STDs 'drive' the HIV epidemic. A systematic review is required to clarify this issue. Such a review should be based on an extensive search for relevant studies, published and unpublished, and should include a careful assessment of the design and methodological quality of studies. Much emphasis should be given to the exploration of possible sources of heterogeneity. In view of the continued high prevalence and incidence of HIV in many countries in sub-Saharan Africa, the question of whether circumcision could contribute to prevent infections is of great importance, and a sound systematic review of the available evidence should be performed without delay."
- Siegfried, N; M Muller, J Volmink, J Deeks, M Egger, N Low, H Weiss, S Walker, P Williamson (July 2003). "Male circumcision for prevention of heterosexual acquisition of HIV in men". In Siegfried, Nandi. Cochrane Database of Systematic Reviews (3): CD003362. doi:10.1002/14651858.CD003362. PMID 12917962. CD003362. Retrieved 2007-12-27. "We found insufficient evidence to support an interventional effect of male circumcision on HIV acquisition in heterosexual men. The results from existing observational studies show a strong epidemiological association between male circumcision and prevention of HIV, especially among high-risk groups. However, observational studies are inherently limited by confounding which is unlikely to be fully adjusted for. In the light of forthcoming results from RCTs, the value of IPD analysis of the included studies is doubtful. The results of these trials will need to be carefully considered before circumcision is implemented as a public health intervention for prevention of sexually transmitted HIV."
- Weiss, HA; Quigley MA, Hayes RJ. (Oct 20 2000). "Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis.". Aids. 2000 14 (15): 2361–70. doi:10.1097/00002030-200010200-00018. PMID 11089625. "Male circumcision is associated with a significantly reduced risk of HIV infection among men in sub-Saharan Africa, particularly those at high risk of HIV. These results suggest that consideration should be given to the acceptability and feasibility of providing safe services for male circumcision as an additional HIV prevention strategy in areas of Africa where men are not traditionally circumcised."
- Auvert, B.; D. Taljaard, E. Lagarde, J. Sobngwi-Tambekou, R. Sitta and A. Puren (November 2005). "Randomized, Controlled Intervention Trial of Male Circumcision for Reduction of HIV Infection Risk: The ANRS 1265 Trial" (PDF). PLoS Medicine 2 (11): 1112–1122. doi:10.1371/journal.pmed.0020298. PMC 1262556. PMID 16231970. "There were 20 HIV infections (incidence rate = 0.85 per 100 person-years) in the intervention group and 49 (2.1 per 100 person-years) in the control group, corresponding to an RR of 0.40 (95% CI: 0.24%-0.68%; p < 0.001). This RR corresponds to a protection of 60% (95% CI: 32%-76%)."
- Bailey, Robert C.; Stephen Moses, Corette B Parker, Kawango Agot, Ian Maclean, John N Krieger, Carolyn F M Williams, Richard T Campbell, Jeckoniah O Ndinya-Achola (February 24, 2007). "Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial" (PDF (free registration required)). The Lancet (London: Elsevier) 369 (9562): 643–656. doi:10.1016/S0140-6736(07)60312-2. OCLC 1755507. PMID 17321310. Retrieved 2008-09-04. "The two year HIV incidence was 2.1% (95% CI 1.2-3.0) in the circumcision group and 4.2% (3.0-5.4) in the control group (p=0.0065); the relative risk of HIV infection in circumcised men was 0.47 (0.28-0.78), which corresponds to a reduction in the risk of acquiring an HIV infection of 53% (22-72)."
- Gray, R.H.; et al. (February 2007). "Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial". Lancet 369 (9562): 657–666. doi:10.1016/S0140-6736(07)60313-4. PMID 17321311. "In the modified intention-to-treat analysis, HIV incidence over 24 months was 0.66 cases per 100 person-years in the intervention group and 1.33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% CI 16-72; p=0.006). The as-treated efficacy was 55% (95% CI 22-75; p=0.002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30-77; p=0.003)."
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