Male Circumcision as a Measure to Control HIV Infection and Other Sexually Transmitted Diseases

Introduction

An estimated 5.4 million people world-wide were newly infected with HIV in 1999 [1]. The majority of infections occurred in sub-Saharan Africa, where heterosexual transmission accounts for around 90% of transmission. In the absence of a vaccine that protects against HIV infection, prevention strategies have focused on changing sexual behaviour, promoting condoms, and controlling sexually transmitted diseases (STDs) that are known to enhance HIV spread. There is growing evidence from observational studies that male circumcision is associated with a reduced risk of acquiring HIV infection and ulcerative STDs. However, the causal nature of this association remains unproven and there are much publicized concerns regarding the feasibility of male circumcision as a measure to control HIV and STDs. This review focuses on the recent epidemiological evidence, most of which is from sub-Saharan Africa, of the association between male circumcision and the acquisition of HIV infection. The promotion of male circumcision as a control measure is discussed in the light of these findings.

Biological evidence

Several biological mechanisms have been proposed to explain how the presence of the foreskin may increase susceptibility to HIV infection and ulcerative STDs [2]. First, the foreskin is susceptible to minor trauma during sexual intercourse, and viral entry may occur through the resulting abrasions. Second, minor inflammatory conditions may occur underneath the foreskin, especially where hygiene is poor, and the resultant mucosal discontinuity could act as a portal of entry for HIV and ulcerative STDs. Third, the foreskin has a high density of Langerhans cells which are target cells for HIV. Finally, the presence of a foreskin may increase susceptibility to HIV infection indirectly because of the increased risk of acquiring ulcerative STDs which in turn enhance HIV transmission. Recently, Szabo and Short [3] have reviewed the biological mechanisms for a protective effect of male circumcision against HIV infection. They conclude that the inner surface of the foreskin, which is rich in HIV receptors, and the frenulum, a common site for trauma and other STDs, must be regarded as the most probable sites for viral entry in primary HIV infection in uncircumcised men.

Epidemiological evidence

The epidemiological evidence of the effect of male circumcision on HIV and STDs comes from a large number of observational studies.

Association with HIV infection

A decade has now passed since two ecological studies found a lower HIV prevalence in areas of Africa where circumcision was practised [4,5]. A recent multicentre study of risk factors for HIV infection also observed an ecological association between circumcision and HIV prevalence among sexually active men [6]. In two West African cities where more than 99% of men were circumcised, the HIV prevalence was about four percent. In Kisumu, Kenya, where 27% of men were circumcised, the HIV prevalence was 21.9%, and the highest HIV prevalence (25.9%) was found in Ndola, Zambia, where only 7.6% of men were circumcised. In Kisumu, male circumcision was a strong independent protective factor for HIV infection (odds ratio 0.20; 95% confidence interval 0.09-0.43).

Several reviews of observational studies have found an association between lack of male circumcision and HIV infection [2,7,8], but such studies have inherent limitations mainly due to the confounding effects of factors like sexual behaviour and penile hygiene [2,6]. For example, if circumcised men have a lower risk profile than uncircumcised men then this may explain an observed association between lack of male circumcision and HIV infection. There have been three recent reviews that have included a pooled analysis of the data from observational studies [9,10,11]. The first of these [9] found circumcision to be associated with an increased risk of HIV infection but had statistical and epidemiological limitations which invalidated these findings [12]. When O'Farrell and Egger reanalysed these data using appropriate statistical techniques, they found that circumcision was associated with a significantly reduced risk of HIV infection [10]. However, this analysis was based on the crude results of the observational studies and hence did not take into account potential confounding factors.

Weiss and colleagues performed a systematic review and meta-analysis of observational studies from Africa of the association between male circumcision and the acquisition of HIV-1 infection [11]. Fifteen of the 27 studies included in this meta-analysis were adjusted for potential confounding factors, and these showed that male circumcision was associated with a significantly reduced risk of HIV infection in population-based studies (adjusted risk ratio 0.56; 95% confidence interval 0.44-0.70) and in high-risk groups such as STD clinic attenders (adjusted risk ratio 0.29; 95% confidence interval 0.20-0.41). Notably, in the population-based studies the effect of circumcision was stronger after adjusting for confounding factors because in many of the observational studies circumcised men had a higher risk profile than uncircumcised men. Similarly, a recent study from Uganda found a higher risk profile in 188 circumcised men compared with 177 uncircumcised men [13]. The higher risk behaviour observed among circumcised men in this and some other studies may reflect social and cultural differences between circumcised and uncircumcised men. Alternatively, circumcised men may engage in higher risk behaviour because they perceive themselves to be at low risk of HIV and STDs, or they may take part in high risk behaviour at the circumcision ceremony itself [13]. If circumcision leads to an increase in high-risk behaviour then this has implications for implementing male circumcision as a measure to control HIV and STDs.

Epidemiological studies published since the recent meta-analysis have also found circumcision to be associated with a reduced risk of HIV infection. Lavreys and colleagues [14] conducted a cohort study in 746 Kenyan trucking company employees. A significantly lower incidence of HIV infection was observed in circumcised men (2.5 per 1000 person-years) compared with uncircumcised men (5.9 per 1000 person-years) and this effect was stronger after adjusting for confounders including religion (adjusted rate ratio 0.25; 95% confidence interval 0.1-0.5). A case-control study of HIV incidence conducted in rural Uganda found a nonsignificant protective effect of circumcision (adjusted odds ratio 0.31; 95% confidence interval 0.07-1.35) [15]. However, the effects of religion and circumcision could not be separated in this study because all Muslims and only 6% of non-Muslims were circumcised.

The most compelling evidence to date of the protective effect of circumcision is a study by Quinn and colleagues of 187 discordant couples in Rakai, Uganda [16]. The incidence of HIV infection in men with HIV-infected partners was 0 per 1000 person-years among circumcised men and 16.7 per 1000 person-years among uncircumcised men (P=0.004). This study also examined the effect of male circumcision on HIV transmission in 224 discordant couples in which the female partner was HIV negative at baseline. The incidence of HIV infection was 5.2 per 1000 person-years among women with circumcised partners and 13.2 per 1000 person-years among women with uncircumcised partners. This effect was only statistically significant when restricted to women whose partner had a plasma viral load less than 50 000 copies per millilitre. In the population-based analysis of the non-Muslims in this study [17], circumcision was protective (odds ratio 0.80; 95% confidence interval 0.33-1.95) but the association was not statistically significant. However, most of the circumcised men in this study were Muslim and hence there is insufficient power to observe a significant effect of circumcision in non-Muslims, or to separate out the effects of circumcision and religion.

Association with sexually transmitted diseases

The effect of male circumcision on the risk of acquiring STDs is difficult to assess due to the transient nature of many STDs. Further, reviews of studies of this association are prone to difficulties due to the absence of consistent case definitions. Nevertheless, a review of observational studies found an association between lack of male circumcision and increased risk of genital ulcer disease, particularly chancroid and syphilis [8]. There was no clear association between male circumcision and other STDs due to too few studies or inconsistent findings between studies. A more recent review of the literature confirmed the association between lack of male circumcision and increased risk of genital ulcer disease [18]. The Kenyan cohort study described above [14] observed a significantly lower incidence of genital ulcer disease in circumcised men (6.5 per 1000 person-years) compared with uncircumcised men (15.2 per 1000 person-years) even after adjusting for confounders. However, they observed no effect of circumcision on urethritis or genital warts. A study conducted in Mwanza, Tanzania observed a nonsignificant protective effect of male circumcision on seropositivity for herpes simplex virus type 2 (adjusted odds ratio 0.39; 95% confidence interval 0.10-1.52) [19].

Effect of age at circumcision

The age at which males are circumcised varies according to different factors, most notably religion and ethnic group. Muslims and Jews traditionally circumcise during the neonatal period although African Muslims may circumcise later in life, such as during the preschool years [20] or around puberty [13]. Many African tribes circumcise around puberty to mark the passage into adulthood. It seems biologically plausible that circumcision offers the same degree of protection against HIV and STDs irrespective of the age at which it is performed. Data on the association between age at circumcision and HIV/STDs are sparse. A study conducted in Mwanza, Tanzania [21] found that the protective effect of circumcision was restricted to those circumcised at the age of 15 years or more. In a recent study of HIV infection conducted in Rakai, Uganda [22] the strongest effect of circumcision was observed in those circumcised before age 21 years. It may be that a protective effect in men circumcised at older ages has been diluted, because some men may have been circumcised after exposure to HIV and STDs or for medical reasons (as treatment for balanitis or an STD). Further studies of the effect of age at circumcision are needed.

Potential confounding effect of penile hygiene

No epidemiological study to date has adjusted for the potential confounding effect of penile hygiene. It is possible that at least some of the observed protective effect of circumcision is due to penile hygiene practices such as post-coital cleansing. Some circumcised men may have better penile hygiene which in turn protects them from HIV and other STDs. If penile hygiene reduces the occurrence of minor inflammatory conditions underneath the foreskin then this may protect against HIV/STDs in the same way as an absent foreskin.

Safety and acceptability of circumcision

Complications following circumcision have been studied in infants undergoing circumcision in the USA. Published data are lacking, however, on complications following circumcision in developing countries, where the procedure is often performed around puberty as part of a coming of age ceremony, and usually by traditional practitioners in unsanitary conditions. Two recent studies have investigated complications following traditional circumcision although neither study was able to estimate the complication rate. In a Nigerian hospital, Ahmed and colleagues [20] observed 48 complications following traditional male circumcision in boys aged seven years or less during a 15-year period, and a complication rate of 0.32% among 1563 hospital circumcisions during the same period. Importantly, the number of complications following traditional circumcision increased when the hospital fees increased, and hence more traditional circumcisions were performed. In hospitals in Nigeria and Kenya [23] a complication rate of 11% was observed in 249 consecutive circumcisions performed on males of all ages under sterile conditions.

The promotion of male circumcision cannot be considered unless it is acceptable in traditionally noncircumcising regions. There is growing evidence to suggest that circumcision is on the increase in traditionally noncircumcising groups due to the perception that it is associated with a reduced risk of HIV and STDs [24]. Bailey and colleagues have studied the acceptability of male circumcision in Uganda [13] and Kenya [25]. In Uganda, 29% of uncircumcised men said that they would like to be circumcised if it could be done at minimal cost, and the reasons they gave were to improve hygiene and reduce the risk of HIV and STDs. Among the Luo in Kenya, 60% of uncircumcised men said that they would prefer to be circumcised and 62% of women said that they would prefer a circumcised partner.

Feasibility and cost-effectiveness of circumcision

If male circumcision protects against HIV and STDs and is an acceptable practice that may be safely implemented then is it a feasible and cost-effective measure for controlling HIV/STDs? The magnitude of the protective effect of circumcision is likely to vary between different populations. Although the meta-analysis showed a protective effect against HIV infection in all types of population, there was significant heterogeneity, with the strongest effect observed in the high-risk groups. The greatest efficacy of circumcision is likely to be in populations at high risk of both HIV infection and ulcerative STDs, since circumcised men in this group will be protected from HIV acquisition both directly and also indirectly through a reduced risk of acquiring ulcerative STDs. Circumcision may have a lower efficacy in populations with a low prevalence of STDs, where, in the absence of an STD cofactor, the probability of HIV acquisition is extremely small. Even within these groups the efficacy of circumcision will vary between individuals. For example, among discordant couples drawn from a community-based study in Rakai, the strongest predictor of HIV acquisition in men was their partner's viral load [16]. Nevertheless, circumcision still protected against the acquisition of HIV infection. If a circumcision programme was implemented in this study population and had 50% coverage it is estimated that HIV acquisition may be reduced by 12% to 22% [26]. Data on the utility and cost-effectiveness of male circumcision in different settings are urgently needed. These would need to include the cost of promoting and implementing safe circumcision practices and should allow for any increases in HIV incidence associated with changes in sexual behaviour.

Action for research and policy

As part of the Horizons project, Van Dam and Anastasi produced comprehensive recommendations for future research [27]. These include studies on religion, penile hygiene, safety, acceptability, feasibility, and cost-effectiveness. The most rigorous scientific method for answering these questions would be to conduct randomized controlled trials in consenting adults, although observational studies may address questions on penile hygiene, safety and acceptability, and mathematical models could be used to estimate utility and cost-effectiveness in different settings. In their recent editorial [24], Halperin and Bailey recommend providing the training and resources needed to offer safe, voluntary, male circumcision in which pain is kept to a minimum. They warn that ignoring the issue of male circumcision may even be harmful, as increasing numbers of men turn to unsafe circumcision as a means of preventing HIV and STDs.

Conclusion

There is compelling biological and epidemiological evidence of the protective effect of circumcision on the acquisition of HIV infection and ulcerative STDs. It is unlikely that any single control measure will reduce HIV transmission sufficiently and therefore circumcision needs to be investigated as part of a package that includes education, condom promotion, and STD control. The potential adverse effects of promoting male circumcision need to be carefully monitored. In spite of the difficulties associated with promoting male circumcision as a measure to control HIV and STDs, this promising strategy should not be ignored.

References

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