Male circumcision and HIV prevention: current knowledge and future research directions

Over the past decade, numerous epidemiological studies have reported a significant association between lack of male circumcision and risk for HIV infection, leading to recommendations for male circumcision to be added to the armamentarium of effective HIV prevention strategies. We review the epidemiological data from studies that have investigated this association, including ecological, cross-sectional/case-control, and prospective studies. We discuss problematic issues in interpreting the epidemiological data, including the presence of other sexually transmitted infections, age of circumcision, and potential confounders such as religion, cultural practices, and genital hygiene. In addition, we review studies of biological mechanisms by which the presence of the foreskin may increase HIV susceptibility, data on risks associated with the circumcision procedure, and available data on the acceptability and feasibility of introducing male circumcision in societies where it is traditionally not practised. Although the evidence in support of male circumcision as an effective HIV prevention measure is compelling, residual confounding in observational studies cannot be excluded. Taken together with concerns over the potential disinhibiting effect of male circumcision on risk behaviour, and safety of the circumcision procedure, randomised trials of male circumcision to prevent HIV infection are recommended. An individual's choice to undergo male circumcision or a community's decision to promote the practice should be made in the light of the best available scientific evidence. More knowledge is required to assist individuals and communities in making those decisions. We conclude with recommendations for future research.     

A qualitative study of sexual behavior change and risk compensation following adult male circumcision in urban Swaziland

Male circumcision has been shown to reduce the risk of heterosexual transmission of HIV infection in men by up to 60% in three randomized controlled trials. Less is known, however, about sexual behavior change in men who have been circumcised and whether male circumcision's protective effect leads to riskier sexual behaviors. This study used qualitative in-depth interviews to understand men's sexual behavior after circumcision and to determine whether and how men participated in riskier sexual behaviors following male circumcision. Men in urban Swaziland, circumcised in the previous 12 months, were recruited and asked about their perceptions of sexual risk and sexual behavior post-circumcision. Results showed that following circumcision, men experience changes in both their sexual attitudes and behavior, which can be considered both protective and risky for HIV transmission. Most of them described protective changes (e.g., more responsible attitudes towards safe sex, reducing sexual temptation and partners, easier condom use). A minority, however, experienced increased sexual risk-taking, typically during a brief period of sexual experimentation shortly after circumcision. HIV counseling and counseling throughout the circumcision process is shown to be critical in influencing protective behaviors. Findings in this study confirm the existence of risk compensation following circumcision; however, this study adds important contextual insight about precisely when and why such risk-taking occurs. Nevertheless this study suggests that male circumcision scale-up as an HIV prevention strategy is likely to foster protective behavior change among men. The integration of HIV counseling with circumcision provision remains critical for effectively mitigating HIV risk behavior as male circumcision gains momentum as a viable HIV prevention tool.     

Economics of antiretroviral treatment vs. circumcision for HIV prevention

The HIV Prevention Trials Network (HPTN) 052 study, which showed the effectiveness of antiretroviral treatment in reducing HIV transmission, has been hailed as a “game changer” in the fight against HIV, prompting calls for scaling up treatment as prevention (TasP). However, it is unclear how TasP can be financed, given flat-lining support for global HIV programs. We assess whether TasP is indeed a game changer or if comparable benefits are obtainable at similar or lower cost by increasing coverage of medical male circumcision (MMC) and antiretroviral treatment (ART) at CD4 <350/μL. We develop a new mathematical model and apply it to South Africa, finding that high ART coverage combined with high MMC coverage provides approximately the same HIV incidence reduction as TasP, for $5 billion less over 2009–2020. MMC outperforms ART significantly in cost per infection averted ($1,096 vs. $6,790) and performs comparably in cost per death averted ($5,198 vs. $5,604). TasP is substantially less cost effective at $8,375 per infection and $7,739 per death averted. The prevention benefits of HIV treatment are largely reaped with high ART coverage. The most cost-effective HIV prevention strategy is to expand MMC coverage and then scale up ART, but the most cost-effective HIV-mortality reduction strategy is to scale up MMC and ART jointly. TasP is cost effective by commonly used absolute benchmarks but it is far less cost effective than MMC and ART. Given South Africa’s current annual ART spending, the $5 billion in savings offered by MMC and ART over TasP in the next decade, for similar health benefits, challenges the widely hailed status of TasP as a game changer.     

The changing face of the HIV epidemic in sub‐Saharan Africa

The widespread roll‐out of antiretroviral therapy (ART) has substantially changed the face of human immunodeficiency virus (HIV). Timely initiation of ART in HIV‐infected individuals dramatically reduces mortality and improves employment rates to levels prior to HIV infection. Recent findings from several studies have shown that ART reduces HIV transmission risk even with modest ART coverage of the HIV‐infected population and imperfect ART adherence. While condoms are highly effective in the prevention of HIV acquisition, they are compromised by low and inconsistent usage; male medical circumcision substantially reduces HIV transmission but uptake remains relatively low; ART during pregnancy, delivery and breastfeeding can virtually eliminate mother‐to‐child transmission but implementation is challenging, especially in resource‐limited settings. The current HIV prevention recommendations focus on a combination of preventions approach, including ART as treatment or pre‐ or post‐exposure prophylaxis together with condoms, circumcision and sexual behaviour modification. Improved survival in HIV‐infected individuals and reduced HIV transmission risk is beginning to result in limited HIV incidence decline at population level and substantial increases in HIV prevalence. However, achievements in HIV treatment and prevention are threatened by the challenges of lifelong adherence to preventive and therapeutic methods and by the ageing of the HIV‐infected cohorts potentially complicating HIV management. Although current thinking suggests prevention of HIV transmission through early detection of infection immediately followed by ART could eventually result in elimination of the HIV epidemic, controversies remain as to whether we can treat our way out of the HIV epidemic.     

Male circumcision and prevention of HIV and sexually transmitted infections

Three randomized trials in Africa have shown that adult male circumcision reduces HIV acquisition in men by approximately 60%. It is biologically plausible that circumcision reduces HIV risk in men because the inner mucosa of the foreskin is lightly keratinized and has a high density of dendritic cells and other HIV target cells, making it vulnerable to HIV infection. Also, the foreskin is retracted over the shaft during intercourse, exposing the inner mucosa to vaginal secretions; the prepuce is vulnerable to trauma during coitus, providing a portal for HIV entry. In addition, circumcision reduces the rate of reported genital ulceration, which is a cofactor for HIV acquisition. Male circumcision may also reduce some other sexually transmitted infections in men and their female partners. For these reasons, male circumcision should be promoted as a component of HIV prevention strategies.     

Antiretroviral medication and HIV prevention: new steps forward and new questions

During the past 2 years, several pivotal clinical trials have proven that the use of antiretrovirals by HIV-infected and at-risk uninfected persons can decrease the probability of HIV being transmitted sexually. The initial chemoprophylaxis studies evaluated tenofovir administered topically or orally (with or without emtricitabine). However, several questions remain. Some subsequent primary prevention studies did not replicate the results of the initial studies, raising questions about differences in the behaviors of participants in each study (in particular about medication adherence), as well as whether pharmacologic or local mucosal factors might explain the variable efficacy estimates. Other antiretrovirals and delivery systems are being evaluated to maximize the efficacy of primary chemoprophylactic approaches. At present, increasing access to antiretroviral treatment globally is a priority, because expanding access to medication that can prevent morbidity and mortality is itself an important public health goal and may reasonably be expected to decrease HIV incidence. However, for treatment as prevention to be maximally effective, increases in HIV testing, health care workers, and infrastructure are needed, in addition to medications and laboratory support for clinical monitoring. A combination of approaches is needed to most quickly decrease the current trends in HIV incidence, including early diagnosis and initiation of treatment for HIV-infected persons. These approaches can be coupled with appropriately tailored interventions for populations at greatest risk for infection (for example, men who have sex with men and sex workers), including male circumcision, behavioral interventions, and chemoprophylaxis. However, a substantial gap exists between current expenditures and unmet needs, which suggests that mobilization of political will is needed for this combination approach to be successful.     

Portfolios of Biomedical HIV Interventions in South Africa: A Cost-Effectiveness Analysis

BACKGROUND

Recent clinical trials of male circumcision, oral pre-exposure prophylaxis (PrEP), and a vaginal microbicide gel have shown partial effectiveness at reducing HIV transmission, stimulating interest in implementing portfolios of biomedical prevention programs.

OBJECTIVE

To evaluate the effectiveness and cost-effectiveness of combination biomedical HIV prevention and treatment scale-up in South Africa, given uncertainty in program effectiveness.

DESIGN

Dynamic HIV transmission and disease progression model with Monte Carlo simulation and cost-effectiveness analysis.

PARTICIPANTS

Men and women aged 15 to 49 years in South Africa.

INTERVENTIONS

HIV screening and counseling, antiretroviral therapy (ART), male circumcision, PrEP, microbicide, and select combinations.

MAIN MEASURES

HIV incidence, prevalence, discounted costs, discounted quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios.

KEY RESULTS

Providing half of all uninfected persons with PrEP averts 28 % of future HIV infections for $9,000/QALY gained, but the affordability of such a program is questionable. Given limited resources, annual HIV screening and ART utilization by 75 % of eligible infected persons could avert one-third of new HIV infections, for approximately $1,000/QALY gained. Male circumcision is more cost-effective, but disproportionately benefits men. A comprehensive portfolio of expanded screening, ART, male circumcision, microbicides, and PrEP could avert 62 % of new HIV infections, reducing HIV prevalence from a projected 14 % to 10 % after 10 years. This strategy doubles treatment initiation and adds 31 million QALYs to the population. Despite uncertainty in program effectiveness, a comprehensive portfolio costs less than $10,000/QALY gained in 33 % of simulation iterations and less than $30,000/QALY gained in 90 % of iterations, assuming an annual microbicide cost of $100.

CONCLUSIONS

A portfolio of modestly-effective biomedical HIV prevention programs, including male circumcision, vaginal microbicides, and oral PrEP, could substantially reduce HIV incidence and prevalence in South Africa and be likely cost-effective. Given limited resources, PrEP is the least cost-effective intervention of those considered.     

Circumcision and HIV Infection: Assessment of Causality

Whether the observed association between male circumcision and HIV infection is causal or not has not been verified. We did a meta-analysis of published data and applied Hill’s criteria for causality on all available evidence to assess presence of a causal association. Analysis was by the random effects method. Summary estimates were calculated for all studies combined and for sub groups stratified by type of study population, study design, and method of ascertaining circumcision status. Thirteen studies were included. Circumcised men had a reduced risk for HIV infection (adjusted RRoverall = 0.42, 95% CI 0.33−0.53; RR_RCT = 0.43 95% CI 0.32−0.59, RRobservational = 0.39, 95% CI 0.27−0.56). Available evidence satisfies six of Hill’s criteria: strength of association, consistency, temporality, coherence, biological plausibility, and experiment. These results provide unequivocal evidence that circumcision plays a causal role in reducing the risk of HIV infection among men.     

The impact of male circumcision on HIV incidence and cost per infection prevented: a stochastic simulation model from Rakai, Uganda

OBJECTIVES: To estimate the impact of male circumcision on HIV incidence, the number of procedures per HIV infection averted, and costs per infection averted. METHODS: A stochastic simulation model with empirically derived parameters from a cohort in Rakai, Uganda was used to estimate HIV incidence, assuming that male circumcision reduced the risks of HIV acquisition with rate ratios (RR) ranging from 0.3 to 0.6 in men, their female partners, and in both sexes combined, with circumcision coverage 0-100%. The reproductive number (R0) was also estimated. The number of HIV infections averted per circumcision was estimated from the incident cases in the absence of surgery minus the projected number of incident cases over 10 years following circumcision. The cost per procedure ($69.00) was used to estimate the cost per HIV infection averted. RESULTS: Baseline HIV incidence was 1.2/100 person-years. Male circumcision could markedly reduce HIV incidence in this population, particularly if there was preventative efficacy in both sexes. Under many scenarios, with RR < or = 0.5, circumcision could reduce R0 to < 1.0 and potentially abort the epidemic. The number of surgeries per infection averted over 10 years was 19-58, and the costs per infection averted was $1269-3911, depending on the efficacy of circumcision for either or both sexes, assuming 75% service coverage. However, behavioral disinhibition could offset any benefits of circumcision. CONCLUSION: Male circumcision could have substantial impact on the HIV epidemic and provide a cost-effective prevention strategy if benefits are not countered by behavioral disinhibition.     

Male Circumcision and HIV Prevention: Looking to the Future

Now that male circumcision has been shown to have a protective effect for men against HIV infection when engaging in vaginal intercourse with HIV-infected women, the research focus needs to shift towards the operational studies that can pave the way for effective implementation of circumcision programs. Behavioral research is needed to find out how people perceive the procedure and the barriers to and facilitators of uptake. It should also assess the risk of an increase in unsafe sex after circumcision. Social research must examine cultural perceptions of the practice, in Africa and beyond, including how likely uncircumcised communities are to access surgery and what messages are needed to persuade them. Advocates of male circumcision would benefit from research on how to influence health policy-makers, how best to communicate the benefits to the public, and how to design effective delivery models.     

Acceptability of male circumcision and predictors of circumcision preference among men and women in Nyanza Province, Kenya

Numerous epidemiologic studies report significant associations between lack of male circumcision and HIV-1 infection, leading some to suggest that male circumcision be added to the limited armamentarium of HIV prevention strategies in areas where HIV prevalence is high and the mode of transmission is primarily heterosexual. This cross-sectional survey of 107 men and 110 women in Nyanza Province, Kenya, assesses the attitudes, beliefs, and predictors of circumcision preference among men and women in a traditionally non-circumcising region. Sixty per cent (n=64) of uncircumcised men and 69% (n=68) of women who had uncircumcised regular partners reported that they would prefer to be circumcised or their partners to be circumcised. Men's circumcision preference was associated with the belief that it is easier for uncircumcised men to get penile cancer, sexually transmitted diseases, and HIV/AIDS, and that circumcised men have more feeling in their penises, enjoy sex more, and confer more pleasure to their partners. Women with nine or more years of school were more likely to prefer circumcised partners. Men who preferred to remain uncircumcised were concerned about the pain and cost of the procedure, and pain was a significant deterrent for women to agree to circumcision for their sons. If clinical trials prove circumcision to be efficacious in reducing risk of HIV infection, it is likely that the procedure will be sought by a significant proportion of the population, especially if it is affordable and minimally painful.     

Diagnosis and treatment of tuberculosis in adults with HIV

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), continues to pose a major public health problem and is the leading cause of mortality in people infected with human immunodeficiency virus (HIV). HIV infection greatly increases the risk of developing TB even before CD4+ T-cell counts decrease. Co-infection provides reciprocal advantages to both pathogens and leads to acceleration of both diseases. In HIV-coinfected persons, the diagnosis and treatment of tuberculosis are particularly challenging. Intensifying integration of HIV and tuberculosis control programmes has an impact on reducing diagnostic delays, increasing early case detection, providing prompt treatment onset, and ultimately reducing transmission. In this Review, we describe our current understanding of how these two pathogens interact with each other, new sensitive rapid assays for TB, several new prevention methods, new drugs and regimens.     

Male circumcision and its association with HIV infection and sexually transmitted diseases: evidence from 18 demographic and health surveys in sub-Saharan Africa

The study aimed to assess the association between male circumcision and HIV infection and STDs. The issue is controversial as various studies reported conflicting findings. A cross-sectional comparative study based on the secondary data of 18 Demographic Health Surveys (DHS), carried out in Sub-Saharan Africa starting from 2003, was conducted. From all surveys, information on 70 554 males aged 15 – 59 years was extracted. The association between male circumcision and HIV infection and STD symptoms (genital discharge or genital ulcer/sore) was assessed using binary logistic regression. Adjustment was made for sexual history and basic socio-demographic variables. The weighted prevalence of HIV among men 15 – 59 years was 3.1%. In the bivariate analysis uncircumcised status was significantly associated with risk of HIV, with odds ratio (OR) of 4.12 (95% CI: 3.85 – 4.42). The association was even more significant (4.95 (95% CI: 4.57–5.36)) after adjustment for number of lifetime sexual partners and socio-demographic variables. The risk associated with uncircumcised status is significantly lower among younger men aged 15 – 29 years than those in 30 – 59-year age category. About 5.5% of the study subjects reported either genital discharge or genital sore/ulcer in the preceding 12 months of the surveys. Circumcision status was not significantly associated with either of the symptoms, with adjusted OR of 1.07 (95% CI: 0.99 – 1.15). The study concludes that there is a strong association between uncircumcised status and HIV infection. Hence, male circumcision can be considered as a possible way of reducing the spread of HIV infection in areas where the practice is rare. A comprehensive study to assess the association between circumcision and different types of STDs is recommended.     

Male circumcision as a preventive measure against HIV and other sexually transmitted diseases

PURPOSE OF REVIEW: In 2005, 4.1 million people were infected with HIV. There is an urgent need to intensify and expand HIV prevention methods. Male circumcision is one of several potential approaches. This review summarizes recent evidence for the potential of male circumcision to prevent HIV and other sexually transmitted infections. RECENT FINDINGS: The first randomized controlled trial of adult male circumcision found a highly significant 60% reduction in HIV incidence among men in the intervention arm. Modelling this effect predicts that widespread implementation of male circumcision could avert 2 million HIV infections over the next decade in sub-Saharan Africa. The biological rationale is that the foreskin increases risk of HIV infection due to the high density of HIV target cells and lack of keratinization of the inner mucosal surface. SUMMARY: There is strong evidence that male circumcision reduces risk of HIV, syphilis and chancroid. If results are confirmed by two ongoing trials in sub-Saharan Africa, provision of safe male circumcision could be added to HIV prevention packages in high-incidence settings. This would also provide an opportunity for HIV-prevention education and counselling to young men at high risk of infection.     

Highlights of the 15th Conference on Retroviruses and Opportunistic Infections. HIV testing and prevention strategies

A number of presentations at the 15th Conference on Retroviruses and Opportunistic Infections focused on approaches to identify HIV-infected persons for early referral to treatment and prevention. This year's conference also highlighted the challenges we face in developing effective biomedical preventions, with reports on the failure of a candidate HIV vaccine and chronic herpes simplex virus type 2 suppression to prevent HIV acquisition, and the failure of male circumcision for HIV-seropositive men to prevent HIV transmission to their uninfected female partners. On the other hand, there were presentations on progress being made in animal models of microbicides and preexposure prophylaxis and on prevention of HIV transmission through breastfeeding. Several interesting presentations addressed the need to move beyond individual-level interventions into those that target sexual partnerships, communities, and policy changes, as these larger factors are driving the HIV epidemic in the United States and globally.     

Could male circumcision reduce HIV incidence in the UK?*

We consider the public health relevance of three recent African clinical trials showing male circumcision (MC) to reduce female-to-male transmission of HIV for the UK. Although heterosexually acquired HIV infections now account for the majority of new diagnoses in the UK each year, it is important to note that when considering the public health relevance of MC for the UK a large majority of these infections are acquired abroad. Men who have sex with men (MSM) remain those most at risk of acquiring their HIV infection in the UK. The efficacy and effectiveness of MC among MSM and in particular its protective role in unprotected anal intercourse between men remains unknown. Any future consideration of the role of MC in reducing HIV incidence in the UK should not be at the expense of weakening existing effective interventions.     

Male circumcision for the prevention of heterosexually acquired HIV infection: a meta-analysis of randomized trials involving 11,050 men

Objectives

Observational studies and a small collection of randomized controlled trials (RCTs) suggest that male circumcision may significantly reduce HIV transmission between sero‐discordant contacts. The Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization have recently announced recommendations to scale up male circumcision in countries with generalized epidemics and low levels of male circumcision. However, no meta‐analysis has been conducted to determine the effectiveness of this intervention.

Methods

We conducted a systematic review of medical literature, and included any RCTs assessing male circumcision to prevent heterosexually acquired HIV infection among males. We used the DerSimonian–Laird random effects method to pool study outcomes. We calculated the relative risk (RR), risk difference, number needed to treat (NNT) and I², all with 95% confidence intervals (CIs).

Results

We identified three RCTs that met our inclusion criteria, involving a total of 11 050 men. The pooled RR was 0.44 (95% CI 0.33–0.60, P<0.0001, I²=0%, 95% CI 0–35%). The risk difference was 0.014 (95% CI 0.07–0.21), yielding a NNT of 72 (95% CI 50–143).

Conclusions

Male circumcision is an effective strategy for reducing new male HIV infections. Its impact on a population level will require consistently safe sexual practices to maintain the protective benefit.     

The Promise of Antiretrovirals for HIV Prevention

With an estimated 2.6 million new HIV infections diagnosed annually, the world needs new prevention strategies to partner with condom use, harm reduction approaches for injection drug users, and male circumcision. Antiretrovirals can reduce the risk of mother-to-child HIV transmission and limit HIV acquisition after occupational exposure. Macaque models and clinical trials demonstrate efficacy of oral or topical antiretrovirals used prior to HIV exposure to prevent HIV transmission, ie pre-exposure prophylaxis (PrEP). Early initiation of effective HIV treatment in serodiscordant couples results in a 96% decrease in HIV transmission. HIV testing to determine serostatus and identify undiagnosed persons is foundational to these approaches. The relative efficacy of different approaches, adherence, cost and long-term safety will affect uptake and impact of these strategies. Ongoing research will help characterize the role for oral and topical formulations and help quantify potential benefits in sub-populations at risk for HIV acquisition.     

男性包皮环切作为艾滋病预防策略的伦理规范分析

2008年,卫生部、联合国艾滋病规划署和世界卫生组织,在世界艾滋病新闻发布会上联合通报,目前中国艾滋病的主要传播途径为性传播。流行病学研究表明,包皮环切能降低男性在异性性行为中艾滋病病毒(HIV)感染的危险。该文将从医疗、公共卫生和伦理道德等角度,分析男性包皮环切作为艾滋病预防策略的伦理规范问题。     

Genital ulceration as a risk factor for human immunodeficiency virus infection

Among 115 heterosexual men who presented with genital ulcers to a sexually transmitted disease clinic in Nairobi, Kenya, the prevalence of serum antibody to HIV was 16.5%. A past history of genital ulcers was reported by 12 (63%) of 19 men with antibody to HIV versus 30 (31%) of 96 without antibody (P = 0.008). HIV infection was also positively associated with lack of circumcision, but was not associated with the etiology of the current genital ulcer. Logistic regression analysis (adjusted for age, number of recent sex partners, recent prostitute contact, circumcision, tribal ethnic identity, past history of urethritis, and current diagnoses) confirmed only the association between prior history of genital ulcer disease and HIV infection; (P = 0.04, odds ratio 2.35, 95% confidence limits, 1.01-5.47). The incidence of genital ulcers, particularly chancroid, is much higher in parts of Africa than in Europe or North America. This may contribute to the increased risk of heterosexual transmission of HIV in Africa. Aggressive control of chancroid and syphilis may offer one very feasible approach to reducing transmission of HIV in this region.