Effect of circumcision of HIV-negative men on transmission of human papillomavirus to HIV-negative women: a randomised trial in Rakai, Uganda

doi:10.1016/S0140-6736(10)61967-8

The Lancet

Volume 377, Issue 9761, 15–21 January 2011, Pages 209-218

https://doi.org/10.1016/S0140-6736(10)61967-8 Get rights and content

Summary

Background

Randomised trials show that male circumcision reduces the prevalence and incidence of high-risk human papillomavirus (HPV) infection in men. We assessed the efficacy of male circumcision to reduce prevalence and incidence of high-risk HPV in female partners of circumcised men.

Methods

In two parallel but independent randomised controlled trials of male circumcision, we enrolled HIV-negative men and their female partners between 2003 and 2006, in Rakai, Uganda. With a computer-generated random number sequence in blocks of 20, men were assigned to undergo circumcision immediately (intervention) or after 24 months (control). HIV-uninfected female partners (648 of men from the intervention group, and 597 of men in the control group) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 months, and 24 months. Vaginal swabs were tested for high-risk HPV by Roche HPV Linear Array. Female HPV infection was a secondary endpoint of the trials, assessed as the prevalence of high-risk HPV infection 24 months after intervention and the incidence of new infections during the trial. Analysis was by intention-to-treat. An as-treated analysis was also done to account for study-group crossovers. The trials were registered, numbers NCT00425984 and NCT00124878.

Findings

During the trial, 18 men in the control group underwent circumcision elsewhere, and 31 in the intervention group did not undergo circumcision. At 24-month follow-up, data were available for 544 women in the intervention group and 488 in the control group; 151 (27·8%) women in the intervention group and 189 (38·7%) in the control group had high-risk HPV infection (prevalence risk ratio=0·72, 95% CI 0·60–0·85, p=0·001). During the trial, incidence of high-risk HPV infection in women was lower in the intervention group than in the control group (20·7 infections vs 26·9 infections per 100 person-years; incidence rate ratio=0·77, 0·63–0·93, p=0·008).

Interpretation

Our findings indicate that male circumcision should now be accepted as an efficacious intervention for reducing the prevalence and incidence of HPV infections in female partners. However, protection is only partial; the promotion of safe sex practices is also important.

Funding

The Bill & Melinda Gates Foundation, National Institutes of Health, and Fogarty International Center.

Introduction

Infection with human papillomavirus (HPV) is common in sexually active individuals, especially in developing countries.¹ HPV infection can cause genital warts, and high-risk genotypes cause penile and anal cancers in men, and cervical cancer in women.1, 2 Cervical cancer is the third most common cancer in women worldwide.³ More than 85% of the HPV disease burden is in developing countries, and cervical cancer is the leading cause of cancer mortality in women in east Africa.³

Three randomised trials, done in Uganda,⁴ Kenya,⁵ and South Africa,⁶ showed that male circumcision substantially decreased the risk of HIV acquisition in men. These trials reported that male circumcision also reduced the prevalence of penile high-risk HPV infection by about 35%,7, 8 reduced the acquisition of new high-risk HPV infections, and increased clearance of pre-existing high-risk HPV infection in men without HIV infection.⁹ We have also reported¹⁰ that, compared with female partners of uncircumcised men, female partners of circumcised men had lower rates of genital ulcer disease, Trichomonas vaginalis infection, and bacterial vaginosis. However, male circumcision did not reduce the rate of HIV transmission from men with HIV to their female partners.¹¹

In several observational studies, female partners of circumcised men were found to have a substantially reduced risk of cervical neoplasia,12, 13, 14 but findings are not consistent.15, 16 Many of these observational studies were small, were vulnerable to confounding by sexual behaviours in men and women, and assessed male circumcision status by self-report or the female partners' report, which could have affected the validity of data. Moreover, the long latent interval between initial infection with high-risk HPV and the development of cervical neoplasia complicates causal inferences from retrospective data for previous exposures. Because infection with high-risk HPV is a necessary precondition for cervical neoplasia,¹⁷ the potential efficacy of male circumcision for the prevention of cervical neoplasia can best be assessed in randomised controlled trials of male circumcision that measure incidence, prevalence, and clearance of high-risk HPV infection in female partners of men randomly assigned circumcision immediately or after a delay. In this study, we assessed the effectiveness of male circumcision to prevent high-risk HPV infection in HIV-negative female partners of HIV-negative men who were enrolled in two randomised controlled trials of male circumcision in Rakai, Uganda.

Section snippets

Study design and participants

Two parallel but independent trials of male circumcision for the prevention of HIV and other sexually transmitted infections were done in Rakai, Uganda, as previously described.4, 7, 10, 11, 18 Both trials began enrolment of participants in September, 2003. The first trial enrolled 4996 uncircumcised men who did not have HIV infection and were between 15 and 49 years old. The primary aim was to assess the effectiveness of male circumcision for the prevention of HIV infection; secondary aims

Results

The trial profile is given in the figure. Of the 2786 men in the intervention group who did not have HIV infection at enrolment, 1357 (49%) reported that they were married or in a consensual relationship with a total of 1463 women (mean=1·08 female partners per man). Of the 2810 men in the control group who did not have HIV infection at enrolment, 1349 (48%) reported that they were married or in a consensual relationship with a total of 1429 women (mean=1·06 female partners per man).

Because of

Discussion

Circumcision of adolescent and adult men in a rural Ugandan population significantly reduced the prevalence and incidence of both low-risk and high-risk HPV infections and increased clearance of high-risk HPV infections in their female partners. The efficacy of male circumcision for reducing high-risk HPV prevalence in female partners during the 2-year follow-up was 28%. Our finding of lower prevalence of high-risk HPV infections in female partners of circumcised men than in female partners of

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Cited by (143)

Association between male circumcision and human papillomavirus infection in males and females: a systematic review, meta-analysis, and meta-regression
2023, Clinical Microbiology and Infection
Previous studies have suggested a protective effect of male circumcision on human papillomavirus (HPV) infections in males, and that this protection may be conferred to their female sexual partners.
To synthesize the available evidence on the association between male circumcision and HPV infections in males and females.
We searched MEDLINE, Embase, Scopus, Cochrane, LILACS, and ProQuest Dissertations & Theses Global for records published up to 22 June 2022.
We considered observational and experimental studies that assessed male circumcision status and HPV prevalence, incidence, or clearance in males or females for inclusion.
Males and their female sexual partners who were tested for genital HPV infection.
Male circumcision compared with no circumcision.
The Newcastle-Ottawa scale was used for observational studies, and the Cochrane risk-of-bias tool was used for randomized trials.
We estimated summary measures of effect and 95% CIs for the prevalence, incidence, and clearance of HPV infections in males and females using random-effects meta-analysis. We assessed the effect modification of circumcision on HPV prevalence by the penile site in males using random-effects meta-regression.
Across 32 studies, male circumcision was associated with decreased odds of prevalent HPV infections (odds ratio, 0.45; 95% CI, 0.34–0.61), a reduced incidence rate of HPV infections (incidence rate ratio, 0.69; 95% CI, 0.57–0.83), and an increased risk of clearing HPV infections (risk ratio, 1.44; 95% CI, 1.28–1.61) at the glans penis among male subjects. Circumcision conferred greater protection against infection at the glans than the shaft (odds ratio, 0.68; 95% CI, 0.48–0.98). Females with circumcised partners were protected from all outcomes.
Male circumcision may protect against various HPV infection outcomes, suggesting its prophylactic potential. Understanding the site-specific effects of circumcision on HPV infection prevalence has important implications for studies of HPV transmission.
Mucus-penetrating nonviral gene vaccine processed in the epithelium for inducing advanced vaginal mucosal immune responses
2023, Acta Pharmaceutica Sinica B
Establishment of vaginal immune defenses at the mucosal interface layer through gene vaccines promise to prevent infectious diseases among females. Mucosal barriers composed of a flowing mucus hydrogel and tightly conjugated epithelial cells (ECs), which represent the main technical difficulties for vaccine development, reside in the harsh, acidic human vaginal environment. Different from frequently employed viral vectors, two types of nonviral nanocarriers were designed to concurrently overcome the barriers and induce immune responses. Differing design concepts include the charge-reversal property (DRLS) to mimic a virus that uses any cells as factories, as well as the addition of a hyaluronic acid coating (HA/RLS) to directly target dendritic cells (DCs). With a suitable size and electrostatic neutrality, these two nanoparticles penetrate a mucus hydrogel with similar diffusivity. The DRLS system expressed a higher level of the carried human papillomavirus type 16 L1 gene compared to HA/RLS in vivo. Therefore it induced more robust mucosal, cellular, and humoral immune responses. Moreover, the DLRS applied to intravaginal immunization induced high IgA levels compared with intramuscularly injected DNA (naked), indicating timely protection against pathogens at the mucus layer. These findings also offer important approaches for the design and fabrication of nonviral gene vaccines in other mucosal systems.
Prevention and Screening of HPV Malignancies
2021, Seminars in Radiation Oncology
Citation Excerpt :
Male circumcision is known to reduce the risk of contracting HIV, but it also reduces the risk of HPV infection and penile cancer.41,42 In addition to its direct benefit for males, circumcision may also prevent HPV transmission to sex partners, a finding confirmed in prospective clinical trials.43,44 Cervical cancer is particularly well-suited to screening because the period from initial infection with an oncogenic HPV type to the development of cancer spans many years, and invasive cancer is preceded by an identifiable precursor lesion.45
It is estimated that 5% of the global cancer burden, or approximately 690,000 cancer cases annually, is attributable to human papillomavirus (HPV). Primary prevention through prophylactic vaccination is the best option for reducing the burden of HPV-related cancers. Most high-income countries (HICs) have introduced the HPV vaccine and are routinely vaccinating adolescent boys and girls. Unfortunately, although they suffer the greatest morbidity and mortality due to HPV-related cancers, many lower- and middle-income countries (LMICs) have been unable to initiate and sustain vaccination programs. Secondary prevention in the form of screening has led to substantial declines in cervical cancer incidence in areas with established screening programs, but LMICs with absent or inadequate screening programs have high incidence rates. Meanwhile, HICs have seen incidence rates of anal and oropharyngeal cancers rise owing to the limited availability of organized screening for anal cancer and no validated screening options for oropharyngeal cancer. The implementation of screening programs for individuals at high risk of these cancers has the potential to reduce the burden of cervical cancer in LMICs, of anal and oropharyngeal cancers in HICs, and of anal cancer for highly selected HIV+ populations in LMICs. This review will discuss primary prevention of HPV-related cancers through vaccination and secondary prevention through screening of cervical, anal, and oropharyngeal cancers. Areas of concern and highlights of successes already achieved are included.
Understanding the linkages between male circumcision and multiple sexual partnership among married Ghanaian men: Analysis of data from the 2014 Ghana demographic and health survey
2020, SSM - Population Health
This current study sought to investigate the association between male circumcision status and engaging in multiple sexual partnership among men in Ghana.
Data from this study come from the men's file of the 2014 Ghana demographic and health survey. Both descriptive and inferential statistics were conducted among 1, 948 men and the level of statistical significance was pegged at p < 0.05.
Results revealed that men who have been circumcised were more likely to engage in multiple sexual partnership (AOR = 3.36; CI:1.14–9.89), compared to those who have not been circumcised. With the covariates, men with primary level of education were more likely to have multiple sexual partners (AOR = 2.01; CI:1.10–3.69), compared to those with no education. With wealth status, men with richest (AOR = 2.27; CI:1.04–4.97), richer (AOR = 2.05; CI: 1.03–4.08), and middle wealth status (AOR = 1.83; CI:1.01–3.34) had the highest likelihood of having multiple sexual partners, compared to those with poorest wealth status. Conversely, men who professed the Islamic faith were less likely to engage in multiple sexual partnership (AOR = 0.58; CI: 0.36–0.94), compared to Christians. Similarly, men who resided in the Brong Ahafo (AOR = 0.51; CI: 0.26–0.99), Upper East (AOR = 0.41; CI:0.19–0.89), and Ashanti regions (AOR = 0.39; CI: 0.20–0.78) were less likely to engage in multiple sexual partnership.
Based on the current findings, educational campaigns by stakeholder groups (e.g., Ministry of Health in collaboration with the National Commission on Civic Education, civil society, educational institutions) should sensitize the sexually active population at the community level to consistently use condoms, especially when they have multiple sexual partners, even when a man is circumcised. Campaign messages must clearly emphasize that male circumcision should not substitute precautionary measures such as delay in the onset of sexual relationships, averting penetrative sex, reducing the number of sexual partners as well as correct and consistent use of male or female condoms regardless one's social standing.
A contemporary snapshot of circumcision in US children's hospitals
2020, Journal of Pediatric Surgery
In 2012, the American Academy of Pediatrics (AAP) concluded the health benefits of circumcision during the neonatal period outweigh the risks. This study describes recent trends in male circumcision in freestanding children's hospitals in the United States.
Using the Pediatric Health Information System (PHIS), male patients < 18 years of age who were circumcised without any additional procedures between the years 2010 and 2017 were identified. Data included age at procedure (neonate: 0–30 days, infant: 31–365 days, early childhood: ≥ 1 to < 5 years, and older child: ≥ 5 to < 18 years), cost, and specialty performing the circumcision.
Of the 171,680 circumcisions performed, 85,270 (50%) were during neonatal period, 29,060 (17%) during infancy, 30,276 (18%) early childhood, and 26,355 (16%) thereafter. Circumcision in neonates increased from 39% to 58% (p < 0.001), and the proportion performed during infancy decreased over time. System level cost for ambulatory circumcision averaged $32 million USD annually, and median cost per ambulatory circumcision was $2892 USD. Obstetricians and Pediatricians are performing proportionally more circumcisions.
Since 2012, proportionally more neonates are undergoing circumcision in US children's hospitals. Perinatal specialties are performing an increasing proportion of circumcisions. Circumcision during the birth hospitalization in the neonatal period is more resource-effective than postponing until later in infancy.
Retrospective, cross-sectional analysis.
Level IV.
Estimating incidence rates of grouped HPV types: A systematic review and comparison of the impact of different epidemiological assumptions
2019, Papillomavirus Research
Citation Excerpt :
Table 3 shows the approach the authors used to estimate IR in their study. Of the 57 articles, 22 [32–53], one [22], and two [23,25] used approaches A, B and C respectively, and six [54–59], one [21], and five [24,26,28–30] articles used approaches D, E and F respectively. One study used both approaches B and E [19] and two studies used both C and F [4,20].
Some studies on human papillomavirus (HPV) provide not only type-specific incidence rates (IR), but also IRs of HPV groupings (e.g. the nonavalent grouping). We made an inventory of the different approaches used to calculate such IRs and assessed their impact on the estimated IRs of HPV groupings.
We performed a systematic review assessing all approaches used in literature to estimate IRs. Subsequently we applied these approaches to data of a Dutch cohort study on HPV in men who have sex with men (H2M). IRs were estimated for six different HPV groupings.
The systematic review yielded six different approaches (A-F) for estimating the IRs, varying in exclusion criteria at baseline, and the definitions of an incident event and person-time. Applying these approaches to the H2M dataset (n = 749), we found differences in the number of participants at risk, number of incidents events, person-time, and IR. For example, for the nonavalent grouping, depending on the approach chosen, the IR varied between 3.09 and 6.54 per 100 person-months.
In published studies different epidemiological assumptions are used to estimate IRs of grouped HPV types, leading to widely differing estimates of IRs. IRs between different studies may therefore not be comparable.

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ArticlesEffect of circumcision of HIV-negative men on transmission of human papillomavirus to HIV-negative women: a randomised trial in Rakai, Uganda

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet Infect Dis

Lancet

Lancet

Lancet

Lancet

Epidemiologic classification of human papillomavirus types associated with cervical cancer

N Engl J Med

Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

Int J Cancer

Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial

PLoS Med

Male circumcision for the prevention of HSV-2 and HPV infections and syphilis

N Engl J Med

Effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa

J Infect Dis

Male circumcision decreases acquisition and increases clearance of high-risk human papillomavirus in HIV-negative men: a randomized trial in Rakai, Uganda

J Infect Dis

The effects of male circumcision on female partners' genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda

Am J Obstet Gynecol

Male circumcision, religion, and infectious diseases: an ecologic analysis of 118 developing countries

BMC Infect Dis

Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners

N Engl J Med

Case-control study of risk factors for cervical neoplasia in Denmark—I: role of the “male factor” in women with one lifetime sexual partner

Int J Cancer

Articles
Effect of circumcision of HIV-negative men on transmission of human papillomavirus to HIV-negative women: a randomised trial in Rakai, Uganda