Clinical Chemistry 65:1
15–18 (2019)
Male Circumcision for HIV and STI Prevention:
A Reflection
Ronald H. Gray*
Circumcision is one of the oldest surgical procedures,
dating from the Neolithic age (Fig. 1). It is widely prac-
ticed throughout the world for religious reasons (e.g.,
Muslims and Jews), as part of traditional cultures among
tribal groups in Africa (e.g., Kikuyu in Kenya) and in
Melanesia, and for medical reasons both preventive and
therapeutic. The majority of procedures are performed in
infancy or childhood, but in some cultures circumcision
is part of initiation rituals marking the transition from
adolescence to adulthood (e.g., Xhosa of South Africa).
Since the 1990s, the Rakai Health Sciences Program
has worked on male circumcision for prevention of HIV
and other sexually transmitted infections (STIs) through
a series of studies conducted in rural Rakai district of
south-central Uganda. This reflection summarizes our
work, progressing from observational studies, clinical tri-
als, assessment of effectiveness in programmatic settings,
and implementation science to improve efficiency and
cost-effectiveness. To better understand the biologic ef-
fects of circumcision, we also assessed penile histopathol-
ogy, immunology, and the microbiome. These and other
studies have established circumcision as a major compo-
nent of HIV prevention strategies in sub-Saharan Africa
(1 ) and have affected policies in the US (2 ).
Early epidemiologic studies suggested that male cir-
cumcision was protective against cervical cancer in female
partners of Jewish men, but there was debate as to
whether this was owing to lower sexual risk behaviors
among Jewish women and men than among couples of
other religious denominations or whether the protection
reflected a biologic effect of the procedure (3 ). Similar
questions of potential confounding by differential risk
behaviors were raised early in the HIV epidemic when it
was observed that Muslim men had a lower risk of HIV
acquisition than non-Muslim men (4 ). This differential
risk of HIV could reflect Islamic practices such as poly-
gamy with closed sexual networks or abstinence from
alcohol. In Kenya, the Luo tribe who do not traditionally
practice circumcision had higher rates of HIV infection
Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public
Health, Baltimore, MD.
* Address correspondence to the author at: 627 N Washington Street, Baltimore, MD
21205. E-mail rgray4@jhu.edu.
Received September 25, 2018; accepted September 26, 2018.
DOI: 10.1373/clinchem.2018.286542
© 2018 American Association for Clinical Chemistry
Reflections
than the Kikuyu who circumcised males in childhood,
although behavioral confounding could not be excluded
Downloaded from https://academic.oup.com/clinchem/article-abstract/65/1/15/5607945 by guest on 15 June 2020
(5 ). We conducted a retrospective analysis of HIV trans-
mission among high-risk HIV-discordant couples with
uninfected men and HIV-infected female partners.
There were no transmissions to circumcised men,
whereas HIV incidence was 16.7 per 100 person years if
the man was uncircumcised (6 ), strongly suggesting that
the effect of circumcision was biological rather than be-
haviorally mediated. Nevertheless, the observational data
were considered suggestive, but not conclusive, and in-
sufficient to warrant WHO and Joint United Nations
Program on HIV/AIDS (UNAIDS) recommending the
procedure for HIV control. Moreover, circumcision pre-
sented a new paradigm because a surgical procedure had
never been used to prevent an infectious disease. Thus,
the only way to resolve the question of whether circum-
cision could prevent HIV acquisition was to conduct
randomized trials.
There were 3 randomized trials conducted in South
Africa (7 ), Kenya (8 ), and Uganda (9 ), which all adopted
similar designs enrolling consenting, uncircumcised,
HIV-negative men who were randomized to receive cir-
cumcision at time of enrollment (the intervention arm)
or circumcision delayed for 21–24 months (the control
arm). Participants were followed up to record incident
HIV infections and sexual risk behaviors. The trial set-
tings, background HIV incidence, and age range of par-
ticipants differed substantially. All 3 trials were stopped
early owing to evidence of significant efficacy, with risk
ratios ranging from 0.41 to 0.43. Moreover, the trial
results were similar to a metaanalysis of observational
studies, which estimated a risk ratio of 0.42 (10 ). On the
basis of this evidence, in early 2007, UNAIDS concluded
that circumcision reduced male HIV acquisition by ap-
proximately 58% and recommended that circumcision
be provided as a component of HIV prevention strategy
(1 ).
Major donors such as PEPFAR (The US President’s
Emergency Plan for AIDS Relief) focused funding of
services in 14 priority countries in eastern and southern
Africa where circumcision was uncommon and HIV
prevalence was substantial. The UNAIDS target was to
perform 20.8 million circumcisions to achieve 80% cir-
cumcision coverage (11 ). By 2018 approximately 15 mil-
lion procedures have been performed in these priority
countries (i.e., approximately 75% of the UNAIDS tar-
15
Reflections
Fig. 1. Neolithic circumcision, the unkindest cut.
get), and there is evidence that this has had a major effect
on male HIV incidence in several countries (12 ). Math-
ematical models suggest that circumcision could prevent
500000 male HIV infections by 2030 and that 15 cir-
cumcisions were needed per HIV infection averted over
10 years in high HIV incidence populations (13 ).
Further analyses of data from the trials have shown
that circumcision also prevents other viral STIs and gen-
ital ulcers in men (14 –16 ). Circumcision reduced herpes
simplex virus type by 28% (15 ), high-risk human papil-
loma virus by 34% (6 ), and genital ulcers by 47% (14 ).
There were no significant effects of circumcision on male
trichomonas, gonorrhea, Chlamydia, or Mycoplasma.
However, there were marked reductions in penile anaer-
obes among circumcised men (17 ) and concurrent re-
ductions in inflammatory cytokines (18 ), which might
contribute to the efficacy of circumcision for prevention
of viral STIs.
There were concerns that the protection afforded by
circumcision could lead to risk compensation with con-
sequent increased risky sexual behaviors among circum-
cised men and their female partners. However, the trials
and subsequent observational studies in circumcision
programs showed minimal or no evidence of behavioral
disinhibition (19 ). There were no adverse effects of cir-
cumcision on sexual function or satisfaction in men (20 ),
and 40% of women reported enhanced sexual satisfaction
after their partners were circumcised (21 ).
The safety of circumcision of HIV-infected men and
its effects on transmission to uninfected female partners
were important programmatic issues and were assessed in
1 trial in Rakai, Uganda (22 ). HIV-infected men could
not be excluded from circumcision programs because it
would be stigmatizing, so UNAIDS recommended that
circumcision be provided to them as long as there were no
medical contraindications (1 ). The trial in Rakai showed
that moderate or severe adverse events following surgery
were comparable in HIV-infected and HIV-uninfected
men (3.1% and 3.2%, respectively). However, wound
healing was slower in HIV-positive men than in HIV-
negative men (73% vs 83% at 30 postoperative days),
16 Clinical Chemistry 65:1 (2019)
and a higher proportion of infected men resumed sex
before wound healing (23 ). The latter was of concern
because HIV shedding is increased for 2 weeks after cir-
cumcision of infected men, and thus the risk of transmis-
sion to their uninfected partners might be increased (24 ).
However, the risk of genital ulceration was reduced by
circumcision, which could mitigate this HIV risk.
Two observational studies suggested that circumci-
sion of HIV-infected men might reduce the risk of trans-
mission of HIV to uninfected female partners, but this
Downloaded from https://academic.oup.com/clinchem/article-abstract/65/1/15/5607945 by guest on 15 June 2020
was not confirmed in a trial largely because the risk of
transmission was increased among couples who resumed
intercourse before completed wound healing (22 ). Nev-
ertheless, a trial in HIV-uninfected men showed there are
benefits of circumcision to HIV-negative women, in-
cluding reduced risk of vaginal infections and genital ul-
ceration (25 ) and reduced prevalence and incidence of
high-risk human papillomavirus in female partners (26 ).
The reduction of high-risk human papilloma virus in
both sexes explains why circumcision is associated with
reduced anogenital cancers in women and men.
Implementation science studies showed that non-
physicians (clinical officers) can perform circumcision as
safely as physicians and that it requires experience with
approximately 100 procedures to attain optimal compe-
tence and efficiency of the surgery (27 ). Additionally,
mobile services with “circumcision camps,” which move
between communities, provided the maximum number
of procedures at the lowest costs, compared to static ser-
vices (28 ). We also assessed the safety of 2 circumcision
devices, the Shang Ring and PrePex device, which reduce
the time required for the procedure to approximately 5
min and thus could increase the number of circumcisions
performed per provider. However, the PrePex, which
constricts blood flow to the prepuce, is retained for 7 days
after placement and causes ischemic necrosis of the fore-
skin. If men remove the device themselves, they experi-
ence massive edema, which can cause urinary obstruction
requiring emergency surgery (29 ). In other implementa-
tion science studies, we found that nurse midwives could
safely provide early infant circumcision (30 ); since nurse
midwives have direct contact with the mother and infant,
they could be important to expanding this service.
To better understand the biologic basis for the ef-
fects of circumcision for HIV prevention, we conducted
histopathology studies of the foreskin and showed that
the tissue contained high densities of epidermal dendritic
cells and dermal CD4 and CD8 T cells, which are targets
for HIV (31 ). There are foci of inflammation in the
prepuce, which increase the density of CD4 and CD8
target cells (32 ) and up-regulate proinflammatory cyto-
kines and chemokines (18 ). A larger foreskin surface area
was also shown to be correlated with higher risk of HIV
infection, presumably because of more numerous targets
for the virus (33 ). We also found that HIV-neutralizing
 Reflections

IgA secreted by the foreskin could be protective against

HIV infection, and lower levels of this IgA were associ-
ated with increased risk of acquiring HIV (34 ). This
finding potentially could provide a mechanism for a mu-
cosal vaccine. In studies of the subpreputial microbiome,
we found that circumcision using conventional surgery
reduced the abundance of anaerobic bacteria (17 ). How-
ever, the PrePex device, which causes tissue necrosis, in-
creased anaerobic abundance (35 ). WHO was concerned
about the risk of tetanus following circumcision and on
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 4
requirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data;(b) drafting
or revising the article for intellectual content; (c) final approval of the
published article; and (d) agreement to be accountable for all aspects of
the article thus ensuring that questions related to the accuracy or integ-
rity of any part of the article are appropriately investigated and resolved.
Authors’ Disclosures or Potential Conflicts of Interest: Upon man-

Downloaded from https://academic.oup.com/clinchem/article-abstract/65/1/15/5607945 by guest on 15 June 2020

the basis of our findings recommended 2 tetanus toxoid uscript submission, all authors completed the author disclosure form. Dis-
closures and/or potential conflicts of interest:
immunizations at 28-day intervals before PrePex circum-
cision, but only 1 tetanus toxoid immunization at time of Employment or Leadership: R. Gray, Johns Hopkins University.
surgery for conventional surgical procedures. Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
In summary, male circumcision has now become an
Honoraria: None declared.
integral intervention for HIV prevention in sub-Saharan Research Funding: R. Gray, NIH, Gates Foundation.
African populations with high HIV prevalence and low Expert Testimony: None declared.
prevalence of circumcision. Patents: None declared.

1. UNAIDS. New data on male circumcision and HIV
prevention: policy and programme implications.
Montreux: UNAIDS, 2007. http://www.who.int/hiv/pub/
malecircumcision/research_implications/en/ (Accessed
September 2018).
2. American Academy of Pediatrics Task Force on C, Blank S,
Brady M, Buerk E, Carlo W, Diekema D, Freedman A, et al.
Male circumcision. Pediatrics 2012;130:e756 – 85.
3. Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV,
de Sanjose S, et al. Male circumcision, penile human
papillomavirus infection, and cervical cancer in female
partners. N Engl J Med 2002;346:1105–12.
4. Kelly R, Kiwanuka N, Wawer MJ, Serwadda D, Se-
wankambo NK, Wabwire-Mangen F, et al. Age of male
circumcision and risk of prevalent HIV infection in rural
Uganda. AIDS 1999;13:399 – 405.
5. Weiss HA, Halperin D, Bailey RC, Hayes RJ, Schmid G,
Hankins CA. Male circumcision for HIV prevention: from
evidence to action? AIDS 2008;22:567–74.
6. Gray RH, Kiwanuka N, Quinn TC, Sewankambo NK, Ser-
wadda D, Mangen FW, et al. Male circumcision and HIV
acquisition and transmission: cohort studies in Rakai,
Uganda. Rakai Project Team. AIDS 2000;14:2371– 81.
7. Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J,
Sitta R, Puren A. Randomized, controlled intervention
trial of male circumcision for reduction of HIV infection
risk: the ANRS 1265 Trial. PLoS Med 2005;2:e298.
8. Bailey RC, Moses S, Parker CB, Agot K, Maclean I,
Krieger JN, et al. Male circumcision for HIV prevention
in young men in Kisumu, Kenya: a randomised con-
trolled trial. Lancet 2007;369:643–56.
9. Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S,
Nalugoda F, et al. Male circumcision for HIV prevention
in men in Rakai, Uganda: a randomised trial. Lancet
2007;369:657– 66.
10. Weiss HA, Quigley MA, Hayes RJ. Male circumcision
and risk of HIV infection in sub-Saharan Africa: a sys-
tematic review and meta-analysis. AIDS 2000;14:
2361–70.
11. World Health Organization. Progress in scaling up
voluntary medical male circumcision for HIV preven-
tion in East and Southern Africa, January–December
2012. https://afro.who.int/sites/default/files/2017-06/aids-
progress-in-scaling-up-vmmc-dec2013.pdf (Accessed Sep-
References
tember 2018).
12. WHO. WHO Progress Brief. Voluntary Medical Male Cir-
cumcision for HIV Prevention in 14 Priority Countries in
East and Southern Africa. Geneva, 2015. http://www.
who.int/hiv/pub/malecircumcision/brief2015/en/ (Accessed
September 2018).
13. UNAIDS/WHO/SACEMA. Male circumcision for HIV pre-
vention in high HIV prevalence settings: what can
mathematical modelling contribute to informed deci-
sion making? PLoS Med 2009;6:e1000109.
14. Gray RH, Serwadda D, Tobian AAR, Chen MZ, Makumbi
F, Suntoke T, et al. Effects of genital ulcer disease and
herpes simplex virus type 2 on the efficacy of male cir-
cumcision for HIV prevention: analyses from the Rakai
trials. PLoS Med 2009;6:e1000187.
15. Tobian AAR, Serwadda D, Quinn TC, Kigozi G, Gravitt PE,
Laeyendecker O, et al. Male circumcision for the pre-
vention of HSV-2 and HPV infections and syphilis.
N Engl J Med 2009;360:1298 –309.
16. Gray RH, Serwadda D, Kong X, Makumbi F, Kigozi G,
Gravitt PE, et al. Male circumcision decreases acquisi-
tion and increases clearance of high-risk human papil-
lomavirus in HIV-negative men: a randomized trial in
Rakai, Uganda. J Infect Dis;201:1455– 62.
17. Liu CM, Hungate BA, Tobian AAR, Serwadda D, Ravel J,
Lester R, et al. Male circumcision significantly reduces
prevalence and load of genital anaerobic bacteria.
MBio 2013;4:e00076.
18. Prodger JL, Gray RH, Shannon B, Shahabi K, Kong X,
Grabowski K, et al. Chemokine levels in the penile cor-
onal sulcus correlate with HIV-1 acquisition and are re-
duced by male circumcision in Rakai, Uganda. PLoS
Pathol 2016;12:e1006025.
19. Kong X, Kigozi G, Nalugoda F, Musoke R, Kagaayi J,
Latkin C, et al. Assessment of changes in risk behaviors
during 3 years of posttrial follow-up of male circumci-
sion trial participants uncircumcised at trial closure in
Rakai, Uganda. Am J Epidemiol 2012;176:875– 85.
20. Kigozi G, Watya S, Polis CB, Buwembo D, Kiggundu V,
Wawer MJ, et al. The effect of male circumcision on
sexual satisfaction and function: results from a random-
ized trial of male circumcision for human immunodefi-
ciency virus prevention, Rakai, Uganda. BJU Int 2008;
101:65–70.
21. Kigozi G, Lukabwe I, Kagaayi J, Wawer MJ, Nantume B,
Kigozi G, et al. Sexual satisfaction of women partners of
circumcised men in a randomized trial of male circum-
cision in Rakai, Uganda. BJU Int 2009;104:1698 –701.
22. Wawer MJ, Makumbi F, Kigozi G, Serwadda D, Watya S,
Nalugoda F, et al. Circumcision in HIV-infected men
and its effect on HIV transmission to female partners in
Rakai, Uganda: a randomised controlled trial. Lancet
2009;374:229 –37.
23. Kigozi G, Musoke R, Kighoma N, Kiwanuka N, Ma-
kumbi F, Nalugoda F, et al. Safety of medical male cir-
cumcision in human immunodeficiency virus-infected
men in Rakai, Uganda. Urology 2014;83:294 –7.
24. Tobian AAR, Kong X, Wawer MJ, Kigozi G, Gravitt PE,
Serwadda D, et al. Circumcision of HIV-infected men
and transmission of human papillomavirus to female
partners: analyses of data from a randomised trial in
Rakai, Uganda. Lancet Infect Dis 2011;11:604 –12.
25. Gray RH, Kigozi G, Serwadda D, Makumbi F, Nalugoda
F, Watya S, et al. The effects of male circumcision on
female partners’ genital tract symptoms and vaginal in-
fections in a randomized trial in Rakai, Uganda. Am J
Obstet Gynecol 2009;200:42 e1–7.
26. Wawer MJ, Tobian AA, Kigozi G, Kong X, Gravitt PE, Ser-
wadda D, et al. Effect of circumcision of HIV-negative
men on transmission of human papillomavirus to HIV-
negative women: a randomised trial in Rakai, Uganda.
Lancet 2011;377:209 –18.
27. Kiggundu V, Watya S, Kigozi G, Serwadda D, Nalugoda
F, Buwembo D, et al. The number of procedures re-
quired to achieve optimal competency with male
circumcision: findings from a randomized trial in Rakai,
Uganda. BJU Int 2009;104:529 –32.
28. Alfonso YN, Bishai D, Nantongo A, Kakembo R, Kobus-
inge S, Kacker S, et al. Trends in the marginal cost of
male circumcision in rural Rakai Uganda. J Acquir Im-
mune Defic Syndr 2017;7:564 –71.
29. Kigozi G, Musoke R, Watya S, Kighoma N, Nkale J, Na-
kafeero M, et al. The safety and acceptance of the
PrePex device for non-surgical adult male circumcision
in Rakai, Uganda. A non-randomized observational
study. PLoS One 9:e100008, 2014.
30. Kankaka EN, Murungi T, Kigozi G, Makumbi F, Nabu-
kalu D, Watya S, et al. Randomised trial of early infant

Clinical Chemistry 65:1 (2019) 17

Reflections
circumcision performed by clinical officers and regis-
tered nurse midwives using the Mogen clamp in Rakai,
Uganda. BJU Int 2017;119:164 –70.
31. Johnson KE, Redd AD, Quinn TC, Collinson-Streng AN,
Cornish T, Kong X, et al. Effects of HIV-1 and herpes
simplex virus type 2 infection on lymphocyte and den-
dritic cell density in adult foreskins from Rakai, Uganda.
J Infect Dis 2011;203:602–9.
18 Clinical Chemistry 65:1 (2019)
32. Johnson KE, Sherman M, Ssempijja V, Tobian AA, Ze-
nilman JM, Duggan MA, et al. Foreskin inflammation is
associated with HIV and HSV-2 infections in Rakai,
Uganda. AIDS 2009;23:1807–15.
33. Kigozi G, Wawer M, Ssettuba A, Kagaayi J, Nalugoda F,
Watya S, et al. Foreskin surface area and HIV acquisition in
Rakai, Uganda (size matters). AIDS 2009;23:2209 –13.
34. Hirbod T, Kong X, Kigozi G, Ndyanabo A, Serwadda D,
Prodger JL et al. HIV acquisition is associated with in-
creased antimicrobial peptides and reduced HIV neu-
tralizing IgA in the foreskin prepuce of uncircumcised
men. PLoS Pathog 2014;10:e1004416.
35. Liu CM, Prodger JL, Tobian AA, Serwadda D, Galiwango
RM, Nalugoda F, et al. Genital anaerobic bacterial over-
growth and the PrePex male circumcision device,
Rakai, Uganda. J Infect Dis 2016;214:595– 8.
Downloaded from https://academic.oup.com/clinchem/article-abstract/65/1/15/5607945 by guest on 15 June 2020