Commentary: Male circumcision for prevention of heterosexual acquisition of HIV in men: Perspective from a trial team

Abstract

The aim of the Column is to highlight Cochrane Reviews of relevance to public health, and to stimulate debate on relevance, feasibility and acceptability. This month, we feature the review assessing the effects of male circumcision on heterosexual transmission of HIV in men.

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COCHRANE COLUMN
Taryn Young
RYTD Consultancy, PO Box 38580, Pinelands 7430, South Africa. E-mail: tyoung@rytdconsult.co.za
The aim of the Column is to highlight Cochrane
Reviews of relevance to public health, and to stimu-
late debate on relevance, feasibility and acceptability.
This month, we feature the review assessing the
effects of male circumcision on heterosexual trans-
mission of HIV in men.
Male circumcision for preventing heterosexual
acquisition of HIV in men
Nandi Siegfried,* Martie Muller, Jon Deeks and James Volmink
*Corresponding author. South African Cochrane Centre, South African Medical Research Council, PO Box 19070, Tygerberg,
South Africa
Background
The Cochrane Collaboration (http://www.cochrane
.org) is an international, non-profit organization that
prepares and disseminates up-to-date systematic
reviews on the effects of health-care interventions in
order to help people make well-informed decisions.
Systematic reviews aim to answer focused health-care
questions by systematically identifying and evaluating
all relevant research studies and synthesizing their
results.
In 2003, a Cochrane review of 35 observational
studies investigating the effect of male circumcision
on HIV acquisition in heterosexual men concluded
that there was insufficient evidence of a protective
effect against HIV.
1
About that time, three rando-
mized controlled trials (RCTs) to assess the efficacy of
male circumcision for preventing HIV acquisition in
men started recruiting in Africa. This review evaluates
the results of these trials.
Methods
Search strategy
We searched for all relevant studies, regardless of
language or publication status in June 2007, including
MEDLINE, EMBASE and CENTRAL; conference data-
bases, NLM Gateway and AID Search; and trials
registries. We also checked reference lists and
contacted researchers in the field.
Selection criteria
RCTs of male circumcision vs no circumcision in HIV-
negative heterosexual men with HIV incidence as an
outcome were selected for inclusion.
Data collection and analysis
Two review authors independently assessed study
eligibility, extracted data and graded methodological
quality. Differences were resolved by a third author.
We considered the trials clinically homogeneous and
performed meta-analyses and sensitivity analyses.
Results
Three large RCTs that individually randomized men
from the general population were conducted in South
Africa (N¼3274),
2
Uganda (N¼4996)
3
and Kenya
(N¼2784)
4
between 2002 and 2006. All three trials
were stopped at interim analyses due to significant
findings. We combined the trial survival estimates at
12 months and at 21 or 24 months with a random
effects model using available case analyses.
The resultant incidence risk ratio (IRR) was 0.50
at 12 months with a 95% confidence interval (CI)
These summaries have been derived from Cochrane reviews published
in The Cochrane Database of Systematic Reviews in The Cochrane Library.
Their content has, as far as possible, been checked with the authors
of the original reviews, but the summaries should not be regarded as
an official product of The Cochrane Collaboration (www.cochrane.org).
Published by Oxford University Press on behalf of the International Epidemiological Associatio n
ßThe Author 2010; all rights reserved. Advance Access publication 12 July 2010
International Journal of Epidemiology 2010;39:968–972
doi:10.1093/ije/dyq108
968

of 0.34–0.72; and 0.46 at 21 or 24 months (95% CI
0.34–0.62) (Figure 1). This indicates that circumcision
results in a relative risk reduction of acquiring HIV of
50% at 12 months and 54% at 21 or 24 months. There
was little statistical heterogeneity between the trial
results (
2
¼0.60; df ¼2; P¼0.74 and 
2
¼0.31;
df ¼2; P¼0.86), respectively, quantified by the I
2
at
0% in both analyses. Sensitivity analyses using
reported IRRs, the reported per-protocol IRRs and
reported full intention-to-treat analysis did not
influence these estimates.
For secondary outcomes, the Kenyan and Ugandan
trials had data on sexual behaviour, and no differ-
ences were detected. For the South African trial,
the mean number of sexual contacts at the 12-month
visit was 5.9 in the circumcision group vs 5 in the
control group (P< 0.001). This remained statistically
significant at the 21-month visit (7.5 vs 6.4;
P¼0.0015). No other significant differences were
observed.
Incidence of adverse events following the
surgical circumcision procedure was low in all three
trials.
We judged the potential for biases affecting the
results to be low to moderate given the large sample
sizes, the balance of possible confounding variables at
baseline and the use of acceptable statistical early
stopping rules.
Conclusions
There is strong evidence that medical circumcision in
heterosexual men reduces HIV acquisition by 38–66%
over a 2-year period. Adverse events are uncommon
when conducted under sterile conditions. The trials
did not assess the effects of male circumcision on the
women partners of HIV-infected men. Future studies
should focus on feasibility, acceptability and cost-
effectiveness of incorporating circumcision into HIV
prevention programmes.
References
1
Siegfried N, Muller M, Deeks JJ, Volmink J. Male
circumcision for prevention of heterosexual acquisition
of HIV in men. Cochrane Database of Systematic Reviews
2009; Issue 2. Art. No.: CD003362. DOI: 10.1002/
14651858.CD003362.pub2.
2
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.
3
Gray RH, Kigozi G, Serwadda D et al. Male circumcision
for HIV prevention in men in Rakai, Uganda: a
randomised trial. Lancet 2007;369:657–66.
4
Bailey RC, Moses S, Parker CB et al. Male circumcision for
HIV prevention in young men in Kisumu, Kenya: a
randomised controlled trial. Lancet 2007;369:643–56.
Figure 1 Meta-analysis, calculated using an available case analysis, of circumcision vs no circumcision in general
population groups with the outcome of HIV incidence
COCHRANE COLUMN 969

Commentary: Male circumcision for prevention
of heterosexual acquisition of HIV in men:
perspective from a trial team
RH Gray,* A Tobian, G Kigozi, MJ Wawer and D Serwadda
*Corresponding author. Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA
A Cochrane review of three randomized trials of male
circumcision conducted in South Africa, Kenya and
Uganda estimated a 54% (95% confidence interval 38–
66) reduction of HIV acquisition in men.
1
The three
trials were all stopped early due to efficacy observed
at interim analyses;
2–4
and there was remarkable
homogeneity between trial results despite differences
in participant age, HIV incidence, surgical procedures
and urban–rural settings. Adult circumcision was
shown to be safe in all the three trials.
2–5
The trial
results are consistent with prior observational stu-
dies.
6
On the basis of this evidence in 2007, WHO/
UNAIDS recommended that male circumcision be
provided as an additional method of HIV prevention.
7
We conducted one of the trials in Rakai Uganda.
3
We were pleasantly surprised that, contrary to our
expectations, enrolment of participants was accom-
plished ahead of schedule, and men readily accepted
being randomized to immediate circumcision, or
circumcision delayed for 2 years. The rates of cross-
overs were lower than anticipated and retention was
higher than expected. The major difficulty encoun-
tered was delays in funding. We also conducted a
parallel trial of circumcision in HIV-infected men to
assess male-to-female HIV transmission. However,
this latter trial, funded by the Gates Foundation,
proved to be difficult and did not achieve its
recruitment goals. Nevertheless, because the Gates-
supported trial allowed enrollment and follow-up of
female partners, we have been able to assess the
effects of male circumcision on female sexually
transmitted infections (STIs), behaviours and sexual
satisfaction.
Although the Cochrane review only evaluated HIV
prevention, subsequent analyses of secondary end-
points from the trials have demonstrated the efficacy
of male circumcision for prevention of other STIs.
The South African and Ugandan trials have shown
that male circumcision is efficacious for prevention of
herpes simplex virus-type 2 and human papilloma-
virus in men.
8–10
The procedure also reduced male
genital ulcer disease.
3
Observational studies suggested that men circum-
cised in childhood were less likely to transmit HIV
to their female partners.
11
However, a randomized
trial of male circumcision of HIV-infected adults did
not show efficacy of circumcision for reduction of
male-to-female HIV transmission.
12
The discordance
between the observational studies and the trial may be
due to early resumption of intercourse before wound
healing, leading to increased female HIV infection.
However, male circumcision was shown to reduce
bacterial vaginosis in female partners,
13
and to reduce
the penile carriage of anaerobic bacteria, which have
been implicated in bacterial vaginosis.
14
Additionally,
female partners of circumcised men had lower rates of
Trichomonas vaginalis and less genital ulcer disease.
13
The utility of circumcision for HIV and STI preven-
tion will largely be felt in East and Southern Africa
where circumcision is uncommon and HIV incidence
is high. However, implementation of large circumci-
sion campaigns in Africa is a daunting task given the
weakness of the health infrastructure and skilled
manpower.
There has been debate about the possible role of
circumcision for prevention of HIV and STIs in the
USA. Centres for Disease Control consultation con-
cluded that there was insufficient evidence for HIV
prevention in men who have sex with men, but there
was sufficient evidence that circumcision provides
partial protection from HIV in heterosexual men and
recommended that parents be informed of potential
health benefits, and that financial barriers to neonatal
circumcision be removed.
15
References
1
Siegfried N, Muller M, Deeks JJ, Volmink J. Male
circumcision for prevention of heterosexual acquisition
of HIV in men. Cochrane Database of Systematic Reviews
2009; Issue 2. Art. No.: CD003362. DOI: 10.1002/
14651858.CD003362.pub2.
2
Bailey RC, Moses S, Parker CB et al. Male circumcision for
HIV prevention in young men in Kisumu, Kenya: a
randomised controlled trial. Lancet 2007;369:643–56.
3
Gray RH, Kigozi G, Serwadda D et al. Male circumcision
for HIV prevention in men in Rakai, Uganda: a
randomised trial. Lancet 2007;369:657–66.
4
Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J,
Sitta R, Puren A. Randomized, controlled intervention
970 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

trial of male circumcision for reduction of HIV infection
risk: the ANRS 1265 Trial. PLoS Med 2005;2:e298.
5
Kigozi G, Gray RH, Wawer MJ et al. The safety of adult
male circumcision in HIV-infected and uninfected men in
Rakai, Uganda. PLoS Med 2008;5:e116.
6
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.
7
UNAIDS. New Data on Male Circumcision and HIV Prevention:
Policy and Programme Implications. Montreux: UNAIDS,
2007.
8
Tobian AA, Serwadda D, Quinn TC et al. Male circumci-
sion for the prevention of HSV-2 and HPV infections and
syphilis. N Engl J Med 2009;360:1298–309.
9
Auvert B, Sobngwi-Tambekou J, Cutler E et al. 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 2009;199:14–19.
10
Sobngwi-Tambekou J, Taljaard D, Lissouba P et al.
Effect of HSV-2 serostatus on acquisition of HIV by
young men: results of a longitudinal study in Orange
Farm, South Africa. J Infect Dis 2009;199:958–64.
11
Gray RH, Kiwanuka N, Quinn TC et al. Male circumcision
and HIV acquisition and transmission: cohort studies
in Rakai, Uganda. Rakai Project Team. AIDS 2000;
14:2371–81.
12
Wawer MJ, Makumbi F, Kigozi G et al. Circumcision in
HIV-infected men and its effect on HIV transmission to
female partners in Rakai, Uganda: a randomised con-
trolled trial. Lancet 2009;374:229–37.
13
Gray RH, Kigozi G, Serwadda D et al. 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 2009;200:42 e1–7.
14
Price LB, Liu CM, Johnson KE et al. The effects of
circumcision on the penis microbiome. PLoS One
2010;5:e8422.
15
Smith DK, Taylor A, Kilmarx PH et al. Male circumcision
in the United States for the prevention of HIV infection
and other adverse health outcomes: report from a CDC
consultation. Pub Hlth Rep 2010;125(Suppl. 1):72–82.
Commentary: One snip doesn’t fit all
Elizabeth Pisani
Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
Removing a man’s foreskin reduces the chance that
he will become infected with HIV if he has sex with
an infected woman—the studies cited in the Cochrane
review and the commentary by Gray and colleagues
agree. Perhaps belatedly, a number of governments in
countries where HIV is hyperendemic among the men
and women in the general population are beginning
to agree too, and to support programmes offering
circumcision to large numbers of men.
HIV is also entrenched at hyperendemic levels
among gay men in wealthy countries (and it is
rapidly reaching those levels among gay men in some
developing countries, too). Once successful condom
promotion efforts are wilting in the face of boredom
and the virtual disappearance of AIDS in an era of
greatly improved treatment. Lower viral load at the
individual level does not appear to be translating into
fewer new infections among gay men.
1,2,3
This has led some to grasp for the only newish
prevention bullet we have, and to call for randomized
controlled trials of circumcision among men who
enjoy anal sex with other men.
4
The response is an
example of the tendency of public health workers to
privilege technology over culture. After all, if remov-
ing Langerhans cells and the anaerobic bacteria that
come with them reduces susceptibility to HIV, would
not it do that regardless of the orifice of exposure?
It is possible that the protection offered by
circumcision in vaginal sex may be reduced by the
more abrasive nature of anal sex. But there is another
important aspect in which sex between men differs
from sex between a man and a women: role switch-
ing. The loss of a foreskin is of no consequence in
determining the risk of a man who is the receptive
partner (or ‘bottom’) in anal sex. And since the
majority of sexually active gay men at least in most
Western countries sometimes act as the insertive (or
‘top’) and sometimes as the receptive partner in anal
sex, widespread circumcision of gay men is unlikely,
by itself, to have a sizeable effect on the acquisition
of HIV.
This common sense conclusion is supported by
recent publications. A re-analysis of data collected
from gay men during a vaccine trial found no pro-
tective effect of circumcision among 4889 gay men in
three countries.
5
No wonder: unprotected insertive
and receptive anal sex were so highly correlated in
this population that most men potentially protected
by circumcision when they were tops had also been
potentially exposed in the much higher risk bottom
position. There are some indications from cross-
sectional studies that circumcision may be protective
for men who confine themselves to the insertive role
in anal sex, especially where treatment is rare.
6,7
COCHRANE COLUMN 971

While logical, this is not confirmed in cohort studies
where treatment is common: Australian data show no
significant reduction in HIV incidence among the
small proportion of men who report only unprotected
insertive sex, with no unprotected anal sex, according
to circumcision status. The study shows that men
who say they prefer to be ‘tops’ in general terms are,
however, less likely to become infected if they are
circumcised (hazard ratio 0.19, P¼0.049).
8
Although public health officials flutter about the
dangers of ‘behavioural disinhibition’ if marginal
benefits of circumcision are made known, gay men
are way ahead of us.
4
The fact is, gay men already
choose from a menu of risk reduction options accord-
ing to partner, mood and other factors, in often quite
sophisticated ways. Men who believe they are unin-
fected and want to stay that way are already choosing
to have unprotected sex only when they are the inser-
tive partner—a practice known as strategic position-
ing. At least one cohort study shows this works well
at the individual level, leading to no added risk of
infection for the insertive partner compared with
those who report no unprotected anal sex at all.
9
If
existing cohort studies indicated that circumcision
cuts the risk for the top further still, that is a bonus
and we should make that known. But in cultures
where role-switching is the norm and men make risk
reduction decisions on a sex-act by sex-act basis,
and especially in countries such as the USA close to
80% of men are already circumcised,
10
the added
value of a large, expensive randomized controlled
trial of circumcision for gay men must surely be
questioned.
References
1
Davidovich U, de Wit JB, Albrecht N, Geskus R,
Stroebe W, Coutinho R. Increase in the share of steady
partners as a source of HIV infection: a 17-year
study of seroconversion among gay men. AIDS 2001;15:
1303–08.
2
Grulich AE, Kaldor JM. Trends in HIV incidence in homo-
sexual men in developed countries. Sex Health 2008;
5:113–18.
3
Stolte IG, Dukers NH, de Wit JB, Fennema JS,
Coutinho RA. Increase in sexually transmitted infections
among homosexual men in Amsterdam in relation to
HAART. Sex Transm Infect 2001;77:184–86.
4
Smith DK, Taylor A, Kilmarx PH et al. Male circumcision
in the United States for the prevention of HIV infection
and other adverse health outcomes: report from a
CDC consultation. Public Health Rep 2010;125
(Suppl. 1):72–82.
5
Gust DA, Wiegand RE, Kretsinger K et al. Circumcision
status and HIV infection among MSM: reanalysis
of a Phase III HIV vaccine clinical trial. AIDS 2010;24:
1135–43.
6
Lane T, Raymond HF, Dladla S et al. High HIV prevalence
among men who have sex with men in Soweto, South
Africa: results from the Soweto Men’s Study. AIDS Behav
n.d. doi:10.1007/s10461-009-9598-y [Epub ahead
of print].
7
Millett GA, Flores SA, Marks G, Reed JB, Herbst JH.
Circumcision status and risk of HIV and sexually
transmitted infections among men who have sex with
men: a meta-analysis. JAMA 2008;300:1674–84.
8
Templeton DJ, Jin F, Mao L et al. Circumcision and risk
of HIV infection in Australian homosexual men. AIDS
2009;23:2347–51.
9
Jin F, Crawford J, Prestage GP et al. Unprotected anal
intercourse, risk reduction behaviours, and subsequent
HIV infection in a cohort of homosexual men. AIDS
2009;23:243–52.
10
Xu F, Markowitz LE, Sternberg MR, Aral SO. Prevalence
of circumcision and herpes simplex virus type 2 infection
in men in the United States: the National Health and
Nutrition Examination Survey (NHANES), 1999–2004.
Sex Transm Dis 2007;34:479–484.
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