Male circumcision for prevention of homosexual acquisition of HIV in men

Male circumcision for prevention of homosexual acquisition of

HIV in men (Review)

Wiysonge CS, Kongnyuy EJ, Shey M, Muula AS, Navti OB, Akl EA, Lo YR

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 6

http://www.thecochranelibrary.com

Male circumcision for prevention of homosexual acquisition of HIV in men (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Male circumcision versus no male circumcision, Outcome 1 HIV infection (all MSM). . 40

Analysis 1.2. Comparison 1 Male circumcision versus no male circumcision, Outcome 2 HIV infection (by sexual

position). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Analysis 1.3. Comparison 1 Male circumcision versus no male circumcision, Outcome 3 Sexually transmitted infection. 44

44HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

45INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iMale circumcision for prevention of homosexual acquisition of HIV in men (Review)


[Intervention Review]

Male circumcision for prevention of homosexual acquisition ofHIV in men

Charles Shey Wiysonge1 , Eugene J Kongnyuy2, Muki Shey3, Adamson S Muula4, Osric B Navti5, Elie A Akl6, Ying-Ru Lo7

1School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. 2Child and Reproductive Health Group,

Liverpool School of Tropical Medicine, Liverpool, UK. 3Institute of Infectious Disease and Molecular Medicine (IIDMM), University

of Cape Town, Cape Town, South Africa. 4Department of Public Health; College of Medicine, University of Malawi, Blantyre,

Malawi. 5Directorate of Women’s, Perinatal and Sexual Health Services, University Hospitals of Leicester NHS Trust, Leicester, UK.6Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA. 7Department of HIV/AIDS, World Health

Organization, Geneva, Switzerland

Contact address: Charles Shey Wiysonge, School of Child and Adolescent Health, University of Cape Town, Institute of Infec-

tious Disease and Molecular Medicine, Anzio Road, Observatory, Cape Town, 7925, South Africa. [email protected].

[email protected].

Editorial group: Cochrane HIV/AIDS Group.

Publication status and date: New, published in Issue 6, 2011.

Review content assessed as up-to-date: 9 May 2011.

Citation: Wiysonge CS, Kongnyuy EJ, Shey M, Muula AS, Navti OB, Akl EA, Lo YR. Male circumcision for prevention of

homosexual acquisition of HIV in men. Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD007496. DOI:

10.1002/14651858.CD007496.pub2.


A B S T R A C T

Background

Previous systematic reviews found inconsistent effects of male circumcision on HIV acquisition in men who have sex with men (MSM).

However, a number of new studies have become available in the three years since the last systematic review.

Objectives

To assess the effects of male circumcision for preventing HIV acquisition by men through sex with men.

Search strategy

In June 2010 we electronically searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, AIDS Education

Global Information System, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform; hand-searched reference lists

of relevant articles; and contacted relevant organisations and experts. We updated the search in March 2011.

Selection criteria

We looked for randomised controlled trials (RCTs) and observational studies that assessed the effects of male circumcision on HIV

acquisition in MSM.

Data collection and analysis

Two authors independently assessed study eligibility and methodological quality, and extracted data. We expressed study results as odds

ratios (OR) with 95% confidence intervals (CI), and conducted random-effects meta-analysis.

1Male circumcision for prevention of homosexual acquisition of HIV in men (Review)


mailto:[email protected]

mailto:[email protected]

Main results

We found no completed RCT and included 21 observational studies with 71,693 participants. The only eligible RCT is currently

ongoing among MSM in China. The pooled effect estimate for HIV acquisition was not statistically significant (20 studies; 65,784

participants; OR 0.86, 95% CI 0.70 to 1.06) and showed significant heterogeneity (I²=53%). In a subgroup analysis, the results were

statistically significant in studies of men reporting an insertive role (7 studies, 3465 participants; OR 0.27, 95% CI 0.17 to 0.44; I²=

0%) but not in studies of men reporting a receptive role (3 studies, 1792 participants; OR 1.20, 95% CI 0.63 to 2.29; I² = 0%). There

was no significant association between male circumcision and syphilis (8 studies; 34,999 participants: OR 0.96, 95% CI 0.82 to 1.13;

I² = 0%), herpes simplex virus 1 (2 studies, 2740 participants; OR 0.90, 95% CI 0.53 to 1.52; I²=0%), or herpes simplex virus 2 (5

studies;10,285 participants; OR 0.86, 95% CI 0.62 to 1.21; I²=0%). The overall GRADE quality of evidence was low. None of the

included studies assessed adverse effects associated with male circumcision.

Authors’ conclusions

Current evidence suggests that male circumcision may be protective among MSM who practice primarily insertive anal sex, but the

role of male circumcision overall in the prevention of HIV and other sexually transmitted infections among MSM remains to be

determined. Therefore, there is not enough evidence to recommend male circumcision for HIV prevention among MSM at present.

Further research should be of high quality and further explore interaction with the predominant sexual role.

P L A I N L A N G U A G E S U M M A R Y

Male circumcision for prevention of homosexual acquisition of HIV in men

At present there is no completed randomised controlled trial that has assessed the effects of male circumcision on acquisition of HIV

and other sexually transmitted infections among men who have sex with men (MSM). Results from observational studies suggest that

circumcision may be protective among MSM who practice primarily insertive anal sex, but the role of male circumcision overall in the

prevention of HIV and other sexually transmitted infections among MSM remains to be determined.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Male circumcision for prevention of HIV and other STIs among men who have sex with men and transgender people

Patient or population: Men who have sex with men and transgender persons

Settings: High-income countries (16 studies), low and middle-income countries (5)

Intervention: Male circumcision

Comparison: No male circumcision

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Assumed risk Corresponding risk

No male circumcision Male circumcision

HIV infection (all studies to-

gether, regardless of sexual

role)

Lab test or self report

268 per 1000 239 per 1000

(204 to 280)

OR 0.86

(0.7 to 1.06)164915

(20 studies)

⊕⊕©©

low

HIV infection (mainly recep-

tive anal sex)

294 per 1000 333 per 1000

(208 to 488)

OR 1.20

(0.63 to 2.29)2876

(3 studies)

⊕©©©

very low3

HIV infection (mainly in-

sertive anal sex)

126 per 1000 37 per 1000

(24 to 60)

OR 0.27

(0.17 to 0.44)42098

(7 studies)

⊕⊕©©

low

Syphilis 13 per 1000 12 per 1000

(11 to 15)

OR 0.96

(0.82 to 1.13)

31174

(6 studies)

⊕⊕©©

low

Herpes simplex virus - 1 415 per 1000 390 per 1000

(273 to 519)

OR 0.90

(0.53 to 1.52)

2740

(2 studies)

⊕©©©

very low3

Herpes simplex virus - 2 178 per 1000 157 per 1000

(118 to 208)

OR 0.86

(0.62 to 1.21)

10285

(4 studies)

⊕©©©

very low3

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*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the

assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

1 Two studies (Reissen 2007 and Tabot 2002) reported the adjusted OR for the association between MC and HIV; with no corresponding

count data. The 2 studies had a total of 869 participants with complete data on MC and HIV status. The total number of participants is

therefore 65,784; and not 64,915.2 The Sanchez 2007 study (with 906 participants who self-identified as mainly receptive) reported the adjusted OR for the association

between MC and HIV; with no corresponding count data.The total number of participants is therefore 1,782; and not 876.3 Very small proportion of the 21 studies reported separate data for this outcome (possibility of publication bias); rated down by 1.4 The Sanchez 2007 study (with 1931 participants who self-identified as mainly insertive) reported the adjusted OR for the association

between MC and HIV; with no corresponding count data.The total number of participants is therefore 4,029; and not 2,098.

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B A C K G R O U N D

Male circumcision is the surgical removal of the foreskin of the

penis. Starting in the mid-1980s (Fink 1986), two decades of ob-

servational data indicated that circumcised heterosexual men have

lower incidence and prevalence of HIV infection than uncircum-

cised men (Fink 1986; Moses 1990; O’Farrell 2000; Weiss 2000;

Auvert 2001; Drain 2004; Baeten 2005). However, it was unclear

whether this observation is the result of a biological effect of male

circumcision, or due to cultural, social, or behavioural factors that

occur in association with or as a consequence of male circumci-

sion. Subsequently, three randomised controlled trials were set up

to examine the impact of adult male circumcision on HIV acqui-

sition in heterosexual men in South Africa (Auvert 2005), Kenya

(Bailey 2007), and Uganda (Gray 2007). A meta-analysis of all

three trials shows that medical adult male circumcision reduces the

acquisition of HIV by heterosexual men by 54% (95% confidence

intervals (CI): 38% to 66%) over 24 months (Siegfried 2009).

There are many concerns about the applicability of these results to

men who have sex with men (MSM) and male-to-female transexu-

als as well as their generalisability to other contexts. First, the HIV

epidemic in Africa occurs largely among heterosexuals, whereas

MSM remain the most affected risk group in other parts of the

World (Hall 2008; UNAIDS 2008; Le Vu 2010). Second, the

African data would be most relevant to MSM who only take the

insertive role during anal sex, because being the receptive partner

during anal sex would involve an HIV transmission route that

is likely to be unaffected by circumcision (Koblin 2006; Sullivan

2007). Third, the concentration of HIV in rectal secretions may be

greater than in vaginal secretions, which may increase HIV trans-

mission risk per act of unprotected insertive anal sex compared

with unprotected vaginal sex (Koblin 2006; Sullivan 2007).

Two systematic reviews published in 2008 (Fankem 2008; Millet

2008) pooled published and unpublished observational studies

and found insufficient evidence that male circumcision prevents

the acquisition of HIV or other sexually transmitted infections

(STIs) in MSM. However, more studies on the effect of male

circumcision on HIV transmission through anal sex have been

published since then (Templeton 2009; Thornton 2009; Gust

2010; Jameson 2010; McDaid 2010; Jozkowski 2010; Lane 2011;

Sanchez 2011).

O B J E C T I V E S

To assess the effects of male circumcision for preventing acquisition

of HIV by men through sex with men.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We preferentially looked for randomised controlled trials. Since

we did not find completed randomised controlled trials (RCTs)

or controlled clinical trials, we included observational studies i.e.

cohort, case-control, and cross-sectional studies.

Types of participants

Men who have sex with men.

Types of interventions

Intervention: Surgical removal of the foreskin of the penis as de-

termined by direct observation, objective medical records, self re-

port, or partner-report.

Comparison: No circumcision

Types of outcome measures

Primary outcome: HIV infection (incidence or prevalence), as

defined by the authors.

Secondary outcomes: Other sexually transmitted infections

(STIs) and adverse effects associated with circumcision, as defined

by the authors.

Search methods for identification of studies

See: Cochrane HIV/AIDS Review Group search strategy.

We attempted to identify all relevant studies regardless of language

or publication status. In June 2010 we electronically searched

PubMed (Table 1), EMBASE (Table 2), the Cochrane Central

Register of Controlled Trials (CENTRAL: Table 3), Clinical-

Trials.gov, and the WHO International Clinical Trials Registry

Platform (http://www.who.int/ictrp/search/en/) using terms spe-

cific to male circumcision, HIV, and MSM. We also conducted

an electronic search for conference abstracts in the GATEWAY

and the AIDS Education Global Information System (AEGIS:

www.aegis.com) databases, and the web sites of relevant scien-

tific conferences (i.e. International AIDS Conference, Interna-

tional AIDS Society Conference on HIV Pathogenesis and Treat-

ment, British HIV/AIDS Association, Conference on Retroviruses

and Opportunistic Infections, European AIDS Conference, HIV

Pathogenesis & Treatment, National HIV Prevention Conference,

and Australasian Society for HIV Medicine Conference). We re-

peated these electronic searches in March 2011.



Table 1. Search strategy for PubMed

Number Search terms Hits

#5 Search #1 AND #2 AND #3 Limits: Publication Date from

1980/01/01 to 2011/03/17

69

#4 Search #1 AND #2 AND #3 69

#3 Search homosexuality, male[mh] OR bisexual*[tiab] OR

gay*[tiab] OR transgender[tiab] OR MSM[tiab] OR ho-

mosexual*[tiab]

20787

#2 Search circumcision, male[mh] OR circumcis*[tiab] OR

uncircumcis*[tiab]

4774

#1 Search HIV Infections[MeSH] OR HIV[MeSH] OR

hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR

hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency

virus[tw] OR human immunedeficiency virus[tw] OR hu-

man immuno-deficiency virus[tw] OR human immune-de-

ficiency virus[tw] OR ((human immun*) AND (deficiency

virus[tw])) OR acquired immunodeficiency syndrome[tw]

OR acquired immunedeficiency syndrome[tw] OR acquired

immuno-deficiency syndrome[tw] OR acquired immune-

deficiency syndrome[tw] OR ((acquired immun*) AND

(deficiency syndrome[tw])) OR “sexually transmitted dis-

eases, viral”[MESH:NoExp]

269843

Table 2. Search strategy for EMBASE


#5 #1 AND #2 AND #3 AND [humans]/lim AND [embase]/

lim AND [1980-2011]/py

98

#4 #1 AND #2 AND #3 121

#3 ’homosexuality’/syn OR ’male homosexual’/syn OR homo-

sexual*:ab,ti OR bisexual*:ab,ti OR transgender*:ab,ti OR

transsexual*:ab,ti OR msm:ab,ti OR gay*:ab,ti

31975

#2 ’circumcision’/syn OR uncircumcis*:ab,ti OR circumcis*:

ab,ti

6312

#1 ’human immunodeficiency virus infection’/exp OR ’human

immunodeficiency virus infection’/de OR ’human immun-

odeficiency virus infection’ OR ’human immunodeficiency

virus’/exp OR ’human immunodeficiency virus’/de OR ’hu-

344053



http://www.ncbi.nlm.nih.gov/pubmed/advanced?querykey=6%26dbase=pubmed%26querytype=eSearch%26

http://www.ncbi.nlm.nih.gov/pubmed/advanced?cmd=HistorySearch%26querykey=6%26









Table 2. Search strategy for EMBASE (Continued)

man immunodeficiency virus’ OR hiv:ti OR hiv:ab OR ’hiv-

1’:ti OR ’hiv-1’:ab OR ’hiv-2’:ti OR ’hiv-2’:ab OR ’human

immunodeficiency virus’:ti OR ’human immunodeficiency

virus’:ab OR ’human immuno-deficiency virus’:ti OR ’hu-

man immuno-deficiency virus’:ab OR ’human immuned-

eficiency virus’:ti OR ’human immunedeficiency virus’:ab

OR ’human immune-deficiency virus’:ti OR ’human im-

mune-deficiency virus’:ab OR ’acquired immune-deficiency

syndrome’:ti OR ’acquired immune-deficiency syndrome’:

ab OR ’acquired immunedeficiency syndrome’:ti OR ’ac-

quired immunedeficiency syndrome’:ab OR ’acquired im-

munodeficiency syndrome’:ti OR ’acquired immunodefi-

ciency syndrome’:ab OR ’acquired immuno-deficiency syn-

drome’:ti OR ’acquired immuno-deficiency syndrome’:ab

Table 3. Search strategy for CENTRAL


#1 MeSH descriptor HIV Infections explode all trees 6413

#2 MeSH descriptor HIV explode all trees 2045

#3 hiv OR hiv-1* OR hiv-2* OR hiv1 OR hiv2 OR HIV

INFECT* OR HUMAN IMMUNODEFICIENCY

VIRUS OR HUMAN IMMUNEDEFICIENCY VIRUS

OR HUMAN IMMUNE-DEFICIENCY VIRUS

OR HUMAN IMMUNO-DEFICIENCY VIRUS

OR HUMAN IMMUN* DEFICIENCY VIRUS OR

ACQUIRED IMMUNODEFICIENCY SYNDROME

OR ACQUIRED IMMUNEDEFICIENCY

SYNDROME OR ACQUIRED IMMUNO-

DEFICIENCY SYNDROME OR ACQUIRED

IMMUNE-DEFICIENCY SYNDROME OR

ACQUIRED IMMUN* DEFICIENCY SYNDROME

9888

#4 MeSH descriptor Lymphoma, AIDS-Related, this term

only

21

#5 MeSH descriptor Sexually Transmitted Diseases, Viral,

this term only

19

#6 (#1 OR #2 OR #3 OR #4 OR #5) 9976

#7 MeSH descriptor Circumcision, Male, this term only 179

#8 circumcis*:ti,ab,kw OR uncircumcis*:ti,ab,kw 251



http://onlinelibrary.wiley.com/o/cochrane/searchHistory?mode=runquery%26amp;qnum=1













































































































Table 3. Search strategy for CENTRAL (Continued)

#9 (#7 OR #8) 251

#10 MeSH descriptor Homosexuality, Male, this term only 139

#11 MeSH descriptor Bisexuality, this term only 33

#12 homosexual*:ti,ab,kw OR bisexual*:ti,ab,kw OR

gay*:ti,ab,kw OR transgender*:ti,ab,kw OR msm:ti,ab,kw

469

#13 (#10 OR #11 OR #12) 469

#14 (#6 AND #9 AND #13) 3

#15 (#6 AND #9 AND #13), from 1980 to 2011 3

We complemented the electronic search by hand searching the

reference lists of identified articles and relevant previous reviews

(Fankem 2008; Millet 2008; Templeton 2010). We identified pre-

vious reviews of male circumcision for prevention of HIV acqui-

sition in MSM by searching PubMed, EMBASE, the Cochrane

Database of Systematic Reviews, and the York Database of Ab-

stracts of Reviews of Effectiveness (DARE). In addition, we con-

sulted the WHO Department of HIV/AIDS in Geneva and mem-

bers of the WHO MSM guideline development working group,

and presented the findings of an earlier version of this review to

experts attending the WHO meeting on “Development of Guid-

ance for the Prevention and Treatment of HIV and other Sexu-

ally Transmitted Infections among Men having Sex with Men and

Transgender People” in September 2010 in Beijing, China.

The Cochrane HIV/AIDS Group assisted with the electronic

search.

Data collection and analysis

Each of four review authors (CSW, EJK, MS, OBN) indepen-

dently screened the titles, abstracts and descriptor terms of cita-

tions identified by the searches for potential eligibility. We then

obtained full articles for citations judged as potentially eligible by

at least one author. The authors screened in duplicate and inde-

pendently the full texts for eligibility based on types of partic-

ipants, exposures, and outcome measures. The authors resolved

disagreements by discussion and consensus.

For each included study, two authors (CSW, MS) conducted dupli-

cate and independent extraction of data on study methods (study

design and time period), participant characteristics (sample size,

location, population demographics, and risk characteristics), in-

terventions (method for assessing circumcision status, and preva-

lence of circumcision), outcomes (HIV or STI incidence or preva-

lence, measures of effect and their 95% CI, adverse effects, and

methods used to diagnose HIV infection), and other notes. The

two authors (CSW, MS) then assessed the possibility of bias in

included studies by evaluating the adequacy of the methods used

to ascertain circumcision status and outcomes, the handling of

confounding, and the completeness of outcome data. The authors

resolved disagreements by discussion and consensus.

We calculated the natural logarithm of the odds ratio and its stan-

dard error for each study. We then expressed each study result as

an odds ratio (OR) with its 95% CI using inverse variance. We

examined statistical heterogeneity between studies using the chi-

square test of homogeneity and the Higgins I2 statistic (Higgins

2003). Due to the variation in study designs (i.e. cohort, case-con-

trol, and cross-sectional), we decided to combine the study results

using the random-effects method; irrespective of whether there

was significant statistical heterogeneity or not. We conducted a

subgroup analysis to explore the cause of significant statistical het-

erogeneity in study results, with subgroups defined by predomi-

nant role during sexual intercourse.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

The search yielded 320 records, 56 of which were judged to be

potentially eligible by at least one reviewer. Following independent

duplicate screening of the full-text of each of the potentially eligible















































records, we included 21 primary studies which were reported in

30 separate publications. Among the other 26 potentially eligible

records is an ongoing RCT being conducted among MSM in 8

cities in China by the National Center for AIDS/STD Control and

Prevention, China CDC (MSM Trial 2010). We provide a more

detailed describtion of this study in the table of Characteristics of

ongoing studies.

The 21 included studies with a total of 71,693 participants are

all observational: 6 cohort (Buchbinder 2005; Bartholow 2006;

Buchbinder 2007; Templeton 2009; Gust 2010; Jameson 2010),

1 case-control (Calzavara 2007), and 14 cross-sectional (Kreiss

1993; Reid 2001; Kumta 2002; Tabet 2002; Lai 2004; Millett

2007 (Black); Millet 2007 (Latino); Mor 2007; Reisen 2007;

Sanchez 2007; Xu 2007; Begley 2008; McDaid 2010; Lane 2011)

studies. One study (Mor 2007) reported STI data separately for

HIV-positive (Mor 2007 (HIV-pos)) and HIV-negative partici-

pants (Mor 2007 (HIV-neg)), and the latter are treated as sepa-

rate studies in the STI meta-analyses. Another study (Templeton

2009) reported STI data separately for the baseline and prospec-

tive components of the study (Templeton 2009 (CS); Templeton

2009 (P)) respectively; and these are also treated as separate studies

in the analyses. A detailed description of each included study is

provided in the table of Characteristics of included studies.

Each of the remainining 25 records (Beyrer 2010; Botros 2009;

Coplan 1996; Dandona 2008; Fankem 2008; Farr 2010; Grulich

2001; Jewkes 2006; Jin 2010; Jozkowski 2010; Kloos 2007;

Lafferty 1997; Lau 2010; MacDonald 2008; McKinney 2008;

Millet 2008; Perisse 2009; Sanchez 2011; Smith 2010; Sullivan

2007; Templeton 2010; Thornton 2009; Vermund 2008; Wei

2010) was excluded either because the (primary) study does not

report analysable data or because it is a review article, view point

or editorial with no relevant primary data. We provide detailed

reasons for excluding each of these publications in the table of

Characteristics of excluded studies.

Risk of bias in included studies

All the included studies, as indicated earlier, were observational in

nature. In six studies, circumcision status was assessed by genital

examination while in the remaining 15 it was assessed by self-

report. We judged the ascertainment of outcomes in 18 studies

to be adequate because the HIV or STI status was determined

by appropriate laboratory diagnostic tests; and we presume that

the laboratory technicians did not know the circumcision status

of the participants. Ascertainment of outcomes in the remaining

three studies was judged to be inadequate because HIV status

was assessed by self-report. Attrition and exclusions from analyses

were minimal and we, therefore, judged that incomplete outcome

data were adequately addressed by all studies. However, given the

observational nature of the studies there might be other factors

that confound the relationship between male circumcision and

HIV. We therefore agreed that none of the studies was free of other

sources of bias.

We provide a summary of the methodological quality for the in-

cluded studies in Figure 1 and Figure 2.

Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Effects of interventions

See: Summary of findings for the main comparison Male

circumcision for prevention of HIV and other STIs among men

who have sex with men and transgender people

HIV infection

The main analysis found no significant association between male

circumcision status and HIV infection in men who have sex with

men (Analysis 1.1: 20 studies with 65,784 participants; OR 0.86,

95% CI 0.70 to 1.06). However, there was significant statistical

heterogeneity in study results (P = 0.003, I² = 53%).

The inconsistency in study results seemed to be explained by sexual

roles during anal sex (Analysis 1.2). There was a statistically sig-

nificant decrease in HIV infection in studies of circumcised men

who reported a predominantly or exclusively insertive role during

anal sex: 7 studies with 3465 participants (Calzavara 2007; Reisen

2007; Sanchez 2007; Templeton 2009; Jameson 2010; McDaid

2010; Lane 2011) (OR 0.27, 95% CI 0.17 to 0.44; I² = 0%). In

contrast, there was no statistically significant association between

male circumcision status and HIV infection in studies of men who

reported mainly a receptive role during anal sex (3 studies with

1792 participants; OR 1.20, 95% CI 0.63 to 2.29; I² = 0%), and

in studies in which the differentiation between men who reported

insertive versus receptive role was not clear or was not done (17

studies, 64,538 participants; OR 1.00, 95% CI 0.92 to 1.09; (P

= 0.90); I² = 0%).

Other sexually transmitted infections

There was no significant association (Analysis 1.3) between male

circumcision and acquisition of syphilis (8 studies; 34,999 partic-

ipants: OR 0.96, 95% CI 0.82 to 1.13; Chi² = 2.54, df = 7 (P

= 0.92); I² = 0%), herpes simplex virus 1 (2 studies, 2740 par-

ticipants; OR 0.90, 95% CI 0.53 to 1.52; Chi² = 0.11, df = 1

(P = 0.74); I² = 0%), or herpes simplex virus 2 (5 studies;10,285

participants; OR 0.86, 95% CI 0.62 to 1.21; Chi² = 0.48, df = 4

(P = 0.98); I² = 0%).

Adverse effects associated with circumcision

None of the included studies reported this outcome.

D I S C U S S I O N

Summary of main results

Current evidence suggests that male circumcision may be protec-

tive among MSM who practice primarily insertive anal sex, but

the role of male circumcision overall in the prevention of HIV and

other sexually transmitted infections among MSM remains to be

determined. Adverse effects of male circumcision have not been

studied among MSM but potentially include risk compensation,

surgical complications, pain, and stigma (if circumcision is offered

only to MSM).

Overall completeness and applicability ofevidence

The strength of this systematic review lies in the large number of

study participants and our adherence to the standardised guide-

lines on the conduct and reporting of systematic reviews (Higgins

2011; Moher 2009). However, there are limitations to our finding

that male circumcision conferred significant benefit among men

who primarily or exclusively practised insertive anal sex including

the low quality of data in the studies and the observational rather

than experimental nature of the studies. In addition, most MSM

who become infected are likely infected through receptive rather

than insertive anal sex so the impact of circumcision in this pop-

ulation may not be substantial. Furthermore, circumcision status

and predominant role during sexual intercourse were self-reported

by study participants. To the effect that these were mis-reported,

the findings from the individual studies could be biased. However,

Templeton and colleagues have found self-report to be a valid mea-

sure of circumcision status in a group of predominantly Anglo gay-

community-attached men in Sydney, Australia (Templeton 2008).

RCTs are the “gold standard” for testing the effects of an interven-

tion, but there are several concerns with conducting RCTs to assess

the effects of male circumcision on HIV acquisition in MSM. First,

the only subgroup of MSM who would plausibly gain benefit are

the “insertive” MSM (as shown in our subgroup analysis). Second,

most MSM are “versatile” and there are some studies suggesting

that a minority of MSM predominantly practice the insertive role

(Calzavara 2007; Reisen 2007; Sanchez 2007; Templeton 2009;

Jameson 2010; McDaid 2010; Lane 2011). Thus, huge numbers

of participants with low baseline circumcision prevalence and high

incidence of HIV would be needed for an adequately powered

RCT to answer this question definitely. Despite these difficulties,

we have found a registered ongoing RCT being conducted among

MSM in 8 cities in China.

There are also significant concerns with the feasibility of imple-

menting adult male circumcision among men who have sex with

men. First, significant resources are needed for introduction of

the surgical services in settings where male circumcision is not a

standard intervention. Second, there are concerns about discrim-



ination and stigma within an already stigmatised population such

as men who have sex with men.

Protective benefits of male circumcision could be weakened by

risk compensation i.e. increases in unsafe sexual behaviour such as

non-use of condoms and multiple concurrent sex partners, sparked

by decreases in perceived risk (Cassell 2006). In addition, having

sex shortly after circumcision (during the wound healing process)

could increase the risk of HIV infection. These risks are not limited

to men who have sex with men, but are potential adverse effects

associated with male circumcision.

Quality of the evidence

In making healthcare decisions, policymakers, patients and clini-

cians should be influenced not only by the best estimates of the ex-

pected advantages and disadvantages of alternative strategies, but

also by their confidence in these estimates i.e. the quality of the

evidence. We used the GRADE system (Guyatt 2011) to assess

quality of evidence. GRADE provides a structured and transpar-

ent system for making judgements about the quality of evidence.

Overall, the quality of the available evidence on the effect of male

circumcision on HIV or STI acquisition in men who have sex

with men is low; as shown in Summary of findings for the main

comparison. The implication of the low quality of the evidence

is that further research (especially randomised controlled trials)

on this topic is very likely to have an important impact on our

confidence in the estimate of effect and is likely to change the

pooled odd ratios found in this review.

The subgroup effect meets some but not all of the methodological

criteria for believability (Sun 2010). It is plausible, consistent, and

is the only one that we hypothesised and explored. However, the

effect is suggested by a comparison between rather than within

studies, and we do not have a formal interaction test for the sub-

group effect.

Potential biases in the review process

We minimised bias in the process of conducting and reporting the

current review by adhering to standardised international guidelines

(Higgins 2011; Moher 2009).

Agreements and disagreements with otherstudies or reviews

The most comprehensive previous systematic review was published

by Millett and colleagues in 2008 (Millet 2008). These authors

pooled the published and unpublished observational studies avail-

able by February 2008 and found insufficient evidence that male

circumcision prevents acquisition of HIV or other sexually trans-

mitted infections in men who have sex with men. Our findings

are consistent with theirs. However, our systematic review has the

added advantage of subgroup analysis by sexual positioning dur-

ing anal sex and inclusion of more recent data.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Subgroup analysis suggests that male circumcision may be more

effective among MSM with mainly an insertive role in anal sex,

but the overall role of male circumcision in the prevention of HIV

and other sexually transmitted infections among MSM remains

to be determined. Therefore, there is not enough evidence to rec-

ommend male circumcision for HIV prevention among men who

have sex with men at present. However, in settings where adult

male circumcision is being scaled up, men who have sex with men

should not be excluded from the circumcision programmes. In

other settings, individual men who have sex with men who request

circumcision should not be denied this intervention.

Implications for research

Further research (especially RCTs) is needed to examine the ef-

fect of adult male circumcision for prevention of HIV and STI

acquisition among men who have sex with men. Such studies will

better inform if they include data on the predominant role (in-

sertive or receptive) during sexual intercourse. Further disaggre-

gation regarding the various groups of MSM (e.g. bisexual, exclu-

sively MSM) may be valuable. However, there are several concerns

with conducting RCTs to assess the effects of male circumcision on

HIV acquisition in MSM. First, the only subgroup of MSM who

would plausibly gain benefit are the “insertive” MSM. Second,

most MSM are “versatile” and there are some studies suggesting

that a minority of MSM predominantly practice the insertive role.

Thus, huge numbers of participants with low baseline circumci-

sion prevalence and high incidence of HIV would be needed for

an adequately powered RCT to answer this question definitely.

A C K N O W L E D G E M E N T S

We gratefully acknowledge the support obtained from the HIV/

AIDS Department at WHO Headquarters and the contribution

of the Cochrane HIV/AIDS Group editorial base in the comple-

tion of this review. In addition, we are grateful to four enthusi-

astic anonymous referees who reviewed an earlier version of the

manuscript and provided very useful comments and suggestions.



R E F E R E N C E S

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O’Farrell 2000

O’Farrell N, Egger M. Circumcision in men and the

prevention of HIV infection: a ’meta-analysis’ revisited. IntJ STD & AIDS 2000;11:137–142.

Siegfried 2009

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.

Sun 2010

Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect

believable? Updating criteria to evaluate the credibility of

subgroup analyses. BMJ 2010;340:c117.

Templeton 2008

Templeton DJ, Mao L, Prestage GP, Jin F, Kaldor JM,

Grulich AE. Self-report is a valid measure of circumcision

status in homosexual men. Sex Transm Infect 2008;84:

187–88.

UNAIDS 2008

UNAIDS. Report on the global AIDS epidemic-2008.

Geneva: Joint United Nations Programme on HIV/AIDS,

2008.

Weiss 2000

Weiss HA, Quigley MA, Hayes RJ. Male circumcision and

risk of HIV infection in sub-Saharan Africa: a systematic

review and meta-analysis. AIDS 2000;14:2361–2370.∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Bartholow 2006

Methods Prospective study.

Duration of enrolment: June 1998 to November 1999.

Participants 5,095 HIV-seronegative MSM, 18 to 60 years of age. enrolled in a 36-month phase 3

HIV vaccine efficacy trial (VAX004 trial) across 61 sites primarily in North America and

Europe.

Whites 86%, Hispanic 6%, Black 4%, Asian 2%, Other 2%. High school 37%, college

graduate 42%, graduate degree 22%.

Interventions Male circumcision status assessed by self-report. 4381(86%) men were circumcised.

Outcomes HIV status established by ELISA test and confirmed using immunoblot kits.

Notes The VAX004 trial was a randomised, double-blind, placebo-controlled efficacy trial of a

bivalent rgp120 HIV-1 subtype B vaccine and was conducted at 61 sites in the United

States (n = 57), Canada (n = 3), and The Netherlands (n = 1).

Risk of bias

Bias Authors’ judgement Support for judgement

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk Male circumcision status assessed by self-

report

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk HIV status was determined by appropriate

diagnostic tests, and we presume the lab-

oratory technicians did not know the cir-

cumcision status of the participants.

Incomplete outcome data (attrition bias)

All outcomes

Low risk The authors report findings on 5090

(99.9%) participants.

Other bias Unclear risk Given the nature of the study there might

be other factors that confound the relation-

ship between male circumcision and HIV.



Begley 2008

Methods Cross-sectional study.

Duration of enrolment: June to October 2006.

Participants 780 HIV-positive who were interviewed at 7 Gay Pride events in 2006 in 7 US cities

(170 at minority Gay Pride events in Chicago, IL, Charlotte, NC, and St. Louis, MO,

and 609 at Gay Pride events in Birmingham, AL, Anchorage, AK, Raleigh-Durham,

NC, and Springdale, UT)

Of the 780, 43 were Hispanic, 198 non-Hispanic Black, 436 non-Hispanic White, and

103 others.

Interventions Male circumcision status assessed by self-report. 667 (86%) men were circumcised.

Outcomes HIV status assessed by self-report

Notes 914 men met definition of MSM. Authors excluded 100 respondents because they were

HIV-positive; an additional 31 respondents were excluded due to missing demographic or

risk characteristics. The authors report findings on 780 (75%) eligible survey respondents

who met their definition of MSM, who were not HIV-positive by self-report, and who

provided complete survey data. 83% circumcised.

Risk of bias



(performance bias)

All outcomes

Unclear risk Male circumcision status assessed by self-

report


bias)

All outcomes

Unclear risk HIV status assessed by self-report


All outcomes

Low risk The authors report findings on all 780

(75%) eligible survey respondents who met

their definition of MSM, who self-iden-

tified as HIV-negative by self-report, and

who provided complete survey data.






Buchbinder 2005

Methods Prospective study

Duration of enrolment: April 1995 and May 1997.

Participants 3257 MSM from the HIV Network for Prevention Trials (HIVNET), conducted in six

US cities: Boston, Chicago, Denver, New York, San Francisco and Seattle. 65% aged

more than 35 years.

White 76%, Latino 12%, Black 7%, other 5%

Interventions Circumcision was assessed by self-report. 2866(88%) men were circumcised.

Outcomes HIV status established by antibody test (tests not specified)

Notes

Risk of bias



(performance bias)

All outcomes

Unclear risk Circumcision was assessed by self-report.


bias)

All outcomes






All outcomes

Low risk Study authors report data on all 3257 par-

ticipants.




Buchbinder 2007


Duration of enrolment: December 2004 to March 2007

Participants 1836 MSM from the STEP Trial, conducted in the US (14 cities), Puerto Rico (1 city)

, Peru (3 cities), Jamaica (1 city), Haiti (1 city), Dominican Republic (2 cities), Canada

(3 cities), Brazil (3 cities), Australia (1 city).

White 50%, multiracial 25%, Latino 10%, Black 10%, other 6%.

Interventions Circumcision status was assessed by self-report. 999(56%) men were circumcised.

Outcomes HIV status established by antibody test (tests not specified)



Buchbinder 2007 (Continued)

Notes

Risk of bias



(performance bias)

All outcomes

Unclear risk Circumcision status was assessed by self-

report.


bias)

All outcomes






All outcomes

Low risk Study authors report data on 1787 (97%)

participants.




Calzavara 2007

Methods Case-control study

Duration of enrolment: 2001 to 2005.

Participants 165 MSM enrolled in the Polaris cohort in Ontario, Canada. Participants in this study

are recruited through Ontario’s HIV diagnostic testing database, physicians, community

organizations and media.

White 85%, Latino 4%, Native American 2%, other 9%

Interventions Circumcision status was assessed by self-report. 11(73%) men were circumcised.

Outcomes HIV status established by diagnostic test (tests not specified).

Notes

Risk of bias



(performance bias)

All outcomes




Calzavara 2007 (Continued)


bias)

All outcomes






All outcomes

Low risk Study authors report data on all 165 par-

ticipants.




Gust 2010

Methods Prospective study

Duration of enrolment: June 1998 to October 1999.

Participants 4,889 MSM (median age 36.8 years) who participated in the VAXGen VAX004 HIV

vaccine clinical trial, which was conducted in 61 sites primarily in North America and

Europe.

Whites 86%, Hispanic 6%, Black 4%, Asian 2%, Other 2%. High school 37%, college

graduate 42%, graduate degree 22%.


Outcomes HIV status established by ELISA test and confirmed using immunoblot kits.

Notes The VaxGen VAX004 was a randomized, double-blind, placebo-controlled efficacy trial

of an HIV vaccine (bivalent rgp120 HIV-1 subtype B). It was carried out at 61 sites (US:

n=57, Canada: n=3; The Netherlands: n=1).

Risk of bias



(performance bias)

All outcomes



bias)

All outcomes






All outcomes

Low risk A total of 5417 participants enrolled in the

study. Removed from the analysis were 309

women, 13 men who were indicated by



Gust 2010 (Continued)

nucleic acid testing to be HIV-infected at

baseline, 1 participant who reported a sex

change, and 5 whose circumcision status

changed during the study. The final num-

ber of participants for this analysis, which

excluded 200 participants who only at-

tended the baseline visit, was 4889. Of

participants in the analysis, 80.2% (3921/

4889) were recorded as completing the

study.




Jameson 2010


Duration of enrolment: October 2001 to May 2006.

Participants 3,828 MSM attending the Public Health-Seattle and King County STD clinic, who

reported anal intercourse in the previous 12 months. 75.7% older than 25 years.

Whites 74.5%, Hispanic 7.9%, Black 6.5%, Asian and Pacific Islander 5.4%, Other

4.8%.

Interventions Clinicians determined circumcision status by examination. 3241(85%) men were cir-

cumcised.

Outcomes HIV status established by ELISA test and confirmed using independently-validated,

quantitative,

real-time polymerase chain reaction assay.

Notes

Risk of bias



(performance bias)

All outcomes

Low risk Circumcision was assessed by clinical ex-

amination.


bias)

All outcomes







Jameson 2010 (Continued)


All outcomes

Low risk Of 4,749 men who visited the clinic during

the study, circumcision status was not as-

sessed or was inconsistently noted for 729

men (15%), and anal sexual repertoire was

incomplete for an additional 192 men (4%)

; the authors excluded these men from fur-

ther analysis. Participants whose circumci-

sion status was not noted were similar to

those whose status was noted .




Kreiss 1993


Duration of enrolment: April 1989 and March 1991.

Participants Men, 17 to 64 years old, reporting a history of homosexual behaviour and attending

any of two AIDS clinic or AIDS Prevention Project (in Seattle, Washington, USA) were

included. 503 men enrolled into the study, (316 HIV-seropositive and 186 seronegative)

. Final analysis included 499 men (97%). 4% Hispanic, 4% non-Hispanic Black, 90%

white, 1% others.

Interventions Circumcision status assessed by self-report. 442(85%) men were circumcised.

Outcomes HIV status established by ELISA test and confirmed by Western Blot or immunofluo-

rescent assays.

Sexually transmitted infections assessed by self-report.

Notes

Risk of bias



(performance bias)

All outcomes


report.


bias)

All outcomes






All outcomes

Low risk Final analysis included 499 men (97%).



Kreiss 1993 (Continued)




Kumta 2002


Duration of enrolment: March 2001 to July 2002

Participants 122 MSM in Mumbia, India. Ethnicity not reported.

Interventions Male circumcision status assessed by genital examination. 27(22%) men were circum-

cised.

Outcomes HIV status assessed by laboratory test.

Notes This is one of the few studies conducted in a low or middle-income country. 22%

circumcised

Risk of bias



(performance bias)

All outcomes

Low risk Circumcision status was assessed by clinical

examination.


bias)

All outcomes






All outcomes

Low risk Information obtained from all study par-

ticipants.




Lai 2004


Study conducted in 2003.

Participants 556 MSM in Taipei, Taiwan. Ethnicity not reported.




Lai 2004 (Continued)

Outcomes HIV status assessed by laboratory test.

Notes 28% circumcised.

Risk of bias



(performance bias)

All outcomes


report.


bias)

All outcomes






All outcomes


ticipants.




Lane 2011


Duration of enrolment: 30 weeks in 2008.

Participants 378 MSM from Soweto, South Africa, were recruited via respondent-driven sampling.

Black 100%, 19% post-secondary education.


Outcomes HIV status was determined though rapid antibody testing.

Notes

Risk of bias



(performance bias)

All outcomes


report.



Lane 2011 (Continued)


bias)

All outcomes

Low risk HIV status was determined by an appropri-

ate diagnostic test, and we presume the lab-




All outcomes


ticipants.




McDaid 2010


Participants were recruited in 2008.

Participants 1,405 MSM who participated in the 2008 MRC Gay Men’s Survey in Glasgow and

Edinburgh (Scotalnd).


Outcomes Oral fluid specimens were screened for anti-HIV antibodies using an enzyme immunoas-

say; positives re-screened, and repeat reactives confirmed using western blot.

Notes

Risk of bias



(performance bias)

All outcomes


report.


bias)

All outcomes






All outcomes

Low risk 1,508 men completed questionnaires

(70.5% response rate) and 1277 provided

oral fluid samples (59.7% response rate).

Overall, 1405 (93.2%) men were eligible

for inclusion in the analyses.



McDaid 2010 (Continued)




Millet 2007 (Latino)


Duration of enrolment: May 2005 to April 2006.

Participants 1,091 Latino MSM were recruited from 3 US cities (New York City, Philadelphia, and

Los Angeles) using respondent-driven sampling.

100% Latino, median age 33.1 years.


Outcomes Participants were tested for HIV antibodies using a rapid oral fluid HIV antibody test.

Notes

Risk of bias



(performance bias)

All outcomes


report.


bias)

All outcomes






All outcomes

Low risk Data available on 957 (87.7%) participants

and missing data not related to intervention

or outcome.






Millett 2007 (Black)


Duration of enrolment: May 2005 and April 2006.

Participants 1,154 Black MSM were recruited from 3 US cities (New York City, Philadelphia, and

Los Angeles) using respondent-driven sampling.

100% Black, median age 42.5 years.


Outcomes Participants were tested for HIV antibodies using a rapid oral fluid HIV antibody test.

Notes

Risk of bias



(performance bias)

All outcomes


report.


bias)

All outcomes






All outcomes

Low risk Data available on 1,079 (93.5%) partici-

pants and missing data not related to inter-

vention or outcome.




Mor 2007


Duration of enrolment: January 1996 to December 2005.

Participants 20,832 MSM attending the San Francisco municipal STD clinic, California, USA. 7%

non-Hispanic Blak, 10% Asian/Pacific Islander, 16% Hispanic, 66% White.

Interventions Male circumcision status assessed by genital examination. 15,207(73%) men were cir-

cumcised.

Outcomes HIV status assessed by laboratory test. STI status assessed by laboratory test.




Mor 2007 (Continued)

Risk of bias



(performance bias)

All outcomes


examination


bias)

All outcomes






All outcomes

Low risk Information obtained from all participants.




Mor 2007 (HIV-neg)






cumcised.



Risk of bias



(performance bias)

All outcomes


amination.


bias)

All outcomes







Mor 2007 (HIV-neg) (Continued)


All outcomes





Mor 2007 (HIV-pos)






cumcised.



Risk of bias



(performance bias)

All outcomes


amination.


bias)

All outcomes






All outcomes







Reid 2001


Duration of enrolment: May 2001 to September 2001.

Participants 13,851 MSM who participated in Vital Statistics 2001 (i.e. the 5th annual national Gay

Men’s Sex Survey in England and Wales). 1% Blak, 2% mixed race, 3% Asian, 93%

White.


Outcomes HIV status assessed by self-report.


Risk of bias



(performance bias)

All outcomes


report.


bias)

All outcomes

Unclear risk HIV status assessed by self-report.


All outcomes





Reisen 2007


Duration of enrolment: Not stated.

Participants 482 immigrant Latino MSM living in the New York Metropolitan Area.

Interventions Male circumcision status assessed by self-report. About 120 (25%) men were circumcised.

Outcomes HIV status assessed by self-report.

Notes Brazilians = 146, Colombians = 169, Dominicans = 167.

Risk of bias




Reisen 2007 (Continued)


(performance bias)

All outcomes


report.


bias)

All outcomes

Unclear risk HIV status was determined by self-report.


All outcomes





Sanchez 2007


Duration of enrolment: February 2006 and June 2006.

Participants 2,884 MSM recruited from Peru (3 cities) and Ecuador (1 city). Ethnicity not reported..

Interventions Male circumcision status assessed by genital examination. 123(4%) men were circum-

cised.

Outcomes HIV status assessed by means of enzyme immunoassay and confirmed by Western blot.

Notes

Risk of bias



(performance bias)

All outcomes

Low risk Circumcision status was assessed by self-

report.


bias)

All outcomes






All outcomes







Tabet 2002


Study conducted in 1996.

Participants 442 MSM (over 17 years of age) recruited in Lima, Peru. Ethnicity not reported.

Interventions Male circumcision status assessed by genital examination. 36(8%) men were circumcised

men.

Outcomes Antibodies to HIV were detected by ELISA and repeatedly reactive sera were confirmed

using Western blot.

Notes

Risk of bias



(performance bias)

All outcomes


examination.


bias)

All outcomes






All outcomes

Low risk Complete information available for 440

(99.5%) participants.




Templeton 2009


Duration of enrolment: 2001 through 2004

Participants 1,426 HIV-negative MSM recruited from community-based sources into the Health in

Men (HIM) study in Sydney, Australia. Median age at enrolment was 35 years (range

18-75 years), 68% Australian-born and 74% of Anglo ethnicity.

Interventions Circumcision status was reported at baseline and self-reported circumcision status was

validated by clinical examination in a subgroup of 240 consecutively presenting partici-

pants. 938(66%) men were circumcised.

Outcomes Participants were tested annually for HIV with western blot confirmation.



Templeton 2009 (Continued)

Notes Study participants followed up until mid-2007.

Risk of bias



(performance bias)

All outcomes


examination.


bias)

All outcomes






All outcomes

Low risk Complete information available on all par-

ticipants.




Templeton 2009 (CS)

Methods Cross-sectional study


In the Templeton 2009 study, the association between circumcision status and STIs were

assessed at baseline (prevalent STIs) and prospectively (incident STIs). Templeton 2009

(CS) refers to the prevalence study.







Outcomes Syphilis: Participants were screened annually by enzyme immunoassay, and positive

assay results confirmed with the Treponema pallidum particle agglutination assay and

fluorescent treponemal antibody absorption test. The rapid plasma reagin test was used

to assist clinical staging and to detect reinfection.

HSV: Baseline serum samples and sequential specimens were tested for antibody to HSV

using ELISA. Equivocal results were resolved by Western blot analysis.

Notes Paticipants were followed up until mid-2007.



Templeton 2009 (CS) (Continued)

Risk of bias



(performance bias)

All outcomes


examination.


bias)

All outcomes






All outcomes


ticipants.




Templeton 2009 (P)



In the Templeton 2009 study, the association between circumcision status and STIs were

assessed at baseline (prevalent STIs) and prospectively (incident STIs). Templeton 2009

(P) refers to the incidence study.







Outcomes Participants were tested annually for HIV with western blot confirmation.

Notes Paticipants were followed up until mid-2007.

Risk of bias



(performance bias)

All outcomes


examination.



Templeton 2009 (P) (Continued)


bias)

All outcomes






All outcomes


ticipants.




Xu 2007

Methods Cross-sectional study

Duration of enrolment: 1999 to 2004.

Participants 6174 MSM participating in the National Health and Nutrition Examination Surveys

(NHANES) in the US from 1999 to 2004.

This analysis was limited to 3850 boys/men 14 to 49 years of age who reported having

had sex and were tested for HSV-2 antibodies

Interventions Circumcision status was assessed by self-report. The overall prevalence of circumcision

was 79% (95% CI 77 to 80).

Outcomes Participants were tested for HSV-2 by antibody tests.

Notes The NHANES is a series of cross-sectional surveys using a complex, stratified, multi-

stage probability sampling design. Briefly, during each year of the survey, a nationally

representative sample of the US civilian, noninstitutionalized population was selected,

interviewed, and examined by medical professionals.

During NHANES 1999-2004, health examinations were conducted in specially

equipped mobile examination Centers.

Risk of bias



(performance bias)

All outcomes


report.


bias)

All outcomes







Xu 2007 (Continued)


All outcomes

Low risk Of 6313 interviewed (“Are you circumcised

or uncircumcised?”), 53 refused to answer

the question and 86 responded with “Don’t

know,” leaving a sample of 6174 persons

(90% of those examined at mobile exami-

nation Centers) for further analyses.




Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Beyrer 2010 This is a review and not a primary study.

Botros 2009 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the

circumcised and uncircumcised groups or the odds ratio and its 95% confidence intervals for the association

between male circumcision and HIV (or syphilis or herpes simplex virus).

Coplan 1996 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



Dandona 2008 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



Fankem 2008 This is a review and not a primary study.

Farr 2010 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



Grulich 2001 At baseline all the participants were HIV infected.

Jewkes 2006 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



Jin 2010 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the





(Continued)

Jozkowski 2010 We need additional information before deciding whether to include this potentially eligible study or not. When

we decide on the final eligibility of this study, we will update this review and move this reference to the appropriate

section.

Kloos 2007 This is a review and not a primary study.

Lafferty 1997 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



Lau 2010 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



MacDonald 2008 This is a review and not a primary study.

McKinney 2008 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



Millet 2008 This is a review and not a primary study.

Perisse 2009 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the



Sanchez 2011 We need additional information before deciding whether to include this potentially eligible study or not. When


section.

Smith 2010 This is a review and not a primary study.

Sullivan 2007 This is a review and not a primary study.

Templeton 2010 This is a review and not a primary study.

Thornton 2009 We need additional information before deciding whether to include this potentially eligible study or not. When


section.

Vermund 2008 This is an editorial and not a primary study.

Wei 2010 The study did not report either the number of persons with HIV (or syphilis or herpes simplex virus) in the





Characteristics of ongoing studies [ordered by study ID]

MSM Trial 2010

Trial name or title Public title: (Men Who Have Sex With Men) MSM Community Intervention Trial

Scientific title: A community-based, randomized controlled trial to evaluate the efficacy of comprehensive

HIV/STIs intervention among men who have sex with men in 8 cities in China.

Main ID: NCT01068015

Methods Allocation: Randomized

Endpoint Classification: Efficacy Study

Intervention Model: Parallel Assignment

Masking: Open Label

Primary Purpose: Prevention

Phases: Phase III

Register: ClinicalTrials.gov

First Received: February 11, 2010

Last Updated: April 7, 2010

Last Verified: April 2010

Participants Target sample size: 3214

Inclusion Criteria: 18 years or above; Male have oral sex or anal sex within 6 months with a man; Accept

questionnaire survey and blood test; Can participate in three surveys in one year; HIV Negative; No mental

disease and can understand informed consent

Interventions Behavior intervention and male circumcision

Outcomes HIV incidence, Syphilis, HSV-2 incidence

Frequency of condom uses, number of sexual partners

The proportion of people who have intention to be circumcised

The proportion of people who have been circumcised

Starting date Start Date: June 2009

Completion Date: December 2010

Primary Completion Date: November 2010

Recruitment status: Active, not recruiting

Contact information Jie Xu, MD, MS, MPH: National Center for AIDS/STD Control and Prevention, China CDC

Zunyou Wu, MD, PhD: National Center for AIDS/STD Control and Prevention, China CDC

Notes URL: http://ClinicalTrials.gov/show/NCT01068015



D A T A A N D A N A L Y S E S

Comparison 1. Male circumcision versus no male circumcision

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 HIV infection (all MSM) 20 Odds Ratio (Random, 95% CI) 0.86 [0.70, 1.06]

2 HIV infection (by sexual

position)

20 Odds Ratio (Random, 95% CI) Subtotals only

2.1 Receptive anal 3 Odds Ratio (Random, 95% CI) 1.20 [0.63, 2.29]

2.2 No differentiation 17 Odds Ratio (Random, 95% CI) 1.00 [0.92, 1.09]

2.3 Insertive anal 7 Odds Ratio (Random, 95% CI) 0.27 [0.17, 0.44]

3 Sexually transmitted infection 9 Odds Ratio (Random, 95% CI) Subtotals only

3.1 Syphilis 8 Odds Ratio (Random, 95% CI) 0.96 [0.82, 1.13]

3.2 Herpes simplex virus - 1 2 Odds Ratio (Random, 95% CI) 0.90 [0.53, 1.52]

3.3 Herpes simplex virus - 2 5 Odds Ratio (Random, 95% CI) 0.86 [0.62, 1.21]

Analysis 1.1. Comparison 1 Male circumcision versus no male circumcision, Outcome 1 HIV infection (all

MSM).

Review: Male circumcision for prevention of homosexual acquisition of HIV in men

Comparison: 1 Male circumcision versus no male circumcision

Outcome: 1 HIV infection (all MSM)

Study or subgroup log [Odds Ratio] Odds Ratio Weight Odds Ratio

(SE) IV,Random,95% CI IV,Random,95% CI

Kreiss 1993 -0.69314718 (0.70729304) 2.0 % 0.50 [ 0.13, 2.00 ]

Reid 2001 0.20701417 (0.17306925) 11.5 % 1.23 [ 0.88, 1.73 ]

Tabet 2002 -1.42711636 (1.43541363) 0.5 % 0.24 [ 0.01, 4.00 ]

Kumta 2002 -0.07257069 (0.26062532) 8.2 % 0.93 [ 0.56, 1.55 ]

Lai 2004 -0.7985077 (0.98850576) 1.1 % 0.45 [ 0.06, 3.12 ]

Buchbinder 2005 -0.69314718 (0.61990951) 2.5 % 0.50 [ 0.15, 1.69 ]

Bartholow 2006 0.0861777 (0.32713645) 6.4 % 1.09 [ 0.57, 2.07 ]

Millett 2007 (Black) 0.20701417 (0.35364652) 5.8 % 1.23 [ 0.62, 2.46 ]

Reisen 2007 -0.63487827 (0.64434456) 2.3 % 0.53 [ 0.15, 1.87 ]

0.01 0.1 1 10 100

Favours circumcision Favours no circumcision

(Continued . . . )



(. . . Continued)Study or subgroup log [Odds Ratio] Odds Ratio Weight Odds Ratio


Sanchez 2007 -0.03045921 (0.59697513) 2.6 % 0.97 [ 0.30, 3.13 ]

Buchbinder 2007 0.39877612 (0.47942407) 3.7 % 1.49 [ 0.58, 3.81 ]

Millet 2007 (Latino) 0.09531018 (0.41914712) 4.6 % 1.10 [ 0.48, 2.50 ]

Mor 2007 -0.03045921 (0.05375537) 16.0 % 0.97 [ 0.87, 1.08 ]

Calzavara 2007 -1.51412773 (2.49699055) 0.2 % 0.22 [ 0.00, 29.37 ]

Begley 2008 -0.51082562 (0.49173116) 3.6 % 0.60 [ 0.23, 1.57 ]

Templeton 2009 -0.24846136 (0.63217557) 2.4 % 0.78 [ 0.23, 2.69 ]

McDaid 2010 -0.24846136 (0.81527731) 1.5 % 0.78 [ 0.16, 3.86 ]

Jameson 2010 0.10436002 (0.10145452) 14.4 % 1.11 [ 0.91, 1.35 ]

Gust 2010 0.0295588 (0.5576741) 2.9 % 1.03 [ 0.35, 3.07 ]

Lane 2011 -1.51412773 (0.27499821) 7.8 % 0.22 [ 0.13, 0.38 ]

Total (95% CI) 100.0 % 0.86 [ 0.70, 1.06 ]

Heterogeneity: Tau2 = 0.07; Chi2 = 40.20, df = 19 (P = 0.003); I2 =53%

Test for overall effect: Z = 1.38 (P = 0.17)

0.01 0.1 1 10 100




Analysis 1.2. Comparison 1 Male circumcision versus no male circumcision, Outcome 2 HIV infection (by

sexual position).



Outcome: 2 HIV infection (by sexual position)



1 Receptive anal

Sanchez 2007 0.19062036 (0.8867629) 13.7 % 1.21 [ 0.21, 6.88 ]

Reisen 2007 -0.09431068 (0.54751694) 36.0 % 0.91 [ 0.31, 2.66 ]

Jameson 2010 0.3852624 (0.46313453) 50.3 % 1.47 [ 0.59, 3.64 ]

Subtotal (95% CI) 100.0 % 1.20 [ 0.63, 2.29 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.45, df = 2 (P = 0.80); I2 =0.0%


2 No differentiation

Kreiss 1993 -0.69314718 (0.70729304) 0.4 % 0.50 [ 0.13, 2.00 ]

Reid 2001 0.20701417 (0.17306925) 6.2 % 1.23 [ 0.88, 1.73 ]

Kumta 2002 -0.07257069 (0.26062532) 2.7 % 0.93 [ 0.56, 1.55 ]

Tabet 2002 -1.42711636 (1.43541363) 0.1 % 0.24 [ 0.01, 4.00 ]

Lai 2004 -0.7985077 (0.98850576) 0.2 % 0.45 [ 0.06, 3.12 ]

Buchbinder 2005 -0.69314718 (0.61990951) 0.5 % 0.50 [ 0.15, 1.69 ]

Bartholow 2006 0.0861777 (0.32713645) 1.7 % 1.09 [ 0.57, 2.07 ]

Millet 2007 (Latino) 0.09531018 (0.41914712) 1.1 % 1.10 [ 0.48, 2.50 ]

Buchbinder 2007 0.39877612 (0.47942407) 0.8 % 1.49 [ 0.58, 3.81 ]

Sanchez 2007 -0.03045921 (0.59697513) 0.5 % 0.97 [ 0.30, 3.13 ]

Mor 2007 -0.03045921 (0.05375537) 64.2 % 0.97 [ 0.87, 1.08 ]

Millett 2007 (Black) 0.20701417 (0.35364652) 1.5 % 1.23 [ 0.62, 2.46 ]

Begley 2008 -0.51082562 (0.49173116) 0.8 % 0.60 [ 0.23, 1.57 ]

Templeton 2009 -0.24846136 (0.63217557) 0.5 % 0.78 [ 0.23, 2.69 ]

Jameson 2010 0.10436002 (0.10145452) 18.0 % 1.11 [ 0.91, 1.35 ]

McDaid 2010 -0.24846136 (0.81527731) 0.3 % 0.78 [ 0.16, 3.86 ]

Gust 2010 0.0295588 (0.5576741) 0.6 % 1.03 [ 0.35, 3.07 ]

Subtotal (95% CI) 100.0 % 1.00 [ 0.92, 1.09 ]

0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup log [Odds Ratio] Odds Ratio Weight Odds Ratio




3 Insertive anal

Reisen 2007 -1.42711636 (1.60415933) 2.3 % 0.24 [ 0.01, 5.57 ]

Sanchez 2007 -1.23787436 (1.20237363) 4.0 % 0.29 [ 0.03, 3.06 ]

Calzavara 2007 -1.51412773 (2.49699055) 0.9 % 0.22 [ 0.00, 29.37 ]

Templeton 2009 -2.20727491 (1.6752114) 2.1 % 0.11 [ 0.00, 2.93 ]

Jameson 2010 0.13102826 (0.66446934) 13.2 % 1.14 [ 0.31, 4.19 ]

McDaid 2010 -0.5798185 (3.06152523) 0.6 % 0.56 [ 0.00, 226.03 ]

Lane 2011 -1.51412773 (0.27499821) 76.9 % 0.22 [ 0.13, 0.38 ]

Subtotal (95% CI) 100.0 % 0.27 [ 0.17, 0.44 ]


Test for overall effect: Z = 5.36 (P < 0.00001)

0.01 0.1 1 10 100




Analysis 1.3. Comparison 1 Male circumcision versus no male circumcision, Outcome 3 Sexually

transmitted infection.



Outcome: 3 Sexually transmitted infection



1 Syphilis

Kreiss 1993 -0.69314718 (0.86976943) 0.9 % 0.50 [ 0.09, 2.75 ]

Tabet 2002 -0.24846136 (1.29233421) 0.4 % 0.78 [ 0.06, 9.82 ]

Mor 2007 (HIV-pos) 0 (0.14235919) 33.2 % 1.00 [ 0.76, 1.32 ]

Sanchez 2007 -0.27443685 (0.79112113) 1.1 % 0.76 [ 0.16, 3.58 ]

Mor 2007 (HIV-neg) -0.02020271 (0.10448695) 61.7 % 0.98 [ 0.80, 1.20 ]

Templeton 2009 (P) -1.02165125 (0.90846233) 0.8 % 0.36 [ 0.06, 2.14 ]

Templeton 2009 (CS) -0.34249031 (0.72166594) 1.3 % 0.71 [ 0.17, 2.92 ]

Jameson 2010 -0.69314718 (1.02801175) 0.6 % 0.50 [ 0.07, 3.75 ]

Subtotal (95% CI) 100.0 % 0.96 [ 0.82, 1.13 ]



2 Herpes simplex virus - 1

Templeton 2009 (CS) -0.13926207 (0.28330479) 90.2 % 0.87 [ 0.50, 1.52 ]

Templeton 2009 (P) 0.16551444 (0.85780738) 9.8 % 1.18 [ 0.22, 6.34 ]

Subtotal (95% CI) 100.0 % 0.90 [ 0.53, 1.52 ]



3 Herpes simplex virus - 2

Sanchez 2007 -0.34249031 (0.44943306) 14.5 % 0.71 [ 0.29, 1.71 ]

Xu 2007 -0.09431068 (0.31817404) 28.9 % 0.91 [ 0.49, 1.70 ]

Templeton 2009 (P) -0.41551544 (0.91100383) 3.5 % 0.66 [ 0.11, 3.94 ]

Templeton 2009 (CS) -0.02020271 (0.3207187) 28.5 % 0.98 [ 0.52, 1.84 ]

Jameson 2010 -0.19845094 (0.34477318) 24.6 % 0.82 [ 0.42, 1.61 ]

Subtotal (95% CI) 100.0 % 0.86 [ 0.62, 1.21 ]



0.01 0.1 1 10 100




H I S T O R Y

Protocol first published: Issue 4, 2008

Review first published: Issue 6, 2011

C O N T R I B U T I O N S O F A U T H O R S

CSW, EJK, ASM and OBN wrote the protocol for the review and CSW, EJK, MS, ASM, OBN, EA and YL contributed important

intellectual content to the review. All authors read and approved the final version.

D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

• University of Cape Town (CSW, MSS), South Africa.

• Liverpool School of Tropical Medicine, Liverpool (EJK), UK.

• Leicester Royal Infirmary (OBN), UK.

• University of Malawi, College of Medicine, Blantyre (ASM), Malawi.

External sources

• Department of HIV/AIDS, World Health Organization, Switzerland.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

MS, EAA and YRL were not authors in the published protocol, but they are included as authors in the review because they have made

substantive contributions in the selection of studies, data extraction and analyses, and/or interpretation of findings.

In addition, in the published protocol, we indicated that we would add transgendered persons as participants in this review. Our aim of

lumping MSM and transgenders was to be able to identify all studies where transmission routes for HIV would likely be similar to that

for MSM (i.e. through anal sex). However, our comprehensive search did not identify any study on transgenders. More importantly,

all four peer-referees expressed concerns about this lumping and we decided to exclude this group of participants from this review.

I N D E X T E R M S



Medical Subject Headings (MeSH)

∗Circumcision, Male; ∗Homosexuality, Male; HIV Infections [∗prevention & control; transmission]; Herpes Simplex [prevention &

control; transmission]; Herpesvirus 1, Human; Herpesvirus 2, Human; Syphilis [prevention & control; transmission]

MeSH check words

Humans; Male



Male circumcision for prevention of homosexual acquisition of HIV in men

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