THE CIRCUMCISION REFERENCE LIBRARY
Male circumcision for prevention of heterosexual acquisition of HIV in men
Siegfried N, Muller M, Volmink J, Egger M, Low N, Weiss H, Walker S, Deeks J, Williamson P
Date of most recent substantive amendment: 3 July 2001
This protocol should be cited as: Siegfried N, Muller M, Volmink J, Egger M, Low N, Weiss H, Walker S, Deeks J, Williamson P. Male circumcision for prevention of heterosexual acquisition of HIV in men (Protocol for a Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software
Male circumcision is defined as the surgical removal of all or part of the prepuce (foreskin) of the penis and may be practiced as part of a religious ritual usually conducted shortly after birth, as a medical procedure related to infections, injury or anomalies of the foreskin, or as part of a traditional ritual performed as an initiation into manhood (Horizons 00). For over a decade observational studies have pointed to an association between male circumcision and HIV infection in males. Most of these studies suggest a protective effect of male circumcision on HIV acquisition in men.
Five reviews (Moses 94; De Vincenzi 94; Moses 98; Van Howe 99; Weiss 00) and one meta-analysis (Weiss 00) of these observational studies have been published, reaching different conclusions on the association between circumcision and HIV infection. However, search strategies are not clearly described in all the reviews, several focused only on published studies and confounding was not always assessed adequately. The most rigorous is a systematic review and meta-analysis recently published by Weiss (Weiss 00), but this review was limited to published studies on HIV-1 infection in sub-Saharan Africa. Adjusted analyses produced a relative risk (RR) of 0.42 (95% CI: 0.34-0.54) for all studies combined (N=15) with a RR of 0.55 (95% CI: 0.42 - 0.72) for population-based cross-sectional studies (N=5) and a RR of 0.24 (95% CI: 0.18 - 0.31) for cross-sectional studies of high-risk groups (N=4). The authors conclude that there is compelling evidence that male circumcision is associated with a reduced risk of HIV infection in sub-Saharan Africa despite warning that residual confounding may exist in some studies due to behavioural or biological factors that are unknown or unmeasured.
Known sources of confounding identified by all the above reviews include sexual behaviour, penile hygiene and religion. Circumcision itself may be a proxy measure of the knowledge and behaviour learnt during the process of initiation during which time young men are taught about traditional sexual practices, including monogamy, and penile hygiene. A potential confounder that has not been measured in any study to date to our knowledge is the use of vaginal drying agents in female partners of the men. This practice is reportedly common in parts of Africa (Brown 93; Kun 98; Runganga 95) and may result in increased vaginal abrasions and micro-lacerations, possibly facilitating HIV transmission in both directions. Viral load is increasingly considered to be a crucial factor in HIV transmission (Quinn 00) and may be both an important confounder and an effect modifier. Misclassification of exposure is also an important source of bias given that some studies classify circumcision status by self-report rather than direct observation.
Biological theories to support the protective effect of circumcision on HIV exist. Researchers have noted that the inner aspect of the foreskin is well-supplied with Langerhans cells (Szabo 00) and that in vitro, HIV-1 demonstrates a specific tropism (attraction) for these cells (Soto-Ramirez 96), in particular the CD4 receptors (Hussain 95). CD4 and other HIV co-receptors have been shown to facilitate HIV entry into host cells, although this has yet to be demonstrated specifically for preputial Langerhans cells. According to this theory, circumcision would remove the potential entry site for HIV. However, not all Langerhans cells are removed during circumcision as even after the procedure, there is residual penile mucosa of the glans and there are also Langerhans cells in the penile shaft (Cold 99). In direct contradiction to the above theory, the inner prepuce contains apocrine glands which secrete lysozyme (Fleiss 98). Lysozyme reportedly kills HIV-1 in vitro (Lee-Huang 99), suggesting a protective effect of the foreskin. As the study of the immunological function of the prepuce is not well-developed (Cold 99), caution must be observed when assuming in vitro viral behaviour is equivalent in vivo.
The presence of a sexually transmitted infection (STI) enhances HIV infection and susceptibility (Cohen 98; Grosskurth 95; Fleming 99). The role circumcision plays in the transmission of STIs is less certain, although it has been reported that male circumcision is associated with a reduced risk of genital ulcer disease, particularly chancroid and syphilis (Moses 98). It would therefore be valuable to examine the relationship between circumcision and STIs. Should this relationship prove to be temporal, it seems likely that circumcision may protect against HIV infection indirectly via decreased STI transmission.
Circumcision practices are largely culturally determined and as a result there are strong beliefs and opinions surrounding its practice. It is important to acknowledge that researchers' personal biases and the dominant circumcision practices of their respective countries may influence their interpretation of findings.
Given the enormous mortality and morbidity associated with HIV/AIDS, it seems reasonable to fully explore potential prevention measures, including male circumcision. However, promoting or instituting mass circumcision may have profound cultural and social implications and represents a formidable public health challenge (Cohen 00). Of particular concern is the potential negative impact introduction of circumcision may have on current health promotion endeavours to promote sexual behavioural change. This may include promulgation of the belief that circumcision completely protects against HIV transmission, resulting in a lack of condom use. The following systematic review seeks to inform this debate by presenting the evidence from both published and unpublished studies from around the world which examine the association between circumcision and HIV-1 and HIV-2 infection.
1) To examine the association between male
circumcision and acquisition of HIV-1 and HIV-2 by
men through heterosexual intercourse.
Types of studies
Randomised or quasi-randomized controlled trials. If insufficient data are available from randomised controlled trials to draw any meaningful conclusions, data from observational studies (e.g. cohort, case-control and cross-sectional studies) will be considered for inclusion in this review. Studies performed in general or specific populations and in hospitals or clinics will be included. Studies performed in any country and published in any language will be included. Studies with historical controls and ecological studies will be excluded.
Types of participants
Heterosexual men included in studies assessing the association between circumcision and HIV-1 and HIV-2. Men are defined as males 12 years or older.
Types of intervention
Male circumcision is defined as removal of the foreskin of the penis either via surgical technique or via cultural practices which involve cutting off the foreskin. Circumcision status can be determined by self- or partner-report or by direct observation.
Types of outcome measures
The outcome measures are:
HIV-1 or HIV-2 infection in men
Any adverse events associated with circumcision will be recorded if reported in the trials.
See: HIV/AIDS Collaborative Review Group search strategy
Electronic searches will be undertaken using the following databases: MEDLINE, Embase, AIDSLINE, CINAHL, Scisearch, the Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effectiveness (DARE), the Cochrane HIV/AIDS and the Cochrane STD registers of studies. Hand searches of the reference lists of all pertinent reviews and studies found will also be undertaken, as well as abstracts from relevant conferences. Agencies, organizations and academic centers, as well as experts in the field of HIV prevention will be contacted to locate any further studies or relevant conference proceedings that may not be included in the databases and to ensure that unpublished studies are included.
The search strategy will be iterative.
The search for trials will be performed with the assistance of the Cochrane HIV/AIDS Group. The selection for potentially relevant studies will be undertaken by NS and MM. The titles, abstracts and descriptor terms of all downloaded material from the electronic searches will be read and irrelevant reports discarded to create a pool of potentially eligible studies. All citations identified will then be independently inspected by NS and MM to establish relevance of the article and whether or not the full article should be acquired. If there is uncertainty, the full article will be obtained.
1. Selection of studies
2. Data extraction
Details of study:
Characteristics of participants:
Details of intervention:
Details of outcomes:
Randomised Controlled Trials:
Reviewers will not be blinded to the names of the authors, institutions, journal of publication or results of the studies.
5. Sub-group analysis,
investigation of heterogeneity and sensitivity
Where possible meta-analysis will be conducted combining odds ratios using a random effects (DerSimonian and Laird) model as between study heterogeneity is anticipated. Heterogeneity will be tested by REVMAN software using the Chi square test for heterogeneity. Between-study heterogeneity (p <0.1) will be explored by subgroup analysis and meta-regression depending on the data available. The following study factors will be examined:
- Circumcision: studies which assess status by
self-report versus direct observation; medical
procedure versus traditional procedure
We will conduct sensitivity analysis based on study quality using meta-regression if appropriate. The following effects will also be investigated using sensitivity analysis:
- Adjusted and unadjusted analyses
Brown J.E., Ayowa O.B., Brown R.C.
tight - sexual practices and potential AIDS risk in
Zaire. Social Science and Medicine
Cohen M.S. Preventing sexual transmission of
HIV - new ideas from sub-Saharan Africa The New
England Journal of Medicine 2000;342:970 -
Cohen M.S. Sexually transmitted
diseases enhance HIV transmission: no longer a
hypothesis. The Lancet 1998;351 Suppl:S5 -
Cold C.J., Taylor J.R. The
prepuce. British Journal of Urology
De Vincenzi I.D., Mertens T. Male
circumcision: a role in HIV prevention?. AIDS
Fleiss P.M., Hodges F.M., Van Howe
function of the human prepuce. Sexually
Transmitted Infections 1998;74:364-367.
D.T. Fleming, J.D. Wasserheit. From
epidemiological synergy to public health policy and
practice: the contribution of other sexually
transmitted diseases to sexual transmission of HIV
infection. Sexually Transmitted Infections
Grosskurth H., Mosha F., Todd J.,
Mwijarubi E., Klokke E., Senkoro K., Mayaud P.,
Changalucha J., Nicoll A., ka-Gina G., Newell J.,
Mugeye K., Mabey D., Hayes R. Impact of
improved treatment of sexually transmitted diseases
on HIV infections in rural Tanzania: randomised
controlled trial. The Lancet
Horizons. Report: Male
circumcision and HIV prevention: Directions for
future research.. Washington DC: Office of Health
and Nutrition, Global Bureau, U.S. Agency for
International Development. 2000.
Hussain L. A., Lehner T.
Comparative investigation of Langerhans' cells and
potential receptors for HIV in oral, gentourinary
and rectal epithelia. Immunology
Kun K.E. Vaginal drying
agents and HIV transmission. Family Planning
Lee-Huang S., Huang P.L., Sun Y.,
Kung H.F., Blithe D.L., Chen H.C.
Lysozyme and RNases as anti-HIV components in
Beta-core preparations of human chorionic
gonadotropin. Proceedings of the National
Academy of Science (USA). 1999;96:2678-2681.
Moses S., Plummer F.A., Bradley
J.E., Ndiya-Achola J.O., Nagelkerke N.J.D., Ronald
association between lack of male circumcision and
risk for HIV infection: a review of the
epidemiological data]. Sexually Transmitted
Moses S., Bailey R.C., Donald A.R.
Male circumcision: assessment of health benefits
and risks. Sexually Transmitted Infections
Quinn T.C., Wawer M.J., Sewankambo
N., Serwadda D., Li C., Wabwoire-Mangen F., Meehan
M.O., Lutalo T., Gray R.H. Viral load and heterosexual
transmission of human immunodeficiency virus type
1. The New England Journal of Medicine
Runganga O.A., Kasule J. The vaginal
use of herbs/substances: an HIV transmission
facilitatory factor?. AIDS CARE
Soto-Ramirez L. E., Renjifo B.,
McLane M. F., Marlink R., O'Hara, C., Sutthent, R.,
Wasi, C., Vithayasi, P., Vithayasai, V.,
Apichartpiyakul, C., Auewarakul, P., Cruz, V. P.,
Chui, D.-S., Osathanondh, R., Mayer, K., Lee,
T.-H., Essex, M. HIV-1 Langerhans' cell tropism
with heterosexual transmission of HIV. Science
Szabo R., Short R.V. How does male
circumcision protect against HIV infection?.
British Medical Journal 2000;320:1592-1594.
R.S. Van Howe. Circumcision
and HIV infection: review of the literature and
meta-analysis. International Journal of STD and
Weiss H.A., Quigley M.A., Hayes R.
Male circumcision and risk of HIV infection in
sub-Saharan Africa: a systematic review and
meta-analysis. AIDS 2000;14:2361-2370.
External sources of support
Internal sources of support
Additional tables are not available for this protocol