HIV/AIDS

While prevention of sexually transmitted infections is irrelevant to non-sexually-active newborns and children, nonetheless, prevention of human immunodeficiency virus (HIV) has become one of the main ‘medical benefits’ rationales given for circumcision.[5]

A decade ago, three randomized controlled trials (RCTs) done in sub-Saharan Africa appeared to show, during the study period, a 38-66% relative reduction for the circumcised subjects in the risk of heterosexual, female to male only, transmission of HIV.[85-87] All three studies were terminated early, due to their apparently clear results. However, Dowsett and Couch examined the results of the three RCTs, but found insufficient evidence to recommend circumcision to prevent HIV infection.[88] Green et al. reviewed the evidence and also found “insufficient data” as well as contrary evidence.[89,90]

While RCTs are often considered the gold standard of medical trials, this only applies to RCTs with study designs that minimize bias. The three African RCTs were very similar in study design and contained multiple sources of bias, outlined below[89-92]:

  • Researcher expectation bias − Many of the investigators had written papers advocating for male circumcision to prevent HIV infection prior to undertaking these RCTs. Siegfried et al. note, on the topic of research on circumcision to prevent HIV, that “researchers’ personal biases and the dominant circumcision practices of their respective countries may influence their interpretation of findings.”[93]
  • Participant expectation bias − The majority of participants were convinced that circumcision would reduce their risk of HIV infection.[94]
  • Lead time bias − Men randomized to the intervention arm of the trials (the group that was circumcised) were considered to be at risk for becoming infected from the time of the surgery, even though they were told to avoid sexual activity during the period of wound healing. Men in the control arm (the ones who were not circumcised) were able to be sexually active from the beginning of the study.
  • Selection bias − Only men who were interested in a free circumcision were eligible to participate, and therefore may not have been representative of the general population.
  • Attrition bias − For every man who became infected with HIV during the trials, 3.5−7.4 men were lost to follow-up. This is a serious methodological problem that could alter the statistical significance of the findings.[95]
  • Early termination bias − Studies that are terminated early are more likely to overestimate any treatment effect.[96,97]
  • Duration bias − Because men who were not initially circumcised were circumcised at the end of the study, long-term comparison of the effects cannot be accurately extrapolated, as some modelers have proposed.[98]
  • Source of infection unknown − If the studies were designed to determine whether circumcision reduced the risk of heterosexually-transmitted HIV, the investigators should have confirmed that the infections were indeed transmitted through heterosexual sexual contact. They did not. Using the data reported, it is estimated that about half of the infections of the men in these studies were not sexually transmitted.[92]

The cumulative treatment effect in these trials – which claimed a 38-66% relative risk reduction[99] – was an absolute risk reduction of 1.3%.[91] This is a very small effect, which could easily have resulted from the various forms of bias, rather than being a true treatment effect. The findings are not robust, given that all of the trials had nearly identical methodologies and nearly identical results.

In any case, it appears that these trials were unnecessary in the first place. Data released before the trials began found a number of African countries where the prevalence of HIV infection was greater in circumcised men than in intact men.[100,101]

Unfortunately, the results from the three RCTs provided the impetus for the WHO to bypass the usual step of performing pilot studies to determine if circumcision was effective outside of a research setting. Instead, it recommended programs to circumcise millions of men in sub-Saharan Africa as quickly as possible. (These programs measure success by the number of males circumcised rather than by their impact on HIV incidence. Since the mass circumcision campaigns began in Uganda and Kenya, the incidence of new cases of HIV in both countries has increased.[102-104]) The WHO recommendations included that circumcision programs should be voluntary, free of coercion, and targeted to areas where the HIV prevalence is high (>15% of the population) and circumcision rates are low (<20%).[105] None of these criteria apply to the situation of newborn babies (who cannot voluntarily consent) in the epidemiological setting of the United States (low HIV prevalence, and already high circumcision rate, as well as a much higher standard of living than Africa).

As with other STIs, there is no evidence that circumcision has had any impact on lowering the incidence of HIV infection in the United States. Of the eight HIV studies in North American heterosexual men,[100,106-112] only one has found a significant association between circumcision and HIV infection risk: it actually found that circumcised men were at greater risk of HIV infection.[112] Furthermore, the HIV epidemic in the United States is concentrated among men who have sex with men (MSM) and injecting drug users. A meta-analysis of the studies published on this topic by the Centers for Disease Control and Prevention (CDC) found that the risk for HIV infection in MSM is the same in intact and circumcised men.[113] A subsequent study yielded similar results.[114]

While some authors have theorized that Langerhans cells present in the foreskin are a significant portal for HIV infection, and have used this as a rationale for circumcision as a preventative,[115] evidence now shows that these cells produce a protein, langerin, that is actually protective against the virus.[116] The authors of the langerin study argue that “strategies to combat [HIV] infection must enhance, preserve or, at the very least, not interfere with langerin expression and function [in the Langerhans cells of the foreskin].”[116]

RCTs carried out among adults in Africa are not relevant to children anywhere, since children are not sexually active and are therefore not at risk of HIV infection by sexual transmission. For adults, condoms are an effective means of preventing sexually transmitted infections, including HIV.[117] Other preventative interventions, such as “treatment as prevention,” pre-exposure prophylaxis (PrEP),[176] and post-exposure prophylaxis (PEP)[177] are more effective, less expensive, and less injurious than circumcision.[118,119]

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References

5. American Academy of Pediatrics Task Force on Circumcision. Male circumcision. Pediatrics. 2012;130(3):e756-85.
85. 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.
86. Bailey RC, Moses S, Parker CB, Agot K, Maclean I, Krieger JN, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007;369:643-656.
87. Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007;369(9562):657-66.
88. Dowsett GW, Couch M. Male circumcision and HIV prevention: is there really enough of the right kind of evidence? Reprod Health Matters. 2007;15(29):33-44.
89. Green LW, McAllister RG, Peterson KW, Travis JW. Male circumcision is not the HIV ‘vaccine’ we have been waiting for! Futur HIV Ther. 2008;2(3):193-9.
90. Green LW, Travis JW, McAllister RG, Peterson KW, Vardanyan AN, Craig A. Male circumcision and HIV prevention: insufficient evidence and neglected external validity. Am J Prev Med. 2010;39(5):479-82.
91. Boyle GJ, Hill G. Sub-Saharan African randomised clinical trial in male circumcision and HIV transmission: methodological, ethical and legal concerns. J Law Med. 2011;19:316-34.
92. Van Howe RS, Storms MR. How the circumcision solution in Africa will increase HIV infections. J Publ Health Afr. 2011;2:e4.
93. Siegfried N, Muller M, Volmink J, Deeks J, Egger M, Low N, et al. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev. 2003;3:CD003362.
94. Wilson NL, Xiong W, Mattson CL. Is sex like driving? HIV prevention and risk compensation. J Dev Econ. 2014;106:78-91.
95. Akl EA, Briel M, You JJ, Sun X, Johnston BC, Busse JW, et al. Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review. BMJ. 2012;344:e2809.
96. Pocock S, White I. Trials stopped early: too good to be true? Lancet. 1999;353:943-4.
97. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303:1180-7.
98. Williams BG, Lloyd-Smith JO, Gouws E, Hankins C, Getz WM, Hargrove J, et al. The potential impact of male circumcision on HIV in sub-Saharan Africa. PLoS Med. 2006;3:e262.
99. Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev. 2009;2:CD003362.
100. Mishra V, Medley A, Hong R, Yuan Gu Y, Robey B. Levels and spread of HIV seroprevalence and associated factors: evidence from national household surveys. DHS Comparative Reports No. 22. Calverton (MD): Macro International Inc; 2009.
101. Garenne M. Long-term population effect of male circumcision in generalised HIV epidemics in sub-Saharan Africa. Afr J AIDS Res. 2008;7:1-8.
102. Ministry of Health, ICF International, Centers for Disease Control and Prevention, U.S. Agency for International Development, WHO Uganda. Uganda AIDS Indicator Survey 2011. Kampala (Uganda): Ministry of Health; 2012.
103. National AIDS Control Council, National AIDS and STD Control Programme. The Kenya AIDS epidemic: update 2011. Nairobi (Kenya): National AIDS Control Council; 2012.
104. Orido G. Push for male circumcision in Nyanza fails to reduce infections. Standard (Kenya) website. 2013 Sep 11. Available at: www.standardmedia.co.ke/article/2000093293/push-for-male-circumcision-in-nyanza-fails-to-reduce-infections
105. WHO/UNAIDS Technical Consultation. Male circumcision and HIV prevention: research implications for policy and programming. Conclusions and recommendations. 2007 March.
106. Chiasson MA, Stoneburner RL, Hildebrandt DS, Ewing WE, Telzak EE, Jaffe HW. Heterosexual transmission of HIV-1 associated with the use of smokable freebase cocaine (crack). AIDS. 1991;5:1121-6.
107. Telzak EE, Chiasson MA, Bevier PJ, Stoneburner RL, Castro KG, Jaffe HW. HIV-1 seroconversion in patients with and without genital ulcer disease. Ann Intern Med. 1993;119:1181-6.
108. Laumann EO, Masi CM, Zuckerman EW. Circumcision in the United States: prevalence, prophylactic effects, and sexual practice. JAMA. 1997;277:1052-7.
109. Thomas AG, Bakhireva LN, Brodline SK Shaffer RA. Prevalence of circumcision and its association with HIV and sexually transmitted infections in a male US Navy population. San Diego (CA): Naval Health Research Center. Report No. 04-10; 2004.
110. Mor Z, Kent CK, Kohn RP, Klausner JD. Declining rates in male circumcision amidst increasing evidence of its public health benefit. PLoS ONE. 2007;2(9):e861.
111. Warner L, Ghanem KG, Newman DR, Macaluso M, Sullivan PS, Erbelding EJ. Male circumcision and risk of HIV infection among heterosexual African American men attending Baltimore sexually transmitted disease clinics. J Infect Dis. 2009;199:59-65.
112. Rodriguez-Diaz CE, Clatts MC, Jovet-Toledo GG, Vargas-Molina RL, Goldsamt LA, García H. More than foreskin: circumcision status, history of HIV/STI, and sexual risk in a clinic-based sample of men in Puerto Rico. J Sex Med. 2012;9:2933-7.
113. 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. JAMA. 2008;300:1674-84. Errata JAMA. 2009;301:1126-9.
114. Crosby RA, Graham CA, Mena L, Yarber WL, Sanders SA, Milhausen RR, et al. Circumcision status is not associated with condom use and prevalence of sexually transmitted infections among young black MSM. AIDS Behav. 2015 Oct 7. Epub ahead of print.
115. Szabo R, Short RV. How does male circumcision protect against HIV infection? BMJ. 2000; 320(7249):1592-4.
116. de Witte L, Nabatov A, Pion M, Fluitsma D, de Jong MAWP, de Gruijl T, et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med. 2007;3:367-71.
117. de Vincenzi I. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. N Engl J Med. 1994;331(6):341-6.
118. Lima V, Anema A, Wood R, Moore D, Harrigan R, Mills E, et al. The combined impact of male circumcision, condom use and HAART coverage on the HIV-1 epidemic in South Africa: a mathematical model. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WECA105; 2009.
119. Donnell D, Baeten JM, Kiarie J, Thomas KK, Stevens W, Cohen CR, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet. 2010;375(9731):2092-8.
176. Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. PrEP. Centers for Disease Control and Prevention website. Last reviewed 2019 Oct 17.
177. Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. PEP. Centers for Disease Control and Prevention website. Last reviewed 2019 Aug 6.

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