Last month saw two further developments in the ongoing US debate over infant male circumcision (MC).  European readers may be surprised to discover that infant MC has traditionally been widely practised in the US – for complex historical reasons (http://blogs.bmj.com/sti/2011/10/15/to-circumcise-or-not-to-circumcise/?preview=true&preview_id=509&preview_nonce=9ecb80c216 ).  MC has shown a sharp decline in the US from around 79% some twenty years ago to 56% as of 2008, with the doubts widely expressed as to its medical justification, and insurance cover withdrawn in 18 US states; yet some paediatricians are making a last-ditch effort to halt the trend, drawing attention to medical benefits of MC as a prevention tool that have been highlighted by recent African studies (e.g. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)60313-4/abstract).

At the end of August came first, on the 20^th, the publication in the Archives of Pediatrics and Adolescent Medicine of an editorial and associated paper seeking to place a speculative figure on the potential health cost to the US of infant MC declining to European levels of 10% (http://archpedi.jamanetwork.com.libproxy.ucl.ac.uk/issue.aspx): then, on the 27^th, a long-awaited policy statement on infant MC by the American Association of Paediatrics (http://www.aap.org/en-us/about-the-aap/aap-press-room/pages/Newborn-Male-Circumcision.aspx?nfstatus=401&nftoken=00000000-0000-0000-0000-000000000000&nfstatusdescription=ERROR%3a+No+local+token).

The paper (Kacker and Tobian) takes into account the health costs not only of increased heterosexual HIV, but of other STI problems in men and women (HPV, HSV-2, bacterial vaginosis) as well as infant male UTIs.  Their model claims to demonstrate a net increased health expenditure of $313 per forgone MC procedure, amounting to a net additional annual health care cost of $505 million, largely driven by male HIV, infant UTIs and high-risk HPV in women.  An associated editorial (http://archpedi.jamanetwork.com.libproxy.ucl.ac.uk/article.aspx?articleid=1352168) reminds us that State Medicaid plans have covered two fifths of infant MCs in the past, but are currently in the process of dropping their coverage.  It also argues that the sectors of US society most affected by the abandonment of insurance cover for MC are precisely the sectors that experience highest levels of STIs and are most likely to benefit from MC.

The policy statement by the AAP, however, declares that, while the benefits of infant MC outweigh the risks, those benefits are not “great enough to recommend universal male newborn circumcision”.  What are we to make of the apparent discrepancy between the conclusions of Kacker & Tobian and the recommendations of the AAP?

The probable role of male circumcision in limiting HIV transmission in African contexts has been recognized (http://sti.bmj.com/content/87/7/640.abstract?sid=3c2776bf-91df-4443-b45c-d91cccd67208), along with its preventative benefits where other STIs are concerned (e.g. chancroid and syphilis (http://sti.bmj.com/content/82/2/101.abstract?sid=4e861499-e57a-40b3-833f-1c3a03449ee8); trichomonas (http://sti.bmj.com/content/85/2/116.abstract?sid=4e861499-e57a-40b3-833f-1c3a03449ee8).  Its effectiveness and acceptability as a prevention tool have been positively evaluated in some cultural contexts (http://sti.bmj.comcontent/79/3/214.abstract?sid=4e861499-e57a-40b3-833f-1c3a03449ee8; http://sti.bmj.com/content/87/Suppl_1/A319.1.abstract?sid=4e861499-e57a-40b3-833f-1c3a03449ee8). In others, however, a link between circumcision and reduced HIV prevalence is not evident, and MC would not be acceptable (http://sti.bmj.com/content/84/1/49.abstract?sid=4e861499-e57a-40b3-833f-1c3a03449ee8 and http://sti.bmj.com/content/86/5/404.abstract?sid=4e861499-e57a-40b3-833f-1c3a03449ee8).

Clearly the feasibility of MC as a prevention tool is highly culture-specific.  This aspect may be  undervalued by Kacker & Tobian, who, in reference to European contexts,  assume a link between low rates of MC and the absence of insurance cover for the procedure – as though, but for insurance, a practice of infant MC would be universally adopted by everybody in the interests of sexual health!  This makes light of the element of culture and tradition.  From an outsider perspective, history would appear to have delivered the US, the shape of infant MS, a fortuitous cultural advantage which it would seem all the more misguided to squander, as it is not something that any rationally-directed health strategy could have delivered to order.  This perspective, which seems a very persuasive one, is as absent from Kacker & Tobian’s paper as it from the AAP recommendation that the authorities proceed on the basis of a calculation of individual benefit and risk.

As three recent randomized control trials undertaken in Africa have shown, male circumcision can reduce risk of HIV transmission by 53-60%.  But sub-Saharan African countries will need to scale up voluntary male medical circumcision (VMMC) hugely if they are to achieve these preventative benefits.  (See our earlier blog: Costing the Scale-Up of Voluntary Male Medical Circumcision).  In these settings the availability and deployment of the necessary resources poses a great challenge.

The development of new medical technologies adapted to resource-limited settings may be the way to make such a scale-up achievable.  Last month saw the successful completion of safety and efficacy trials in Rwanda on a device – the Prepex – designed to achieve circumcision by non-surgical means.  This certainly brings Rwanda’s goal of circumcising 2 million men over the next two years a step closer (and with it the goal of reducing HIV transmission by a half); but is also good news for other sub-Saharan countries facing similar challenges.  Results of the three trials on the Prepex were presented to the 16^th International  Conference on Aids and Sexually Transmitted Infections in Africa (ICASA) at Addis Ababa.  The importance of non-surgical circumcision can be imagined in a country with only 300 trained physicians for a population of 10 million, and 90% of them living in rural areas remote from surgical facilities. But such conditions are replicated in other sub-Saharan countries which share Rwanda’s ambition to achieve HIV reduction through circumcision, and the challenge which this poses for the availability and deployment of resources.

The device itself operates by controlled radial elastic pressure so as to cut off circulation to the foreskin distally.  The necrotic foreskin can be removed bloodlessly from 4 days after the fitting of the device.  The Prepex offers a number of advantages over surgical circumcision that are particularly relevant to resource-limited settings.  The Prepex device does not require anaesthetic or sutures, may consequently be deployed in non-sterile conditions by non-medically trained staff.  Total time required for the procedure is just over 8 minutes, as opposed to the 25-36 minutes required for surgical circumcision.

Of the three Prepex trials successfully undertaken in Rwanda, the first was a non-controlled study of the feasibility of the procedure in 55 adult males; the second was a randomized controlled study comparing the non-surgical Prepex with surgical male circumcision; the third set out to demonstrate that the procedure could be performed safely and effectively by nurses.

The only results as yet published (JAIDS (15^th December 2011) relate to the first of these trials. Following the procedure the 55 subjects were monitored regularly for signs of bleeding, oedema and infection.  Levels of pain experienced at each stage of the procedure were assessed using VAS scores.  The paper makes detailed comparisons between the Prepex device and another circumcision devise – the Shang Ring.  The latter removes the live distal foreskin immediately after placement, and consequently requires anaesthesia and a sterile setting.

The Prepex procedure achieved complete circumcision in all cases with a median healing time of 21 days following removal of the device.  The only adverse event was a case of diffused oedema as a result of chronic urethritis from a belatedly reported STI.  This compares favourably with the six mild adverse events observed in a trial of 40 patients circumcised with the Shang Ring (M.A. Barone & F. Ndede et al., “The Shang Ring device for adult male circumcision: a proof of concept study in Kenya”, JAICS 2011;57: E7-E12).  The most serious issue with the Prepex device appears to be the experience of considerable pain during device removal (mean VAS score 5.4) which was not alleviated by paracetemol.

http://www.prepex.com/Scientific.aspx

Jean Paul Bitega, Agnes Binagwaho et al., “Safety and Efficacy of the PrePex Device for Rapid Scale-Up of Male Circumcision for HIV Prevention in Resource-Limited Settings”, JAIDS, Vol. 58, no. 5, December 15 2011

http://journals.lww.com/jaids/Fulltext/2011/12150/Safety_and_Efficacy_of_the_PrePex_Device_for_Rapid.16.aspx

The end of November saw the first in a series of nine new articles produced by researchers associated with the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United States President’s Emergency Plan of AIDS Relief (PEPFAR).  This article proposes a rapid (five-year) scale-up of voluntary medical male circumcision (VMMC) in 13 priority sub-Saharan countries, and its maintenance through to 2025. The ensuing eight papers will focus on the various factors that go into effective program expansion of VMMC, including data for decision making, policy and programmatic frameworks, logistics, demand creation, human resources, and translating research into services.

The paper argues that VMMC should be a vital element in the HIV prevention toolbox in view of its proven effectiveness, low relative  cost and cultural acceptability: three randomised control trials have demonstrated a 57% protective effect for males against HIV; mathematical modelling has shown it is cost-effective, with costs to avert on HIV infection ranging from US$150 to US$900; it is also a widely accepted practice, with 67% sub-Saharan males already circumcised.

Maximum impact will require coverage of 80% across the 13 countries – a target which is very much more ambitious for some countries than for others, given the very different levels of circumcision constituting their point of departure.  The number of circumcisions needed to reach this coverage is estimated at 20.3 million.

The cost of scaling up VMMC over the years 2011-2015 in order to reach this figure is estimated at US$1.5 billion, and a further 0.5 billion is allowed for the maintenance of this coverage from 2015 through to 2025. Given discounted individual lifetime cost of antiretroviral therapy of US$7,400, net saving from 2011-2015 due to averted treatment and care cost would be US$16.5 billion.  The scale-up of VMMC would therefore be not only cost-effective but highly cost-saving.  It would “create fiscal space” that would otherwise have been encumbered by treatment costs.

If implemented, the scale-up would avert 3.4 million HIV infections.  The paper gives estimated percentages for proportion of infections averted for each of the 13 countries.  The figures vary from 9.2% for Swaziland to 41.7% for Zambia, with a million infections averted in South Africa alone.  Initial impact would largely be among men, but the proportion of infections averted in women steadily increases over time until 2025 when nearly half the infections averted would have been among women.

According to the authors, it is the need for accountable leadership and vision on the part of government leaders, and not access to funding, that poses the greatest challenge to the success of VMMC scale-up.  They draw particular attention to the challenge of mobilising human resources, and refer to the work of Curran et al. which reviews the concepts of task shifting and task sharing and describes approaches to expanding the health sector workforce through redeployment of personnel and use of expatriate volunteers (“Voluntary medical male circumcision: strategies for meeting the human resource needs of scale-up in southern and eastern Africa”). PLoS Medicine (November 2011) 8: e1001129).

Catherine Hankins et al., “Voluntary Medical Male Circumcision: An Introduction to the Cost, Impact, and Challenges of Accelerated Scaling Up”, PLoS Medicine (November 2011) 8 e1001127

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001127

Curran et al., “Voluntary medical male circumcision: strategies for meeting the human resource needs of scale-up in southern and eastern Africa”). PLoS Medicine (2011) 8: e1001129 doi: 10.1371/journal.pmed.1001129

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001129

The publication last August in the Lancet (Aaron A R Tobian, Ronald H Gray et al.) of findings from one of the two randomized control studies undertaken 2004-9 by the Rakkai Health Sciences Program (RHSP), Uganda, on the health impacts of circumcision to reduce HIV/STI transmission, has generated further comment in the Lancet from researchers engaged in the South African context (A R Giuliano, A G Nyitray et al.).  The findings of the initial paper indicate the inefficacy of circumcision of HIV-infected males as means of preventing the transmission of Human Papilloma Virus (HPV) to long-term partners.  The issue of HPV transmission has its own importance, given high levels of oncogenic HPV in African countries (4 in 10,000).  But their public health significance becomes fully apparent when taken in conjunction with the findings of a parallel study within RHSP indicating the same inefficacy in relation to the transmission of HIV (by infected males to partners) (M J Wawer, F Makumbi  & G Kigozi).  Altogether, this amounts to indicating no discernible benefits in the case of HIV-infected males – a result which has to be viewed against the background of earlier studies demonstrating the efficacy of circumcision of non-HIV infected males.  So it seems the balance of benefits and disbenefits of circumcision could vary substantially for different groups of the population, with the net effect of circumcision of HIV-infected males being inefficacious, or even harmful.

The findings raise interesting issues for the circumcision programs now under way in Uganda (as from 2010) and elsewhere in sub-Saharan Africa.  The authors of the initial paper plainly envisage the possibility of HIV-infected males demanding circumcision in contexts where this intervention is being promoted as a means of HIV prevention.  Against whatever limited benefit – if any – circumcision may actually confer in such cases, there evidently needs to be balanced the possible impact on the sexual behaviour of HIV-infected males who believe that their circumcision will minimise the risk of their transmitting the infection.  So what if – as the study would suggest – circumcision confers little or no benefit?  Tobian & Gray recommend that circumcision should still not be refused – on the grounds that this might stigmatize.  But they emphasize that “wherever possible, circumcision should be offered with HIV counselling, condoms, and education about HIV prevention”.

The second issue concerns “the ideal time for male circumcision to optimise prevention of infection and disease”.  Here Giuliano & Nyitray corroborate the conclusion from the trial data that “the greatest population benefit is likely to be achieved if done before sexual debut and first exposure to HIV and HPV”.

These are clearly pressing issues in the context of government-backed HIV prevention through circumcision in Uganda and beyond.  The Rakkai Health Sciences Program, which is involved in the provision of circumcision and the training of circumcision providers who operate throughout Uganda, is well placed to conduct a range of research projects that may contribute to the formation of public policy.  Linked with John Hopkins Bloomberg School of Public Health, the program began in 1987 at the initiative of a group of scientists from Makerere University, Kampala.  It has benefited since then from US and International grants, and has hosted two major, randomized, control trials: one, funded by the NIH, to investigate the efficacy of circumcision for HIV prevention; the other, funded by the Gates Foundation, to investigate circumcision and its behavioural impact in men, women and communities.

A R Giuliano, A G Nyitray et al., “Circumcised HIV-infected men and HPV transmission”, The Lancet Infections Diseases, August 2011, vol 11

http://www.sciencedirect.com.libproxy.ucl.ac.uk/science/article/pii/S1473309911700731

A A R Tobian, Ronald H Gray et al., “Circumcision of HIV-infected men and transmission of human papillomavirus to female partners: analyses of data from a randomised trial in Rakai, Uganda”, The Lancet  Infectious Disease, August 2011, vol 11

http://www.sciencedirect.com.libproxy.ucl.ac.uk/science/article/pii/S147330991170038X

M J Wawer, G Kigozi et al., “Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial”, The Lancet 2009: 374: 229-37

http://www.sciencedirect.com.libproxy.ucl.ac.uk/science/article/pii/S0140673609609983

Celebrating 20+ years of public health research in Uganda

http://www.jhsph.edu/rakai/

Against the background of recent legislation by 18 states of the US to eliminate Medicaid Insurance for male circumcision, an editorial in the latest issue of the Journal of the American Medical Association (JAMA) argues the case for circumcision largely on the basis of evidence from African trials of its benefit in reducing HIV transmission.

In marked contrast with other predominantly white English-speaking nations where the practice of infant circumcision is rare or has steeply declined, in the US circumcision remains the norm (57% of males).  This latest drawing of the battle lines is the most recent phase in a US debate around the practice that has been going on for some time, and may now be reaching a decisive point.

The opponents of circumcision seem to view it, like the abusive tonsillectomy, or the cosmetic total dental extraction, as a practice of dubious medical benefit testifying to the doctrinaire medical interventionism of a bygone era.  They may be right.  One convincing explanation attributes the normalization of circumcision largely to the comprehensive medicalization of childbirth in the US (1% homebirths by 1955) at a time when infant circumcision was being most enthusiastically promoted by health professionals.  Circumcision would appear to have been well entrenched in American custom before more sceptical voices came to be raised.  Today’s sceptics argue that the relevance to the US of African trials purporting to prove the efficacy of circumcision as a preventative tool against HIV is, to the say least, unclear.  Preventative effects of circumcision have been demonstrated – if they have been demonstrated at all – only in relation to heterosexual transmission of HIV, and that, is of course not the predominant mode of HIV transmission in the US.

So what do the editors of JAMA have to say in response?  Potential benefits, they claim, are in three areas.  First, heterosexual transmission of HIV is an important mode of transmission for certain populations – including, significantly, many of those most likely to be affected by the withdrawal of Medicaid for circumcision, e.g. black and Hispanic populations.  Second, male circumcision may turn out to have preventative effects for homosexual as well as heterosexual transmission (though this is yet to be proved).  Third, circumcision has been demonstrated to have considerable preventative efficacy against other STIs, notably a 28%-34% reduction in the risk of acquiring genital herpes and a 32% reduction for oncogenic HPV.  It has also been shown to have a protective effect for the female partner, notably:  reductions of 28%, 40%, and 48% for ongenic HPV, vaginosis, and trichomoniasis, respectively.

In support of their claims the editors of JAMA refer to a recent cost-effectiveness study (Sansom, Prabhu & Hutchinson).  The latter claims to demonstrate that newborn circumcision in the US results in savings in costs and quality-adjusted life-years for all males, and especially for black and Hispanic males.  The number of circumcisions needed to prevent one HIV infection is calculated at 298 for all males and 65 for black males.  Given the relative cheapness of newborn circumcision, and the high cost of HIV, the cost-effectiveness of the intervention seems evident.  In the case of white males, at 1,231 circumcisions per one HIV infection, the economic argument for circumcision is less clear-cut.  The cost works out at $87,792 for each QALY saved.  This is at the borderline of cost effectiveness:  the traditional US cost-effectiveness threshold has been $50,000 per QALY saved, while the WHO recommends a threshold of three times per capita gross domestic product – which would give $140,000 per QALY.

Clearly, no one would nowadays advocate newly introducing newborn circumcision as a prevention measure in the US, if it didn’t already have a place in American tradition (though the benefits for STI prevention seem hugely more substantial than those envisaged by its original promoters).  Yet, given it does have such a place, it seems a shame not to take advantage of the potential public health benefits it can bring.

Aaron A. R. Tobian and Ronald H. Gray, “The medical benefits of male circumcision”, Editorial, Journal of the American Medical Association, 2011;306(13: 1479-1480

http://jama.ama-assn.org.libproxy.ucl.ac.uk/content/306/13/1479.full?sid=50e1d69b-2bfa-45e1-997a-43e655619a16

Samsom S.I., Prabhu V.S, Hutchinson A.B., et al “ Cost-effectiveness of newborn circumcision in reducing lifetime HIV risk among US males, PLoS One, 20105(1) e8723

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008723

http://www.historyofcircumcision.net/