HIV This Week

Welcome to the forty-eight issue of HIV This Week!  In this issue, we cover country responses (beyond The Gambia, Iran, and South Africa: what countries should do and some are doing to address unproven AIDS cures and counterfeit antiretroviral drugs), epidemiology (can we ever get the BED capture enzyme immunoassay to work well for HIV incidence estimates?; heterosexual transmission clearly on the march in China), basic science (what does HIV get up to in the brain anyway?; no wonder intranasal drug delivery can cause a big bang), global, multilateral and bilateral responses (donor prioritization of HIV: the overall pie for health and population has expanded four-fold but has HIV displaced aid for other health issues?), treatment failure (no randomised controlled trials of second–line therapy?; starting first-line late contributes to 13% mortality but for those who survive, 86% have virological suppression at 12 months in Uganda, sexual transmission and prevention (why knowing someone who died of AIDS in South Africa may not lead to behaviour change), stigma (a study of verbal abuse, physical abuse and neglect in Lesotho, Malawi, South Africa, Swaziland, and Tanzania sets the stage for policy and stigma monitoring systems; involuntary disclosure affects a prevention of mother-to–child transmission programme in Malawi), male circumcision (in case you are not convinced that it is important for high HIV prevalence settings to move on policy and programming), health care delivery (a strikingly low 35% of traditional birth attendants in rural communities in Cross River State, Nigeria have heard of HIV), and public health (the exciting new kid on the block: ‘Implementation Science’ makes its debut ).

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For full pdf access of this issue:HIV This Week Issue #48

Cate Hankins	Nicolai Lohse	Tania Lemay	Diane Addison
Chief Scientific Adviser	Research Officer	Research Consultant	Intern

Amon JJ. Dangerous medicines: Unproven AIDS cures and counterfeit antiretroviral drugs. Global Health. 2008 Feb 27;4(1):5 [Epub ahead of print]

Increasing access to antiretroviral therapy is a critical goal endorsed by the United Nations and all of its member states. At the same time, anecdotal accounts suggest that the promotion of unproven AIDS ‘cures’ and remedies are widespread, and in the case of The Gambia, Iran, and South Africa have been promoted by governments directly. Although a range of legislative and regulatory measures have been adopted by some governments, and technical assistance has been provided by international agencies to address counterfeit medicines generally, the threat of counterfeit antiretroviral drugs is not being addressed. Countries, charged with fulfilling the right to health and committed to expanding access to antiretroviral therapy must explicitly recognize their obligation to combat unproven HIV treatments and ensure the availability of a safe and efficacious drugs supply. International donors must help support and coordinate these efforts.

Editors’ note: In addition to The Gambia, Iran and South Africa, all countries in which the government has played an active role in promoting false cures for AIDS, this article also makes reference to ways in which false claims and counterfeit drugs are being dealt with, or are not being dealt with, in Kenya, Ethiopia, Myanmar, Côte d’Ivoire, Democratic Republic of Congo, China, Nigeria, the United States, Zambia, Mexico, Thailand, India, View Nam, Cambodia, Laos, and Zimbabwe. People whose confidence in antiretroviral treatment is undermined are far less likely to start and maintain the only life-prolonging treatment for AIDS we currently have. Governments have a responsibility to protect their people from any misleading information or treatments that harm health, whether by commission or omission. They need to enact legislation, monitor vigilantly, and act decisively to protect their citizens from unproven AIDS treatment and counterfeit medicines, and at the same time, aggressively and equitably scale-up antiretroviral treatment.

Hargrove JW, Humphrey JH, Mutasa K, Parekh BS, McDougal JS, Ntozini R, Chidawanyika H, Moulton LH, Ward B, Nathoo K, Iliff PJ, Kopp E. Improved HIV-1 incidence estimates using the BED capture enzyme immunoassay. AIDS. 2008;22(4):511-8.

Hargrove and colleagues aimed to validate the BED capture enzyme immunoassay for HIV-1 subtype C and to derive adjustments facilitating estimation of HIV-1 incidence from cross-sectional surveys. Laboratory analysis of archived plasma samples collected in Zimbabwe were performed. Serial plasma samples from 85 women who seroconverted to HIV-1 during the postpartum year were assayed by BED and used to estimate the window period between seroconversion and the attainment of a specified BED absorbance. HIV-1 incidences for the year prior to recruitment and for the postpartum year were calculated by applying the BED technique to HIV-1-positive samples collected at baseline and at 12 months. The mean window for an absorbance cut-off of 0.8 was 187 days. Among women who were HIV-1 positive at baseline and retested at 12 months, a proportion (epsilon) 5.2% (142/2749) had a BED absorbance < 0.8 at 12 months and were falsely identified as recent seroconverters. Consequently, the estimated BED annual incidence at 12 months postpartum (7.6%) was 2.2 times the contemporary prospective estimate. BED incidence adjusted for epsilon was 3.5% [95% confidence interval (CI), 2.6-4.5], close to the 3.4% estimated prospectively. Adjusted BED incidence at baseline was 6.0% (95% CI, 5.2-6.9) and, like the prospective estimates, declined with maternal age. Unadjusted BED incidence estimates were largely independent of age; the pooled estimate was 58% higher than adjusted incidence. The authors conclude that the BED method can be used in an African setting, but further estimates of epsilon and of the window period are required, using large samples in a variety of circumstances, before its general utility can be gauged.

Editors’ note: In December 2005, UNAIDS recommended against the use of the BED technique during routine HIV surveillance for estimating absolute HIV incidence or monitoring trends. This was because of the high number of false positive results for HIV incidence, i.e. people who had been living with HIV infection for a long time appeared to be recent seroconverters. The compensatory procedure identified here for sub-type C epidemics is promising but requires estimates of ‘epsilon’ in large samples from a variety of circumstances. Ideally, these should be obtained by comparing BED estimates with HIV incidence figures from other sources, as was done here.

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Chen XS, Yin YP, Tucker JD, Gao X, Cheng F, Wang TF, Wang HC, Huang PY, Cohen MS. Detection of Acute and Established HIV Infections in Sexually Transmitted Disease Clinics in Guangxi, China: Implications for Screening and Prevention of HIV Infection. J Infect Dis. 2007;196:1654-61.

Human immunodeficiency virus (HIV) has spread throughout China and to some degree has penetrated the general heterosexual population in some regions. A cross-sectional survey of 11,461 sexually transmitted disease (STD) clinic attendees in 8 cities in Guangxi, China, was conducted for syphilis and for acute and established HIV infections. The prevalence of HIV was 1.2% among the participants. Five acute (pre-seroconversion) HIV infections were detected. Multivariate analysis showed that HIV infection was independently related to unmarried status (odds ratio [OR], 1.73 [95% confidence interval {CI}, 1.00-2.99), less education (OR for less than primary school, 4.21 [90% CI, 1.21-14.58]), residence in city A (OR, 11.48 [95% CI, 2.05-64.31]) or city B (OR, 7.93 [95% CI, 1.75-35.91]), working in the entertainment industry (OR, 3.98 [95% CI, 1.14-13.88]), injection drug use (OR, 25.09 [95% CI, 10.43-60.39]), no condom use during most recent sexual intercourse (OR, 4.97 [95% CI, 1.38-17.88]), and syphilitic infection (OR, 1.91 [95% CI, 1.03-3.56]). Chen and colleagues conclude that the HIV prevalence in STD clinics is significantly greater than that in the general population, and subjects were identified who would be missed by conventional surveillance. China’s nationwide system of public STD clinics, which reach down to the township level, should be used for HIV control programs.

Editors’ note: With nearly half of new HIV infections in China in 2006 a result of heterosexual transmission, China needs to rapidly move on this front to increase the low condom use rates, particularly in the context of sex work. Large numbers of migrant labourers are on the move and sex with a sex worker in the previous year was reported by 9% of men in a population-based survey. In addition, China’s imbalanced sex ratios have created a population of young, poor, unmarried men of low education who are at higher sexual risk of HIV infection, Changing the conditions of sex work to 100% condom use and introducing provider-initiated HIV testing in STD clinics under conditions of the 3 Cs (consent, confidentiality, and counselling) are critical actions in what is clearly a shifting epidemic.

Kaul M, Lipton SA. Mechanisms of neuroimmunity and neurodegeneration associated with HIV-1 infection and AIDS. J Neuroimmune Pharmacol. 2006 Jun;1(2):138-51.

Infection with the human immunodeficiency virus-1 (HIV-1) the virus causing acquired immunodeficiency syndrome (AIDS), is a persistent health problem worldwide. HIV-1 seems to enter the brain very soon after peripheral infection and can induce severe and debilitating neurological problems that include behavioural abnormalities, motor dysfunction, and frank dementia. Infected peripheral immune-competent cells, in particular macrophages, appear to infiltrate the CNS and provoke a neuropathological response involving all cell types in the brain. The course of HIV-1 disease is strongly influenced by viral and host factors, such as the viral strain and the response of the host’s immune system. In addition, HIV-1-dependent disease processes in the periphery have a substantial effect on the pathological changes in the central nervous system (CNS), although the brain eventually harbours a distinctive viral population of its own. In the CNS, HIV-1 also incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes, and glutamate receptor-mediated excitotoxicity, all of which can initiate numerous downstream signalling pathways and disturb neuronal and glial function. Although there have been many major improvements in the control of viral infection in the periphery, an effective therapy for HIV-1-associated dementia (HAD) is still not available. This article addresses recently uncovered pathologic neuroimmune and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and discusses experimental and potentially future therapeutic approaches.

Editors’ note: This review provides an overview of how HIV in the brain stimulates immune system reactions, including inflammatory cytokines that are highly toxic to cells of the central nervous system. Prior to combination antiretroviral treatment, the majority of patients with HIV associated dementia would deteriorate rapidly over several months. Now it appears that virological improvement of patients with dementia who are on antiretroviral treatment correlates with neurological improvement, leading to a more favourable prognosis. Differences in the abilities of specific antiretroviral drugs to penetrate the central nervous system may explain why some people with dementia and not others respond well.

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Hanson LR, Frey WH 2nd. Strategies for intranasal delivery of therapeutics for the prevention and treatment of neuroAIDS. J Neuroimmune Pharmacol. 2007;2(1):81-6. Epub 2006 Sep 15.

Intranasal drug administration is a noninvasive method of bypassing the blood-brain barrier to deliver neurotrophins and other therapeutic agents to the brain and spinal cord. This method allows drugs that do not cross the blood-brain barrier to be delivered to the central nervous system (CNS) and eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways. Intranasal delivery occurs by an extracellular route and does not require that drugs bind to any receptor or undergo axonal transport. Intranasal delivery also targets the nasal associated lymphatic tissues and deep cervical lymph nodes. In addition, intranasally administered therapeutics are observed at high levels in the blood vessel walls and perivascular spaces of the cerebrovasculature. Using this intranasal method in animal models, researchers have successfully reduced stroke damage, reversed Alzheimer’s neurodegeneration, reduced anxiety, improved memory, stimulated cerebral neurogenesis, and treated brain tumors. In humans, intranasal insulin has been shown to improve memory in normal adults and patients with Alzheimer’s disease. Intranasal delivery strategies that can be employed to treat and prevent NeuroAIDS include: (1) target antiretrovirals to reach HIV that harbors in the CNS; (2) target therapeutics to protect neurons in the CNS; (3) modulate the neuroimmune function of monocyte/macrophages by targeting the lymphatics, perivascular spaces of the cerebrovasculature, and the CNS; and (4) improve memory and cognitive function by targeting therapeutics to the CNS.

Editors’ note: The blood – brain barrier serves to protect the brain and spinal cord from a variety of pathogens and toxic substances, but it is also a barrier to treatment of central nervous system disorders, including those caused by HIV infection. Intranasal drug delivery, which patients can do themselves, targets therapeutic agents directly to the brain, by-passing the blood-brain barrier and reducing systemic exposure. It can be used to treat neuroAIDS by targeting antiretroviral drugs, including neuroimmune modulators, to reach HIV that harbours in the central nervous system (CNS), to protect neurons in the CNS, and to improve memory and cognitive function. Intranasal insulin anyone?

Shiffman J. Has donor prioritization of HIV/AIDS displaced aid for other health issues? Health Policy Plan. 2008 Mar;23(2):95-100.

Advocates for many developing-world health and population issues have expressed concern that the high level of donor attention to HIV is displacing funding for their own concerns. Even organizations dedicated to HIV prevention and treatment have raised this issue. However, the issue of donor displacement has not been evaluated empirically. This paper attempts to do so by considering donor funding for four historically prominent health agendas - HIV, population, health sector development, and infectious disease control - over the years 1992 to 2005. The paper employs funding data from the Organization for Economic Cooperation and Development’s (OECD) Development Assistance Committee, supplemented by data from other sources. Several trends indicate possible displacement effects, including HIV’s rapidly growing share of total health aid, a concurrent global stagnation in population aid, the priority HIV control receives in US funding, and HIV aid levels in several sub-Saharan African states that approximate or exceed the entirety of their national health budgets. On the other hand, aggregate donor funding for health and population quadrupled between 1992 and 2005, allowing for funding growth for some health issues even as HIV acquired an increasingly prominent place in donor health agendas. Overall, the evidence indicates that displacement is likely occurring, but that aggregate increases in global health aid may have mitigated some of the crowding-out effects.

Editors’ note: Although this study considers only aggregate donor funding, does not evaluate national health funding in depth, and does not account for factors influencing funding for other health issues, such as disease burden and effectiveness of advocacy, it will definitely start you thinking. We can only imagine how funding flows might have evolved in a world without AIDS, the so-called ‘counterfactual’ of which economists speak. More in-depth studies are needed to examine the politics of aid provision in high-income countries, interactions among donors themselves, and dynamics in low- and middle-income countries in the context of donor harmonization initiatives and the Three Ones principles that place countries squarely in the driver’s seat.

Humphreys E, Hernandez L, Rutherford G. Antiretroviral regimens for patients with HIV who fail first-line antiretroviral therapy. Cochrane Database Syst Rev 2007;(4):CD006517.

Highly active antiretroviral therapy (ART) has reduced the morbidity and mortality of patients with HIV. A common first-line ART regimen includes a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs). If treatment failure occurs, a change to second-line therapy is necessary. This meta-analysis aimed to assess the optimum antiretroviral regimen for patients with HIV who fail first-line therapy (ART-naive) with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV. As a search strategy, electronic databases and conference proceedings were searched with relevant search terms without limits to language. In the selection, randomised controlled trials of adult persons living with HIV administered second-line ART after virologic failure of a first-line regimen were included. The primary outcome measure included the proportion of patients achieving undetectable plasma HIV RNA concentration. Secondary outcome measures included change in mean CD4 cell count, clinical resolution of symptoms, rate of adverse events, rate of change in therapy for failure, rate of change in therapy for toxicity, and mortality. Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. Twenty-one records were identified in total, 6 of which were duplicates. None of the records met inclusion criteria. Humphreys and colleagues conclude that there is insufficient evidence to evaluate second-line therapies in patients with HIV who fail first-line treatment with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV. Current recommendations are based on available resources and results from individualised treatment decisions based on resistance testing and clinician choice.

Editors’ note: Discouragingly, the authors were unable to find randomised controlled trials of people receiving second-line antiretroviral treatment after virologic failure of the most common first-line regimens. In the absence of results from such trials, antiretroviral treatment programmes need to closely document the effects of switches to second treatment on clinical prognosis. This is increasingly important as first-line failures accrue in the coming decade.

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Kamya MR, Mayanja-Kizza H, Kambugu A, Bakeera-Kitaka S, Semitala F, Mwebaze-Songa P, Castelnuovo B, Schaefer P, Spacek LA, Gasasira AF, Katabira E, Colebunders R, Quinn TC, Ronald A, Thomas DL, Kekitiinwa A; the Academic Alliance for AIDS Care and Prevention in Africa. Predictors of Long-Term Viral Failure Among Ugandan Children and Adults Treated With Antiretroviral Therapy. J Acquir Immune Defic Syndr 2007;46:187-193.

HIV RNA viral load testing is costly and is generally unavailable in resource-limited settings. Kamya and colleagues identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART). From April 2004 to June 2005, consecutive treatment-naive patients beginning ART at a university clinic in Uganda were enroled. Clinical information, CD4 cell count, and HIV RNA level were collected at baseline and every 3 to 6 months. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with viral failure at 12 months was measured at baseline and at 6 and 12 months. Five hundred twenty-six adults and 250 children (0 to 18 years of age) were started on first-line ART regimens and followed for 12 months. Outcomes could not be assessed in 13% of patients (79 died and 21 were withdrawn). Children were almost twice as likely to have viral failure compared with adults (26% vs. 14%; P = 0.0001). In adults, the sole independent predictor of viral failure was treatment with stavudine(d4T)/lamivudine(3TC)/nevirapine(NVP) versus zidovudine (ZDV)/3TC/efavirenz (EFV) (odds ratio [OR] = 2.59, 95% confidence interval [CI]: 1.20 to 5.59). In children, independent predictors of viral failure included male gender (OR = 2.44, 95% CI: 1.20 to 4.93), baseline CD4% <5 (OR = 2.69, 95% CI: 1.28 to 5.63), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR = 2.46, 95% CI: 1.23 to 4.90). All 8 patients with viral breakthrough and genotypic drug resistance results had nonnucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC-associated mutations. In conclusion, these data demonstrate the effectiveness of ART in a low-resource setting. Children and patients of all ages taking the d4T/3TC/NVP regimen were more likely to have viral failure. The data suggest that viral failure occurring 6 months or more after the start of ART regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus.

Editors’ note: Profound immunosuppression at ART initiation, high levels of TB-HIV co-infection, and unstructured treatment interruptions due to drug stockouts or cost can all contribute to treatment failure. Early mortality was high in this study (13% of people had died by 12 months). However, adherence among the survivors was very high (treatment was free of charge) and 86% of people had achieved viral suppression 12 months after starting ART. Pharmacokinetic studies of the drugs being used in standard regimens may help determine the likely origin of NNRTI and 3TC resistance in this population.

Palekar R, Pettifor A, Behets F, Macphail C. Association Between Knowing Someone Who Died of AIDS and Behavior Change Among South African Youth. AIDS Behav 2007 Nov 6; [Epub ahead of print]

In South Africa, the rising AIDS-related mortality has increased the publicity of the HIV epidemic and may have an impact on behaviour change. Palekar and colleagues examined the association between knowing someone who has died of AIDS and self-reported behaviour change, condom use at last intercourse, number of partners in the prior 12 months, and attitudes towards HIV, among South African youth aged 15-24. The authors found that over 40% of youth reported knowing someone who died of AIDS, most commonly a neighbour. Using multivariable logistic regression, the authors found that high school-educated youth who knew someone who died of AIDS were significantly more likely to report having changed their behaviour as a result of HIV (OR 2.01, 95% CI: 1.32;3.06). The authors found no association between knowing someone who died of AIDS and other HIV prevention-related behaviours. While youth tended to have increased odds of perceiving HIV to be serious, they did not consistently perceive their risk of contracting HIV to be higher when they knew someone who died of AIDS. The results suggest that part of the key to creating behaviour change in youth may lie in better understanding what factors increase youth’s perceived risk of contracting HIV which will help us better target these interventions. If youth are affected by personal knowledge of an AIDS death, to the point that they change their behaviours, we must continue to encourage discourse about HIV with the hope that persons dying from AIDS will feel more comfortable disclosing their diagnosis to youth they know and others.

Editors’ note:The authors hypothesized that knowing someone who died of AIDS would be associated with increased condom use, decreased numbers of sexual partners, and increased perceived risk of contracting HIV. Although a striking 40% of study participants knew someone who had died of AIDS, this person may not have been someone they felt emotionally close to or identified with. This may account for the finding that most of the young people who knew someone who had died did not perceive themselves to be at increased risk of HIV infection in this cross-sectional study. With no increase in risk perception, it is not difficult to understand why, in most cases, death did not catalyze significant behaviour change.

Dlamini PS, Kohi TW, Uys LR, Phetlhu RD, Chirwa ML, Naidoo JR, Holzemer WL, Greeff M, Makoae LN. Verbal and physical abuse and neglect as manifestations of HIV/AIDS stigma in five African countries. Public Health Nurs 2007;24:389-99.

Dlamini and colleagues aimed to explore the experience of HIV-related stigma for people living with HIV in Lesotho, Malawi, South Africa, Swaziland, and Tanzania. The authors conducted a descriptive study using 43 focus groups (n=251 participants), which included male and female people living with HIV from both rural and urban areas and nurses working with people living with HIV. Participants were asked to relate incidents of HIV-related stigma that they had experienced or observed. Focus group discussions were taped, and data were content analyzed to identify examples of abuse (verbal and physical abuse and neglect) related to HIV stigma. Data analysis also explored targets of abuse, abusers, and consequences of abuse. Participant reports documented extensive verbal and physical abuse and neglect or negating ( disallowing of access to services and opportunities) experienced by people living with HIV and observed by nurses caring for them, and identified negative consequences experienced by people living with HIV whose HIV-positive status was disclosed to family, friends, or community members. The authors conclude that health care workers who encourage people living with HIV to disclose their HIV status must carefully consider the implications of encouraging disclosure in an environment with high levels of stigma, and must recognize the real possibility that persons living with HIV may experience serious verbal and physical abuse as a consequence of disclosure.

Editors’ note: In this five-country study, verbal abuse was common but physical abuse less so. The authors anticipate that, in contrast to the high HIV prevalence communities in which this study was conducted where many individuals, families, and health workers have already been confronted with their own feelings about HIV, there would be a higher incidence of abuse in communities where AIDS is less common. Neglect, including by health care workers, was also reported. Governments need to firmly address the problem of abuse, by explicit polices backed up by a system for monitoring their implementation and effects.

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Thorsen VC, Sundby J, Martinson F. Potential initiators of HIV-related stigmatization: ethical and programmatic challenges for pmtct programs. Dev World Bioeth. 2008 Feb 5 [Epub ahead of print].

HIV continues to constitute a serious threat to the social and physical wellbeing of African mothers and their babies. In the hardest hit countries of sub-Saharan Africa, more than 60% of all new HIV infections are occurring in women, infants and young children. Mother-to-child transmission constitutes 90% of new HIV infections among infants and young children. Most of these infections can be prevented. However, the social stigma of HIV insidiously continues to undermine the success of prevention programmes. Ironically, some attributes or characteristics of prevention of mother-to-child transmission (PMTCT) programmes may in fact serve as catalysts to the stigmatization process. This paper identifies and discusses six potential initiators: (1) Routine HIV testing, (2) Six months exclusive breastfeeding, (3) Incentives, (4) Home visits, (5) Location of PMTCT program, and (6) PMTCT terminology. In all these areas, there are practical strategies that may be applied to reduce the chances of being stigmatized. These strategies are introduced and discussed.

Editors’ note: This paper describes a Malawian PMTCT programme that unintentionally discloses its clients’ HIV-positive status, thus compromising its ability to protect their right to privacy and confidentiality and contributing to their stigmatization. Lack of attention to the sociocultural and political tapestry in which women live will lead to similar negative results as PMTCT programmes are scaled up. This paper makes several suggestions on practical ways to better protect confidentiality and increase community acceptance, all of which could lead to increased programme uptake.

Weiss HA, Halperin D, Bailey RC, Hayes RJ, Schmid G, Hankins CA. Male circumcision for HIV prevention: from evidence to action? AIDS. 2008 Mar 12; 22( 5): 567-74.

The conclusive results of three randomized controlled trials (RCT) showing that male circumcision reduces the risk of HIV acquisition by 58% (95% CI 43–69%) are both promising and challenging. To guide the translation of these research findings into public health policy, Weiss and colleagues estimate the global prevalence and distribution of male circumcision, summarize the evidence of an impact on HIV incidence, and highlight the major public health opportunities and challenges raised by these findings. The authors estimate that 30–34% of adult men are circumcised worldwide. Overall, an estimated 68% of circumcised men are Muslim and 1% are Jewish, with coverage almost universal in the Middle East, north Africa, Pakistan, Bangladesh, and Indonesia. The results of the RCTs confirmed the findings of a previous meta-analysis of 15 observational studies that circumcised men had a large, highly statistically significant reduced risk of HIV acquisition (risk reduction 58%, 95% CI 46–66%). Further, the high density of HIV target cells that are relatively accessible to HIV infection in the inner foreskin provides a plausible biological mechanism that could explain the increased risk of HIV in uncircumcised men. Several countries are planning to introduce or expand safe male circumcision programmes, including Kenya, Zambia, Swaziland and Rwanda, and international funding agencies are backing this strategy. National policies, however, are needed to maximize the safety, efficiency, and availability of male circumcision service provision. Challenges include potential behaviour change following male circumcision (risk compensation), predicting the potential population-level epidemic impact and cost-effectiveness of male circumcision, knowing the impact on female partners, and knowing the impact for men who have sex with men. In summary, male circumcision provides a much needed addition to the current HIV prevention armamentarium. It is not a new, untested or unknown technology, but possibly the oldest, and certainly the most common, surgical procedure known. The evidence from the trials is conclusive, and the challenges to implementation must now be faced.

Editors’ note:This editorial review constitutes an overview of why male circumcision is currently on the policy agenda of a number of countries, particularly those in southern and eastern Africa with a high HIV prevalence overall or among sub-populations. The WHO/UNAIDS position on male circumcision for HIV prevention may be found at http://data.unaids.org/pub/Report/2007/mc_recommendations_en.pdf.

Bassey EB, Elemuwa CO, Anukam KC. Knowledge of, and attitudes to, acquired immune deficiency syndrome (AIDS) among traditional birth attendants (TBAs) in rural communities in Cross River State, Nigeria. Int Nurs Rev 2007;54:354-8.

Bassey and colleagues aimed to survey knowledge of, and attitudes towards HIV held by traditional birth attendants (TBAs) in rural communities in Cross River State, Nigeria. As the HIV epidemic continues to spread, undermining development, reversing health gains and exacerbating poverty, TBAs in rural communities in Cross River State, Nigeria are still less informed about this dreadful disease. A survey consisting of structured questionnaires was used with 140 randomly selected TBAs to assess their knowledge of HIV, source of information on HIV, and protective practices. Sixty-two (44.3%) of the TBAs had no formal education. Forty-four (31.4%) had primary education, while 19 (13.6%) had secondary education. On knowledge of HIV and sources of information, 49 (35.0%) of respondents reported knowing what HIV means. While 26.4% indicated that they received information about HIV from the government health centres, 23.6% had no information about the disease. There was a great disparity between male (73.7%) and female (28.9%) respondents on knowledge about HIV. On the use of protective safety procedures during delivery, 61 (43.6%) used sterilized blades, while 10.7% admitted wearing protective clothes and gloves. Only three (2.1%) of the respondents said that they were aware of the HIV status of their clients prior to delivery. The authors conclude that this survey has demonstrated that few TBAs in the communities studied in Cross River State are informed about HIV, and that this has revealed the urgency of starting a programme specifically designed for TBAs in rural communities towards a massive educational campaign on HIV.

Editors’ note: These are extraordinary (we hope) and highly discouraging findings in this day and age – 35% of traditional birth attendants in this Nigerian study knew about HIV and less than half were using sterilised blades – a problem for HIV, hepatitis B and C and other blood borne infections including tetanus. Education and training in universal precautions for all traditional birth attendants should be a priority on public health grounds.

Madon T, Hofman JK, Kupfer L, Glass RI. Implementation Science. Science. 2007 Dec 14;318(5857):1728-9.

Nearly 14,000 people in sub-Saharan Africa and South Africa die daily from HIV, malaria, and diarrhoeal disease, even though scientific advances have enabled prevention, treatment, and, in some cases, elimination of these diseases in developed countries. Many evidence-based innovations fail to produce results when transferred to communities in the global south, largely because their implementation is untested, unsuitable, or incomplete. Why is effective implementation, particularly in resource-poor countries, such as an intractable problem? The reasons are complex. First, scientists have been slow to view implementation as a dynamic, adaptive, multiscale phenomenon that can be addressed through a research agenda. Second, people living in poverty face a bewildering constellation of social constraints and health threats that make prevention and treatment more difficult. Realizing the need for a quantitative, scientific framework to guide health-care scale up in developing countries, researchers in health, engineering, and business are building interest in implementation science. Unlike routine applied (or operations) research, which may identify and address barriers related to the performance of specific objects, implementation sciences creates generalizable knowledge that can be applied across settings and contexts to answer central questions. Why do established programs lose effectiveness over days, weeks, or months? Why do tested programs sometimes exhibit unintended effects when transferred to a new setting? How can multiple interventions be effectively packaged to capture cost efficiencies and to reduce the splintering of health systems into disease-specific programs? Many implementation experiments- particularly cluster-randomized trials and agent-based models that compare the population level health impacts of different delivery strategies-can be coupled with the planning and roll-out of new programs by health ministries, making the cost of research marginal. They can also be used to model the potential gains of health-system designs, policies, and multisector interventions that cannot be tested experimentally. These approaches all require the involvement of scientists in early planning to ensure that research questions are incorporated into program design. There are three additional imperatives facing the research community. First, we must advance theoretical models and new analytic methods that apply to resource-poor settings. Second, we need to train a generation of researchers who can effectively bridge the implementation gap. A final imperative is for researchers to collaborate with developing country governments, nongovernmental organizations (NGOs), and communities. Although implementation experiments and computational modelling may be more complex- in terms of study design and data analysis- than the monitoring and observational studies currently funded by donors, any inconvenience is outweighed by the profound ability of scientifically rigorous findings to focus limited health resources and to save more lives.

Editors’ note: Donors and governments are increasingly aware of the importance of monitoring and evaluation and of operational research to improve the quality, efficiency, and effectiveness of programmes. This article draws attention to the exciting new ‘implementation science’ which can provide answers to central questions about how to maximise impact across different settings.