HIV This Week: what scientific journals said

Welcome to the 86th issue of HIV This Week ! In this issue, we cover the following topics:
1. HIV Testing If you build it, they will come: success of an integrated prevention campaign in rural Kenya. 2. Risk compensation "When I was circumcised I was taught certain things Decreased sexual risk behaviour in South Africans on antiretroviral treatment 3. Epidemiology How to use mortality rates to adjust HIV prevalence for survey non-response 4. Sexual transmission Modelling the impact of viral load reductions on heterosexual transmission risk 5. Resources and Financing Are countries spending too much on HIV? 6. Pre-Exposure Prophylaxis Preparing for PrEP: questions for implementation science 7. Adolescents living with HIV High time for provider-initiated testing and counselling in southern Africa primary care settings 8. Treatment Stavudine (d4T) toxicity in Ugandan women 9. Disease progression and alcohol Should you adjust your alcohol intake yet? 10.Health care delivery Has HIV service scale-up helped other services in Zambia? 11.Economics Return to employment and daily life activities: the effect of 3 years on treatment in South Africa 12.Street youth Disturbing HIV prevalence among Ukrainian street youth 13.Vaccines First step on the road to an oral HIV vaccine 14.Basic Science What coreceptor HIV prefers can make a difference to disease progression 15.Prevention of mother-to-child transmission Traditional birth attendants in rural Mysore, India: a long way to go to improve maternal child health outcomes 16.Paediatric diagnosis A point of care p24 antigen rapid test comes on the stage 17.Sex and gender Women and clinical trials: sex-based outcomes of darunavir-ritonavir therapy

Cate Hankins Chief Scientific Adviser to UNAIDS

Precious Lunga Research officer

Tania Lemay Research consultant

Sylvia Beke-Wilson Assistant

To find out how you can access a majority of scientific journals free of charge, please see the last page of this issue or check the HIV This Week website clicking here. If you are reading this through the kindness of a friend and would like to subscribe to receive HIV This Week pdf issues by email, you can sign up by clicking here. To unsubscribe, please click the following link: unsubscribe. We want to be as helpful to you as we can, so please let us know what your interests are and what you think of HIV This Week by sending a comment to hivthisweek(at)unaids.org or by posting one on the HIV This Week weblog. If you would like to recommend an article for inclusion, please contact HIV This Week here. Dont forget that you can find a wealth of information on the HIV epidemic and responses to it at www.unaids.org.

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1. HIV Testing
Rapid implementation of an integrated large-scale HIV counselling and testing, malaria, and diarrhoea prevention campaign in rural Kenya.
Lugada E, Millar D, Haskew J, Grabowsky M, Garg N, Vestergaard M, Kahn J, Muraguri N, Mermin J. PLoS One. 2010;5(8):e12435.

Integrated disease prevention in low resource settings can increase coverage, equity and efficiency in controlling high burden infectious diseases. A public-private partnership with the Ministry of Health, Centers for Disease Control, Vestergaard Frandsen and CHF International implemented a one-week integrated multi-disease prevention campaign. Residents of Lurambi, Western Kenya were eligible for participation. The aim was to offer services to at least 80% of those aged 15-49. 31 temporary sites in strategically dispersed locations offered: HIV counselling and testing, 60 male condoms, an insecticide-treated bednet, a household water filter for women or an individual filter for men, and for those testing positive, a 3-month supply of cotrimoxazole and referral for follow-up care and treatment. Over 7 days, 47,311 people attended the campaign with a 96% uptake of the multi-disease preventive package. Of these, 99.7% were tested for HIV (87% in the target 15-49 age group); 80% had previously never tested. 4% of those tested were positive, 61% were women (5% of women and 3% of men), 6% had median CD4 counts of 541 cell/L (IQR; 356, 754). 386 certified counsellors attended to an average 17 participants per day, consistent with recommended national figures for mass campaigns. Among women, HIV infection varied by age, and was more likely with an ended marriage (e.g. widowed vs. never married, OR.3.91; 95% CI. 2.87-5.34), and lack of occupation. In men, quantitatively stronger relationships were found (e.g. widowed vs. never married, OR.7.0; 95% CI. 3.5-13.9). Always using condoms with a non-steady partner was more common among HIV-infected women participants who knew their status compared to those who did not (OR.5.4 95% CI. 2.3-12.8). Through integrated campaigns it is feasible to efficiently cover large proportions of eligible adults in rural underserved communities with multiple disease preventive services simultaneously achieving various national and international health development goals.
For full text click access here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012435

Editors note: Talk about integration and meeting peoples needs! This exciting 7-day programme in an area of high malaria incidence, poor sanitation and high diarrhoeal disease, and a low knowledge of HIV serostatus elicited high demand. The population consisted of 51,178 people aged 15-49 years living in 157 villages covering an area of 194 square kilometres. Over 87% of them showed up (along with almost 2800 non-residents) for the MPP (multi-disease prevention package) that consisted of a long-lasting impregnated bednet to prevent night-time mosquito bites, a water purification system, 60 condoms, and testing and counselling for HIV. Uptake was higher for the MPP than had ever been seen for social marketing campaigns for its individual components. Following individual pre-test counselling, fully 99.7% consented to have a test for HIV and receive the results. Unique client numbers delinked from personal identifiers protected confidentiality and micro-planning exercises projected daily demand and matched it to personnel and logistics requirements for 30 service delivery sites. A pre-campaign survey identified appropriate media messages and channels for a health education/community mobilisation programme which began one month before and continued during the 7-day campaign. More outside the facility multi-disease integrated campaigns such as this have the potential to achieve rapid, high, equitable coverage to address multiple health challenges on the road to the Millennium Development Goals.

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2. Risk compensation
"When I was circumcised I was taught certain things": risk compensation and protective sexual behaviour among circumcised men in Kisumu, Kenya.
Riess TH, Achieng' MM, Otieno S, Ndinya-Achola JO, Bailey RC. PLoS One. 2010 Aug 25;5(8). pii: e12366.

Male circumcision has been shown to reduce the transmission of HIV from women to men through vaginal sex by approximately 60%. There is concern that men may engage in risk compensation after becoming circumcised, diminishing the benefits of male circumcision. Reiss and colleagues conducted qualitative interviews with 30 sexually active circumcised men in Kisumu, Kenya from March to November 2008. Most respondents reported no behaviour change or increasing protective sexual behaviours including increasing condom use and reducing the number of sexual partners. A minority of men reported engaging in higher risk behaviours either not using condoms or increasing the number of sex partners. Circumcised respondents described being able to perform more rounds of sex, easier condom use, and fewer cuts on the penis during sex. The results illustrate that information about male circumcisions protection against HIV has disseminated into the larger community and male circumcision accompanied by counselling and HIV testing can foster positive behaviour change and maintain sexual behaviour.
For full text access click here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012366

Editors note: This first published qualitative study exploring male circumcision and risk compensation gives us rich insights into young mens motivations for changing or maintaining sexual behaviour following circumcision. The term risk compensation refers to people modifying their behaviour in an offsetting way in response to real or perceived changes in risk. In the case of male circumcision, there have been concerns that men who become circumcised might stop using condoms, increase their number of sexual partners, or choose higher risk sexual partners. This study of 30 circumcised men makes for an interesting read and is a solid contribution to our understanding of how young men perceive the partial protection that male circumcision affords against HIV. Of the five men who reported risk compensation in this study, one stopped using condoms temporarily with his wife and four increased the number of sexual partners but reported using condoms with their new partners. The remainder either maintained their previous behaviour (n=17) or reduced their risk (n=8) by either decreasing their number of partners or increasing condom use. Nine of the men had not received counselling at the time of circumcision and yet they reported no increase in risky behaviour, underscoring the widespread penetration of the partial protection message in the general community in Kisumu. Those who did receive counselling and HIV testing in the context of the surgery, reported it as influential in their subsequent sexual behaviour choices. This gives added fuel to the argument that male circumcision services are best conceived and delivered as male sexual and reproductive health programmes. Decreased sexual risk behavior in the era of HAART among HIV-infected urban and rural South Africans attending primary care clinics.
Venkatesh KK, de Bruyn G, Lurie MN, Mohapi L, Pronyk P, Moshabela M, Marinda E, Gray GE, Triche EW, Martinson NA. AIDS. 2010 24:2687-96

In light of increasing access to antiretroviral therapy in sub-Saharan Africa, the authors conducted a longitudinal study to assess the impact of antiretroviral therapy on sexual risk behaviours among HIVinfected South Africans in urban and rural primary care clinics. This prospective observational cohort was conducted at rural and urban primary care HIV clinics in South Africa consisting of 1544 men and 4719 UNAIDS_CSA-RO_HIVthisweek_86_101121 3

women enrolled from 2003 to 2010, representing 19703 clinic visits. The primary outcomes were being sexually active, unprotected sex and more than one sex partner and were evaluated at 6 monthly intervals. Generalized estimated equations assessed the impact of antiretroviral therapy on sexual risk behaviours. Among 6263 HIV-infected men and women, over a third (37.2%) initiated antiretroviral therapy during study follow-up. In comparison to pre-antiretroviral therapy follow-up, visits while receiving antiretroviral therapy were associated with a decrease in those reporting being sexually active [adjusted odds ratio: 0.86 (95% confidence interval: 0.78-0.95)]. Unprotected sex and having more than one sex partner were reduced at visits following antiretroviral therapy initiation compared to preantiretroviral therapy visits [adjusted odds ratio: 0.40 (95% confidence interval: 0.34-0.46) and adjusted odds ratio: 0.20 (95% confidence interval: 0.14-0.29), respectively]. Sexual risk behaviour significantly decreased following antiretroviral therapy initiation among HIV-infected South African men and women in primary care programs. The further expansion of antiretroviral treatment programs could enhance HIV prevention efforts in Africa.
For abstract access: http://www.ncbi.nlm.nih.gov/pubmed/20808202

Editors note: This large prospective cohort study, nearly a decade long, did not find evidence of sexual risk compensation among people who started antiretroviral treatment in urban and rural primary care settings in South Africa. People had less sex, did not increase unprotected sex, or increase their number of sexual partners after they started treatment, independent of CD4 count. This is an important contribution to a field that has seen differing results from studies of varying sizes and lengths in Kenya, Cameroon, Uganda, and Cote dIvoire. If sexual behaviour becomes safer at the same time that viral loads are declining, secondary transmission of HIV would be further reduced. What is needed now are qualitative studies to explore the reasons for such behaviour change and quantitative studies to determine whether initial declines in sexual risk behaviour are maintained over longer periods of time. It is not possible to disentangle the effects of antiretroviral treatment alone from the ongoing counselling and prevention messages that all of these patients received in their primary care settings. It is highly likely that the contribution of treatment for prevention will depend on comprehensive care that includes a strong focus on safer sex.

3. Epidemiology
Adjusting HIV prevalence for survey non-response using mortality rates: an application of the method using surveillance data from Rural South Africa.
Nyirenda M, Zaba B, Brnighausen T, Hosegood V, Newell ML. PLoS One. 2010 Aug 25;5(8). pii: e12370.

The main sources of HIV prevalence estimates are household and population-based surveys; however, high refusal rates may hinder the interpretation of such estimates. The study objective was to evaluate whether population HIV prevalence estimates can be adjusted for survey non-response using mortality rates. The data come from the longitudinal Africa Centre Demographic Information System (ACDIS), in rural South Africa. Mortality rates for persons tested and not tested in the 2005 HIV surveillance were available from routine household surveillance. Assuming HIV status among individuals contacted but who refused to test (non-response) is missing at random and mortality among non-testers can be related to mortality of those tested a mathematical model was developed. Non-parametric bootstrapping was used to estimate the 95% confidence intervals around the estimates. Mortality rates were higher among untested (16.9 per thousand person-years) than tested population (11.6 per thousand person-years), suggesting higher HIV prevalence in the former. Adjusted HIV prevalence for females (15-49 years) was 31.6% (95% CI 26.1-37.1) compared to observed 25.2% (95% CI 24.0-26.4). For males (15-49 years) adjusted HIV prevalence was 19.8% (95% CI 14.8-24.8), compared to observed 13.2% (95% CI 12.1-14.3). For both sexes (15-49 years) combined, adjusted prevalence was 27.5% (95% CI 23.6-31.3), and observed prevalence was 19.7% (95% CI 19.6-21.3). Overall, observed prevalence underestimates the adjusted UNAIDS_CSA-RO_HIVthisweek_86_101121 4

prevalence by around 7 percentage points (37% relative difference). The authors developed a simple approach to adjust HIV prevalence estimates for survey non-response. The approach has three features that make it easy to implement and effective in adjusting for selection bias than other approaches. Further research is needed to assess this approach in populations with widely available HIV antiretroviral treatment.
For full text access click here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012370

Editors note: Non-response in population-based HIV surveillance is a puzzler. Are people refusing to participate because they know they are HIV-positive or suspect that they may be? Or are they like those who accept to participate and do they therefore have HIV prevalence that is similar to participants? These researchers were keen to find a way to handle refusers in their analysis when 59% of residents in the 2005 surveillance round did not participate. Complex procedures (e.g. multiple imputations, regression equations) have been used in other settings where extensive information on individuals is available. Lacking such information, they used longitudinal demographic data from biannual household and annual individual surveillance to derive mortality rates for people who tested positive and negative as well as those who refused testing in the 2005 round. Mortality in the untested was significantly higher than in the tested population, even after adjusting for age and sex composition. Assuming that much of this difference could be accounted for by AIDS-related mortality, the prevalence estimates for this area of KwaZulu Natal rose 7 percentage points. This method cannot be used to adjust cross-sectional HIV prevalence data when prospective mortality data are not available. When you do have such mortality data, adjusting HIV prevalence estimates for non-participation using this method can improve tracking of the epidemic and the impact of the response.

4. Sexual transmission
Estimating the impact of plasma HIV-1 RNA reductions on heterosexual HIV-1 transmission risk.
Lingappa JR, Hughes JP, Wang RS, Baeten JM, Celum C, Gray GE, Stevens WS, Donnell D, Campbell MS, Farquhar C, Essex M, Mullins JI, Coombs RW, Rees H, Corey L, Wald A; Partners in Prevention HSV/HIV Transmission Study Team. PLoS One. 2010;5(9):e12598.

The risk of sexual transmission of HIV-1 is strongly associated with the level of HIV-1 RNA in plasma making reduction in HIV-1 plasma levels an important target for HIV-1 prevention interventions. A quantitative understanding of the relationship of plasma HIV-1 RNA and HIV-1 transmission risk could help predict the impact of candidate HIV-1 prevention interventions that operate by reducing plasma HIV-1 levels, such as antiretroviral therapy, therapeutic vaccines, and other non-antiretroviral therapy interventions. The authors use prospective data collected from 2004 to 2008 in East and Southern African HIV-1 serodiscordant couples to model the relationship of plasma HIV-1 RNA levels and heterosexual transmission risk with confirmation of HIV-1 transmission events by HIV-1 sequencing. The model is based on follow-up of 3381 HIV-1 serodiscordant couples over 5017 person-years encompassing 108 genetically-linked HIV-1 transmission events. HIV-1 transmission risk was 2.27 per 100 person-years with a log-linear relationship to log(10) plasma HIV-1 RNA. The model predicts that a decrease in average plasma HIV-1 RNA of 0.74 log(10) copies/mL (95% CI 0.60 to 0.97) reduces heterosexual transmission risk by 50%, regardless of the average starting plasma HIV-1 level in the population and independent of other HIV-1-related population characteristics. In a simulated population with a similar plasma HIV-1 RNA distribution the model estimates that 90% of overall HIV-1 infections averted by a 0.74 copies/mL reduction in plasma HIV-1 RNA could be achieved by targeting this reduction to the 58% of the cohort with plasma HIV-1 levels 4 log(10) copies/mL. This log-linear model of plasma HIV-1 levels and risk of sexual HIV-1 transmission may help estimate the impact on HIV-1 transmission and infections averted from candidate interventions that reduce plasma HIV-1 RNA levels.

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For full text access click here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012598

Editors note: This large prospective cohort of serodiscordant couples has already informed us that herpes suppression with acyclovir at standard doses doesnt bring down plasma viral load enough to decrease HIV transmission (http://hivthisweek.unaids.org/post/herpes-and-hiv) and that antiretroviral therapy can reduce the risk of sexual transmission by 92% (http://hivthisweek.unaids.org/post/sexual-transmission-1). Here the authors apply their data on genetically linked transmissions within couples to model population-level effects of reductions in viral load on HIV transmission. The current high cost and poor availability of plasma HIV viral load monitoring limit the application of their findings in most settings but they are nonetheless tantalizing. The model predicts that if antiretroviral therapy could be provided to the people living with HIV who have plasma viral loads above 4 log (10)/mL (less than 60% of those living with HIV), HIV transmission would decline by 50% in a population and 90% of new infections could be averted. This should spur on efforts to develop and implement low cost, accessible viral load testing. Certainly, it will help us assess the potential prevention benefit of reductions in plasma viral load achieved through treatment of concurrent infections such as herpes simplex, schistosomiasis, and other opportunisitic and endemic infections.

5. Resources and Financing

HIV Spending as a Share of Total Health Expenditure: An Analysis of Regional Variation in a MultiCountry Study.
Amico P, Aran C, Avila C (2010) PLoS ONE 5(9): e12997

HIV has devastated numerous countries in sub-Saharan Africa and is a dominant health force in many other parts of the world. Its undeniable importance is reflected in the establishment of Millennium Development Goal No. 6. Unprecedented amounts of funding have been committed and disbursed over the past two decades. Many have argued that this enormous influx of funding has been detrimental to building stronger health systems in recipient countries. This paper examines the funding share for HIV measured against the total funding for health. A descriptive analysis of HIV and health expenditures in 2007 from 65 countries was conducted. Comparable data from individual countries was used by applying a consistent definition for HIV expenditures and total health expenditures from national health agencies to align them with National AIDS Assessment Reports. In 2007, the total public and international expenditure in low and middle income countries for HIV was 1.6 percent of the total spending on health, while the share in sub-Saharan Africa was 19.4 percent. HIV prevalence was six-fold higher in sub-Saharan Africa than the next highest region and it is the only region whose share of HIV spending exceeded the burden of HIV disability adjusted life years. The share of HIV spending across the 65 countries was quite moderate considering that the estimated share of deaths attributable to HIV stood at 3.8 percent and disability adjusted life years at 4.4 percent. Several high spending countries are using a large share of their total health spending for HIV health, but these countries are the exception rather than representative of the average sub-Saharan Africa country. There is wide variation between regions, but the burden of disease also varies significantly. The percentage of HIV spending is a useful indicator for better understanding health care resources and their allocation patterns.
For full text access click here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012997

Editors notes: The National AIDS Spending Assessment (NASA) tool developed by UNAIDS applies standard accounting methods to reconstruct all transactions, following the money from the source right through to the beneficiaries. NASA organises financial flows into six areas: financing sources, agents, providers, production factors, HIV spending categories, and beneficiary populations. Its biggest failing is that it does not capture out-of-pocket spending or private insurance expenditures so for this comparative UNAIDS_CSA-RO_HIVthisweek_86_101121 6

analysis these were removed from the National Health Accounts data sets. In the context of the continuing debate about vertical versus horizontal health financing, this analysis examines whether HIV is receiving a disproportionate share of resources and finds that, if anything, HIV is underfunded globally. HIV has a 1.6% share of overall health spending despite contributing 3.8% of deaths and 4.4% of disability adjusted life years. The only region with higher spending patterns is sub-Saharan Africa but HIV prevalence and population size predicted over 58% of HIV health expenditures and only a few countries may be overspending on HIV. Evidence on the extent to which HIV financing has health system strengthening spinoff benefits through training staff, building infrastructure, improving supply chains, etc. would increase the evidence-informed part of the debate.

6. Pre-Exposure Prophylaxis
Implementation Science of Pre-exposure Prophylaxis: Preparing for Public Use.
Underhill K, Operario D, Mimiaga MJ, Skeer MR, Mayer KH. Curr HIV/AIDS Rep. 2010;7:210-9.

As efficacy trials of antiretroviral pre-exposure prophylaxis (PrEP) continue, a growing literature has begun anticipating the potential challenges of implementing PrEP for HIV prevention. These efforts coincide with a shift toward combination interventions for preventing HIV, which integrate biomedical, behavioural, and structural components. The optimal implementation of PrEP would exemplify this combination model, incorporating not only PrEP drugs, but also HIV testing, safety screening, behavioural interventions addressing adherence and risk behaviour, and long-term monitoring. Efforts to plan for PrEP implementation therefore present an opportunity to advance the science of implementation and delivery in HIV prevention, in order to better address the challenges of scaling up combination approaches. The authors review the published and unpublished literature on PrEP implementation, organizing themes into five categories: scientific groundwork, regulatory and policy groundwork, stakeholder and infrastructure groundwork, delivery, and long-term monitoring. The lessons from PrEP planning can benefit the scale-up of future combination interventions.
For abstract access click here: http://www.ncbi.nlm.nih.gov/pubmed/20820971

Editors note: This paper on preparing for pre-exposure prophylaxis (PrEP) trial results conceptualises PrEP as being composed of biomedical, behavioural, and structural components, following the combination prevention paradigm. Planning for PrEP implementation has both a lot to learn from the experience of medical male circumcision introduction and scale-up and is an opportunity to build the emerging field of implementation and programme delivery science by documenting lessons for scaling up future combination prevention approaches. PrEP delivery will face many challenges including drug cost, active outreach to marginalized communities, provider training, education and awareness-raising strategies, safety screening, clinical monitoring for adverse events, frequent HIV testing, behavioural support, long-term follow-up, prevention of drug resistance, comparative cost-effectiveness, and ethical issues of financing antiretroviral prevention in the face of unmet treatment demand. With 5 large trials of daily oral PrEP ongoing among diverse populations (men who have sex with men, people who inject drugs, heterosexual discordant couples, and women at higher risk of HIV exposure), we need to ask how PrEP works will be defined and are we ready to grapple with the complex implementation challenges that PrEP entails? Kenya, Tanzania, Uganda, Zambia, Zimbabwe, and Brazil have already held stakeholder consultations on PrEP. Regional consultations in West and Central Africa and East Africa, chaired by UNAIDS regional support team directors and academics, have explored the challenges and opened up dialogue between policy makers and representatives of men who have sex with men, in anticipation of the first PrEP results which will come from the 4-continent iPrEx study (Peru, Ecuador, Brazil, USA, Thailand, South Africa). Dont just watch this space, start thinking about this.

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7. Adolescents living with HIV

Undiagnosed HIV Infection among Adolescents Seeking Primary Health Care in Zimbabwe.
Ferrand RA, Munaiwa L, Matsekete J, Bandason T, Nathoo K, Ndhlovu CE, Munyati S, Cowan FM, Gibb DM, Corbett EL. Clin Infect Dis. 2010; 51:844-51

Mother-to-child transmission of human immunodeficiency virus (HIV) infection was extremely common in southern Africa during the 1990s, and a substantial minority of infected infants have survived to reach adolescence undiagnosed. Studies have shown a high prevalence of HIV infection in hospitalized adolescents who have features associated with long-standing HIV infection, including stunting and frequent minor illnesses. The authors therefore investigated the epidemiology of HIV infection at the primary care level. Adolescents (aged 10-18 years) attending two primary care clinics underwent HIV and Herpes simplex virus-2 (HSV-2) serological testing, clinical examination, and anthropometry. All were offered routine HIV counselling and testing. Patients attending for acute primary care who were HIV infected were asked about their risk factors. Five hundred ninety-four participants were systematically recruited (97% participation), of whom 88 (15%) were attending for antenatal care. HIV infection prevalence was higher among acute primary care attendees than among antenatal care attendees (17% vs 6%), but for the prevalence of HSV-2 infection, a marker of sexually acquired HIV, the converse was true (4% vs 14%). Seventy (81%) of 86 HIV-positive acute primary care attendees were previously undiagnosed. They had a broad range of presenting complaints, with a median CD4 cell count of 329 cells/muL(interquartile range, 176-485 cells/muL) and a high prevalence of stunting, compared with the corresponding prevalence among HIV-negative attendees (40% vs12%). Maternal transmission was considered to be likely by 69 (80%) of the 86 HIV-positive acute primary care attendees, only one of whom was HSV-2positive. Unrecognized HIV infection was a common cause of primary care attendance. Routine HIV counselling and testing implemented at the primary care level may provide a simple and effective way of identifying older long-term survivors of mother-to-child transmission before the onset of severe immunosuppression and irreversible complications.
For access to full text click here: http://www.journals.uchicago.edu/doi/full/10.1086/656361

Editors note: Adolescents living in countries with longstanding generalised HIV epidemics should be offered HIV testing and counselling by health care providers, regardless of their presenting complaint. Given the high number of infants infected in the 1990s before the introduction of programmes to prevent motherto-child transmission and evidence that up to a third may be slower progressors, it is estimated that as much as 1 to 2% of all children aged 10 to 15 years in such settings may have HIV infection. That the vast majority of these children will have been infected through vertical transmission is not in doubt. In this study, there was an equal sex distribution, a strong association with maternal but not paternal orphanhood, and a low prevalence of herpes simplex 2 infection. The latter is an independent marker of sexually acquired HIV because it is a highly prevalent sexually transmitted infection among southern Africans. Finally, Zimbabwe instituted effective polices to stop transmission through contaminated blood and blood products early on in its epidemic. The point is that there are thousands and thousands of undiagnosed young adolescents in southern Africa that could benefit from clinical assessment, prophylaxis for opportunistic illness, and antiretroviral therapy initiation before life-threatening illness and chronic complications announce the possibility of HIV infection, if only they had the chance to learn their serostatus.

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8. Treatment
Stavudine Toxicity in Women Is the Main Reason for Treatment Change in a 3-Year Prospective Cohort of Adult Patients Started on First-Line Antiretroviral Treatment in Uganda.
Castelnuovo B, Kiragga A, Kamya MR, Manabe Y. J Acquir Immune Defic Syndr. 2010; Sep [Epub ahead of print]

In resource-limited settings, there are only a few antiretroviral treatment options. The objective was to evaluate the reasons for first-line antiretroviral therapy changes in resource-limited settings. The study was a prospective research cohort of patients initiating antiretroviral therapy between April 2004 and April 2005 in Kampala, Uganda. The main endpoint was the substitution of at least 1 drug included in the initial combination. Five hundred fifty-nine patients were initiated on antiretroviral therapy, 70% were female, median CD4+ count 98 (21-163) cells per microlitre, median HIV RNAlog10 5.4 (5.0-5.8). 413 (74%) patients were started on stavudine, lamivudine, and nevirapine, and 146 (36%) on zidovudine, lamivudine, and efavirenz. One hundred forty-eight (26.5%) had at least one treatment change (incidence rate 14.3 per 100 person-years; confidence interval: 12.2 to 16.9). The main reason for first treatment change was drug toxicity (n = 91, 61.5%). Stavudine accounted for the majority of the toxicities that led to drug substitution (n = 76, 84%).In the multivariate analysis, being female (P = 0.011) and being stage 3-4 as compared with 1-2 at antiretroviral therapy initiation were predictive of stavudine substitution (P = 0.05). There was no difference in virologic outcome in patients who changed due to toxicity compared with those who did not. The majority of the treatment changes were due to stavudine-related toxicity. Long-term stavudine use is less well tolerated in women.
For abstract access click here: http://www.ncbi.nlm.nih.gov/pubmed/20861741

Editors note: In 2006 WHO recommended that the stavudine (d4T) dosage be reduced from 40 mg to 30 mg to reduce the risk of toxicity. In 2010 WHO recommended that countries move progressively away from including stavudine in their first-line regimens. As noted in our last issue, cumulative exposure to d4T may cause disfiguring lipodystrophy, painful peripheral neuropathy, and life threatening lactic acidosis (http://hivthisweek.unaids.org/post/treatment-4). This Ugandan prospective study shows that women are almost twice as likely as men to be switched from stavudine due to toxicity. The rate of substitution for lipodystrophy was ten times higher. Is this because women are more likely to report disfigurement; because women are at higher risk of the mitochondrial toxicity that causes lactic acidosis, lipodystrophy, and peripheral neuropathy; or because a standard 30 mg dose regardless of weight or sex is a disservice to them? As the Treatment 2.0 campaign begins to examine the possibility of reducing the dosage of various antiretroviral drugs, it would do well to consider whether dosages should be adjusted down differently for women.

9. Disease progression and alcohol

Alcohol and HIV Disease Progression: Weighing the Evidence.
Hahn JA, Samet JH. Curr HIV/AIDS Rep. 2010 7:226-33

Heavy alcohol use is commonplace among HIV-infected individuals; however, the extent that alcohol use adversely impacts HIV disease progression has not been fully elucidated. Fairly strong evidence suggests that heavy alcohol consumption results in behavioural and biological processes that likely increase HIV disease progression, and experimental evidence of the biological effect of heavy alcohol on simian immunodeficiency virus in macaques is quite suggestive. However, several observational studies of the effect of heavy alcohol consumption on HIV progression conducted in the 1990s found no association of heavy alcohol consumption with time to AIDS diagnosis, while some more recent studies showed UNAIDS_CSA-RO_HIVthisweek_86_101121 9

associations of heavy alcohol consumption with declines of CD4 cell counts and nonsuppression of HIV viral load. The authors discuss several plausible biological and behavioural mechanisms by which alcohol may cause HIV disease progression, evidence from prospective observational human studies, and suggest future research to further illuminate this important issue.
For full text access click here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938419/?tool=pubmed

Editors note: What amount of alcohol intake is too much? The running joke answer is More than what your physician drinks. This review finds that, although there is strong biological plausibility that heavy alcohol intake might increase the rate of disease progression, it is difficult to demonstrate this in humans. In macaques, alcohol-exposed animals may consume fewer calories from food, have immune activation in the gut, and have higher viral loads at certain times but the association with increased progression of simian immunodeficiency virus infection has not been demonstrated. Heavy alcohol intake in human studies is defined as more than 4 drinks on any one occasion (3 for women) or more than 14 drinks a week (7 for women). Moderate drinking is anything between this level and abstinence. The strongest evidence linking alcohol intake and disease progression is the association between heavy alcohol intake and poor drug adherence. While you wait for scientists to disentangle any biological links between alcohol and disease progression, you can focus on the behavioural one it would be smart to cut back on your drinking if you are having any trouble taking your medications regularly.

10. Health care delivery

How HIV/AIDS scale-up has impacted on non-HIV priority services in Zambia.
Brugha R, Simbaya J, Walsh A, Dicker P, Ndubani P. BMC Public Health. 2010 10(1):540.

Much of the debate as to whether or not the scaling up of HIV service delivery in Africa benefits non-HIV priority services has focused on the use of nationally aggregated data. This paper analyses and presents routine health facility record data to show trend correlations across priority services. The authors conducted a review of district office and health facility client records for 39 health facilities in three districts of Zambia, covering four consecutive years (2004-07). Intra-facility analyses were conducted, service and coverage trends assessed and rank correlations between services measured to compare service trends within facilities. Voluntary counselling and testing, antiretroviral therapy and prevention of mother-to-child transmission client numbers and coverage levels increased rapidly. There were some strong positive correlations in trends within facilities between reproductive health services (family planning and antenatal care) and antiretroviral therapy and prevention of mother-to-child transmission, with Spearman rank correlations ranging from 0.33 to 0.83. Childhood immunisation coverage also increased. Stock-outs of important drugs for non-HIV priority services were significantly more frequent than were stock-outs of antiretroviral drugs. The analysis shows scale-up in reproductive health service numbers in the same facilities where HIV services were scaling up. While district childhood immunisations increased overall, this did not necessarily occur in facility catchment areas where HIV service scale-up occurred. The paper demonstrates an approach for comparing correlation trends across different services, using routine health facility information. Larger samples and explanatory studies are needed to understand the client, facility and health systems factors that contribute to positive and negative synergies between priority services.
For full text access click here: http://www.biomedcentral.com/1471-2458/10/540

Editors note: Whether the scale-up of HIV services is strengthening or depleting health systems continues to be hotly debated, usually with little evidence. This analysis of three districts in Zambia based on facility level data contributes interesting evidence to the dialogue. In these three districts where rapid scaling up of

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the delivery and coverage of HIV services was underway the impacts on non-HIV service delivery were mixed. The most positive impacts were seen on antenatal services (the intake for prevention of mother-tochild transmission) and increased client numbers in family planning services (which can help prevent unplanned pregnancy in women living with HIV). The fact that there were fewer antiretroviral drug stockouts than stockouts of other essential medicines (e.g. malaria drugs, oxytocin to accelerate labour, ergometrine for post-partum haemorrhage) suggests spill over positive effects in supply chains were not happening. Clearly more studies are needed to tease out the interactions but already this study is showing the way, highlighting the potential to derive useful evidence from routinely collected health facility data so that national planners and district programme managers can identify and address missed opportunities for synergies.

11. Economics
Economic outcomes of patients receiving antiretroviral therapy for HIV/AIDS in South Africa are sustained through three years on treatment.
Rosen S, Larson B, Brennan A, Long L, Fox M, Mongwenyana C, Ketlhapile M, Sanne I. PLoS One. 2010;5(9):e12731.

Although the medical outcomes of antiretroviral therapy for HIV are well described, less is known about how antiretroviral therapy affects patients' economic activities and quality of life, especially after the first year on antiretroviral therapy. The authors assessed symptom prevalence, general health, ability to perform normal activities, and employment status among adult antiretroviral therapy patients in South Africa over three full years following antiretroviral therapy initiation. A cohort of 855 adult pre- antiretroviral therapy patients and patients on antiretroviral therapy for <6 months was enrolled and interviewed an average of 4.4 times each during routine clinic visits for up to three years after treatment initiation using an instrument designed for the study. The probability of pain in the previous week fell from 74% before antiretroviral therapy initiation to 32% after three years on antiretroviral therapy, fatigue from 66% to 12%, nausea from 28% to 4%, and skin problems from 55% to 10%. The probability of not feeling well physically yesterday fell from 46% to 23%. Before starting antiretroviral therapy, 39% of subjects reported not being able to perform their normal activities sometime during the previous week; after three years, this proportion fell to 10%. Employment rose from 27% to 42% of the cohort. Improvement in all outcomes was sustained over 3 years and for some outcomes increased in the second and third year. Improvements in adult antiretroviral therapy patients' symptom prevalence, general health, ability to perform normal activities, and employment status were large and were sustained through the first three years on treatment. These results suggest that some of the positive economic and social externalities anticipated as a result of large-scale treatment provision, such as increases in workforce participation and productivity and the ability of patients to carry on normal lives, may indeed be accruing.
For full text access click here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012731

Editors note: These are encouraging findings this is the first report to indicate that the benefits of antiretroviral treatment in sub-Saharan Africa, in terms of ability to participate in normal activities, fewer symptoms, and increased employment potential, are sustained to 3 years, well beyond the 12 months documented in the existing small body of literature on antiretroviral treatment and quality of life. The proviso is that these patients were those who continued on antiretroviral treatment in these clinical settings postenrolment loss to follow-up was high. Some indicators were slow to increase, for example, the probability of having a job did not increase until about 18 months after starting treatment. But the median CD4 count at treatment initiation was low at 105 cells/mm, unemployment was high in South Africa at a sustained 24% through the study period, and it takes time to find employment after one becomes capable of working.

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Further studies will help populate the cost-benefit models that inform our thinking about the positive externalities of antiretroviral treatment.

12. Street youth

Multicity HIV seroprevalence in street youth, Ukraine.
Robbins CL, Zapata L, Kissin DM, Shevchenko N, Yorick R, Skipalska H, Finnerty E, Ornstein T, Marchbanks PA, Jamieson DJ, Hillis SD. Int J STD AIDS. 2010;21:489-96.

The authors conducted the first systematic, community-based, multicity assessment outside the USA of HIV seroprevalence, risk factors and linkage into clinical services among 929 street youth. After city-wide mapping, they used time-location sampling and randomly selected 74 venues in Odessa, Kyiv and Donetsk, Ukraine. Rapid HIV testing with post-test counselling was offered to all eligible youths aged 15-24 years. Overall, 18.4% (95% confidence interval 16.2-20.2) were HIV positive and 85% had previously unknown status. Rates were identical by sex. Subgroups with highest rates included orphans (26%), youths with histories of exchanging sex (35%), sexually transmitted infections (37%), injecting drug use (42%) and multiperson use of injection equipment (49%). Independent predictors, similar across age groups and city, included being orphaned, time on the street, history of anal sex, sexually transmitted infections, exchanging sex, any drug use, injecting drug use and multiperson use of injection equipment. Two-thirds (68%) of HIV-positive youths were linked to services. This high-risk population has many immediate needs.
For abstract access click here: http://ijsa.rsmjournals.com/cgi/content/abstract/21/7/489

Editors note: This study makes for sobering reading. The time-location sampling method used here mapped 91 locations where street youth congregate near fast-food restaurants, recreation areas, computer clubs, and metro stops and randomly chose 74 sites. Fully 92% of the youths approached met pre-defined eligibility criteria and of these 97% participated. Demographic and social risks such as being an orphan and living with someone who used illicit drugs or who was incarcerated were associated with a 10fold increase in HIV prevalence compared with the Ukraine national prevalence of 1.5% for young people aged 15 to 24 years. Sexual or substance use risk factors were associated with a 20- to 30-fold increase. Given that many HIV-positive street youth will die within 5 to 10 years without treatment and that there are many political and health-care delivery system barriers to street youth accessing services, attention to this advanced epidemic among the estimated 40,000 to 300,000 street youth in the Ukraine is urgently needed.

13. Vaccines
Oral immunization with a live coxsackievirus/HIV recombinant induces gag p24-specific T cell responses.
Gu R, Shampang A, Nashar T, Patil M, Fuller DH, Ramsingh AI. PLoS One. 2010;5(9). pii: e12499.

The development of an HIV vaccine has proven to be elusive. Because human vaccine trials have not yet demonstrated efficacy, new vaccine strategies are needed for the HIV vaccine pipeline. Gu and colleagues have been developing a new HIV vaccine platform using a live enterovirus, coxsackievirus B4 (CVB4) vector. Enteroviruses are ideal candidates for development as a vaccine vector for oral delivery, because these viruses normally enter the body via the oral route and survive the acidic environment of the stomach. The authors constructed a live coxsackievirus B4 recombinant, CVB4/p24(73(3)), that expresses seventy-three amino acids of the gag p24 sequence (HXB2) and assessed T cell responses after immunization of mice. The CVB4 recombinant was physically stable, replication-competent, and UNAIDS_CSA-RO_HIVthisweek_86_101121 12

genetically stable. Oral or intraperitoneal immunization with the recombinant resulted in strong systemic gag p24-specific T cell responses as determined by the IFN-gamma ELISPOT assay and by multiparameter flow cytometry. Oral immunization with CVB4/p24(73(3)) resulted in a short-lived, localized infection of the gut without systemic spread. Because coxsackieviruses are ubiquitous in the human population, they also evaluated whether the recombinant was able to induce gag p24-specific T cell responses in mice preimmunized with the CVB4 vector. They showed that oral immunization with CVB4/p24(73(3)) induced gag p24-specific immune responses in vector-immune mice. The CVB4/p24(73(3)) recombinant retained the physical and biological characteristics of the parental CVB4 vector. Oral immunization with the CVB4 recombinant was safe and resulted in the induction of systemic HIV-specific T cell responses. Furthermore, pre-existing vector immunity did not preclude the development of gag p24-specific T cell responses. As the search continues for new vaccine strategies, the present study suggests that live CVB4/HIV recombinants are potential new vaccine candidates for HIV.
For full text access click here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012499

Editors note: Yes, this study was in mice, not humans, but that is where the study of oral HIV vaccines begins. Given that HIV infection starts as a disease of the mucosal immune system, particularly the gut, that then extends systemically, it makes sense to see if both mucosal and systemic immune responses can be stimulated with an oral vaccine. That is how the oral Sabin vaccine against poliomyelitis works, so why not an oral vaccine for HIV? These are very early days but this study using a coxsackievirus vector (humans mostly have no symptoms when infected by these common viruses) to carry an HIV recombinant expressing gag p24 found that mice expressed gag p24-specific T cell responses after immunization even when they had pre-existing immunity to coxsackievirus. This constitutes proof of principle at the start of a long road ahead.

14. Basic Science

CXCR4-using viruses in plasma and peripheral blood mononuclear cells during primary HIV-1 infection and impact on disease progression.
Raymond S, Delobel P, Mavigner M, Cazabat M, Encinas S, Souyris C, Bruel P, Sandres-Saun K, Marchou B, Massip P, Izopet J. AIDS. 2010;24:2305-12.

Cysteine-cysteine receptor 5 (CCR5)-using viruses classically predominate during HIV-1 primary infection but the frequency of cysteine-X-cysteine receptor 4 (CXCR4)-using viruses varies between studies and could be different between plasma and peripheral blood mononuclear cells (PBMCs). The authors determined HIV-1 tropism in both these compartments during primary infection and evaluated the impact of CXCR4-using viruses on disease progression. One hundred and thirty-three patients with primary HIV-1 infection were screened for HIV-1 coreceptor usage in plasma and PBMCs using both genotypic and phenotypic methods. The impact of CXCR4-using viruses' transmission on subsequent disease progression was assessed in a case-control study. HIV-1 coreceptor usage was determined using a recombinant virus phenotypic entry assay and V3-based genotypic algorithms. They also monitored CD4 T-cell count, clinical events and therapeutic intervention. There was 6.4% of CXCR4-using HIV-1 in plasma during primary infection as measured by a phenotypic assay and combined criteria from the 11/25 and net charge genotypic rules. Geno2pheno10 overestimated the prevalence of CXCR4-using viruses (12%). HIV-1 tropism in plasma and PBMCs was 98% concordant. The HIV-1 RNA load and CD4 T-cell count during primary infection were not related to virus tropism. Primary infection with CXCR4-using viruses was associated with an accelerated rate of disease progression, estimated by a faster decline of CD4 T-cell count under 350 cells/l and by a reduced delay in initiating a first antiretroviral

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treatment. Plasma or PBMC samples can be used for determining HIV-1 tropism during primary infection. CXCR4-using viruses are rare during primary infection but increase the risk of disease progression.
For abstract access click here: http://www.ncbi.nlm.nih.gov/pubmed/20808203

Editors note: When HIV gp120 binds to the CD4 cell, a chemokine receptor site on the cell becomes exposed for the virus to dock. CCR5 viruses, called R5-tropic viruses, then use the CCR5 chemokine receptor on the cell surface to get entry into the cell while CXCR4 viruses, called X4-tropic viruses, use the CXCR4 receptor. Yet other viruses are dual tropic, using either receptor. Which coreceptor HIV has a predilection for can influence clinical evolution. Fortunately, most people appear to have predominantly CCR5 virus until late in infection when CXCR4 viruses emerge and are associated with accelerated declines in CD4 counts and progression to AIDS. What causes this transition is not clear. This study found that people who inject drugs were more likely to have a dual tropic virus R5X4 in primary infection that was associated with a faster disease progression, measured as time to CD4 count 350 cells/mm or initiation of first antiretroviral treatment. This may be because R4 CD4 cells are more abundant in blood than in genital and rectal mucosa. This is an area for further exploration in larger studies CCR5 antagonists have been developed but we have no drugs to block HIV binding to CXCR4 receptors.

15. Prevention of mother-to-child transmission

Traditional birth attendants lack basic information on HIV and safe delivery practices in rural Mysore, India.
Madhivanan P, Kumar BN, Adamson P, Krupp K. BMC Public Health. 2010;10(1):570.

There is little research on HIV awareness and practices of traditional birth attendants in India. This study investigated knowledge and attitudes among rural traditional birth attendants in Karnataka as part of a project examining how traditional birth attendants could be integrated into prevention-of-mother-to-child transmission of HIV programs in India. A cross-sectional survey was conducted between March 2008 and January 2009 among traditional birth attendants in 144 villages in Mysore Taluk, Karnataka. Following informed consent, traditional birth attendants underwent an interviewer-administered questionnaire in the local language of Kannada on practices and knowledge around birthing and HIV/ prevention-ofmother-to-child transmission. Of the 417 traditional birth attendants surveyed, the median age was 52 years and 96% were Hindus. A majority (324, 77.7%) had no formal schooling, 88 (21.1%) had up to 7 years and 5 (1%) had more than 7 yrs of education. Only 51 of the 417 traditional birth attendants (12%) reported hearing about HIV. Of those who had heard about HIV, only 36 (72%) correctly reported that the virus could be spread from mother to child; 37 (74%) identified unprotected sex as a mode of transmission; and 26 (51%) correctly said healthy looking people could spread HIV. Just 22 of those who had heard about HIV (44%) knew that infected mothers could lower the risk of transmitting the virus to their infants. An overwhelming majority of traditional birth attendants (401, 96.2%) did not provide antenatal care to their clients. Over half (254, 61%) said they would refer the woman to a hospital if she bled before delivery, and only 53 (13%) felt referral was necessary if excessive bleeding occurred after birth. Traditional birth attendants will continue to play an important role in maternal child health in India for the foreseeable future. This study demonstrates that a majority of traditional birth attendants lack basic information about HIV and safe delivery practices. Given the ongoing shortage of skilled birth attendance in rural areas, more studies are needed to examine whether traditional birth attendants should be trained and integrated into prevention-of-mother-to-child transmission and maternal child health programs in India.
For full text access click here: http://www.biomedcentral.com/1471-2458/10/570

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Editors note: That 88% of the 417 traditional birth attendants interviewed in this study had never heard of HIV is astounding given the age of the HIV epidemic in India (more than two decades) and general public awareness documented in sentinel surveillance surveys in rural areas (75% in 2006). But it is not just HIV knowledge that is lacking. Considering that obstetrical haemorrhage and sepsis are the leading causes of maternal deaths in India, knowledge about safe birthing practices was also low. Given that India has a Millennium Development Goal to reduce the estimated maternal mortality ratio from 450 to 109 maternal deaths per 100,000 live births, given that only 20% of the estimated 50,000 HIV-positive pregnant women receive prophylaxis to prevention HIV transmission to their infant, and given the shortage of skilled birth attendants in rural areas, programme planners face a dilemma. Can illiterate, unskilled traditional birth attendants play significant roles in improving maternal and child outcomes and preventing HIV transmission? They could do so if their services could be integrated into maternal child health programmes in India with adequate training, supplies, supervision, and support but this will take some doing.

16. Paediatric diagnosis

p24 Antigen Rapid Test for Diagnosis of Acute Paediatric HIV Infection.
Parpia ZA, Elghanian R, Nabatiyan A, Hardie DR, Kelso DM. J Acquir Immune Defic Syndr. 2010; 55:413-9.

Currently, the majority of HIV-infected infants are found within limited-resource settings, where inadequate screening for HIV due to the lack of access to simple and affordable point-of-care tests impedes implementation of antiretroviral therapy. Here the authors report development of a low-cost dipstick p24 antigen assay using a visual readout format that can facilitate the diagnosis of HIV for infants in resource-poor conditions. A heat shock methodology was developed to optimize disruption of immune complexes present in the plasma of infected infants. The analytical sensitivity of the assay using recombinant p24 antigen is 50 pg/mL (2 pM) with whole virus detection as low as 42.5k RNA copies per millilitre plasma. In a blinded study comprising 51 archived infant samples from the Women and Infants Transmission Study, their assay demonstrated an overall sensitivity and specificity of 90% and 100%, respectively. In field evaluations of 389 fresh samples from South African infants, a sensitivity of 95% and specificity of 99% was achieved. The assay is simple to perform, requires minimal plasma volume (25 muL), and yields a result in less than 40 minutes making it ideal for implementation in resourcelimited settings.
For abstract access click here: http://www.ncbi.nlm.nih.gov/pubmed/20811289

Editors note: HIV This Week reported recently on the advantages of dried blood spot PCR testing for infant HIV diagnosis (http://hivthisweek.unaids.org/2009/11/26/diagnosis-and-monitoring). These authors take the field a step closer to rapid diagnosis they take it to the field. They have developed a simple point of care test that circumvents the challenge of transporting specimens to a centralised laboratory and of finding the mother and her child when the result eventually returns. Results can be provided to parents at the same visit and plans made for the clinical evaluation of infants found to have HIV infection. The description of the test procedure seems quite straightforward, starting with a pre-treatment heat shock step to disrupt complexes that may have formed between maternal antibodies and infant HIV. The next step is develop a prototype portable, battery-powered heating/cooling unit and a prototype plasma separation device that would convert heel stick blood to plasma. Lets hope that this next product development phase is rapid.

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17. Sex and gender

Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial.
Currier J, Averitt Bridge D, Hagins D, Zorrilla CD, Feinberg J, Ryan R, Falcon R, Tennenberg A, Mrus J, Squires K; GRACE Study Group. Ann Intern Med. 2010; 153:349-57.

Women account for an increasing proportion of patients with HIV-1 but remain underrepresented in antiretroviral clinical trials. The objective of the analysis was to evaluate sex-based differences in efficacy and adverse events in treatment-experienced, HIV-positive women and men receiving darunavirritonavir therapy over 48 weeks. This was a multicentre, open-label, phase 3b study designed to enrol a high proportion of women, with sample size determined on the basis of a noninferiority design with a maximum allowable difference of 15% in virologic response favouring men. The study was conducted across 65 sites in the United States, Puerto Rico, and Canada. 287 women and 142 men were enrolled into the trial. Patients received darunavir-ritonavir, 600/100 mg twice daily, plus an investigatorselected optimized background regimen. Virologic response (HIV RNA <50 copies/mL using a time-toloss of virologic response [TLOVR] algorithm) and adverse events were assessed over 48 weeks. 67% of patients were women; 84% of patients were black or Hispanic. A higher proportion of women discontinued treatment than men (32.8% vs. 23.2%; P = 0.042); more women than men discontinued treatment for reasons other than virologic failure. Response rates in women and men at week 48 were 50.9% and 58.5%, respectively (intention-to-treat TLOVR), and 73.0% and 73.5%, respectively (TLOVR censored for patients who withdrew for reasons other than virologic failure). The absolute difference in response, based on logistic regression and adjusted for baseline log(10) viral load and CD4(+) cell count, was -9.6 percentage points (95% CI, -19.9 to 0.7 percentage points; P = 0.067) for intention-to-treat TLOVR and -3.9 percentage points (CI, -13.9 to 6.0 percentage points; P = 0.438) for TLOVR population that censored patients who withdrew for reasons other than virologic failure. Adverse events were similar between the sexes. The most common grade 2 to 4 adverse events that were considered at least possibly treatment related in women and men were nausea (5.2% and 2.8%, respectively), diarrhoea (4.5% and 4.9%, respectively), and rash (2.1% and 2.8%, respectively). A limitation of the study is that baseline characteristics differed between sexes. Non-significant, sex-based differences in response were found during the 48-week study; however, these differences were probably due to higher discontinuation rates in women, suggesting that additional efforts are needed to retain women in clinical trials.
For abstract access click here: http://www.ncbi.nlm.nih.gov/pubmed/20855799

Editors note: This study was designed as a non-inferiority trial, meaning a trial that is intended to determine that the effect of a new treatment is not worse than that of an active control by more than a specified margin. In this case, the researchers wanted to know whether womens response to the treatment regimen was more than 15% different than that of mens, measured by viral load responses. Each site could enrol a man only after they had enrolled three women. The treatment response in men and women was not significantly different but the study did highlight the challenges of retaining women in clinical trials: almost a third of women discontinued treatment compared to 23% of men. The GRACE trial (Gender, Race and Clinical Experience) did note a slightly higher exposure to darunavir (20%) and ritonavir (70%) in women compared to men at week 4 suggesting sex-based differences in pharmacokinetics a finding deserving of further exploration. This applies to these agents as well as to other fixed dose combinations that are used for both men and women. That was HIV this week, signing off.

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Editors notes on journal access

For readers in all countries: All abstracts in HIV This Week are freely available on the Web. You can access many scientific journals free of charge no matter where you are located, but for some journals you do need a subscription to access the full text of an article. Other journals offer free access to full-text articles after a certain period of time - see lists at Pubmed Central (click here) (and High Wire Press (click here). A number of journals are free to readers in all countries through ScienceDirect (click here). Examples of open access journals are BioMed Central journals (click here) and Public Library of Science (PLoS) journals (click here). Open Science Directory (click here) is a global search tool open access journals and journals in special programmes for developing countries. For residents of low- and middle-income countries: The Health InterNetwork Access to Research Initiative (HINARI), set up by the World Health Organisation (WHO) together with major publishers, enables readers at health institutions in low- and middle-income countries to gain access to one of the world's largest collections of biomedical and health literature. Over 6200 journal titles are now available to health institutions in 108 countries, benefiting many thousands of health workers and researchers, and in turn, contributing to improved world health. More information on the HINARI programme and eligible countries is available at their website (click here). Local, not-for-profit institutions in low- and middle- income countries may register for access to the journals through HINARI. Institutions in countries with GNP per capita below $1250 are eligible for free access. Institutions in countries with GNP per capita $1250-$3000 pay a fee of $1000 per year/institution. There is also free access to journals published online with the assistance of HighWire Press. This link: Clicking here will automatically detect if your internet connection is from a developing country and give you free access to their journals. For employees of UNAIDS or WHO: If you work for WHO or UNAIDS in Geneva, you can access a number of journals available from the WHO library by going to the WHO intranet (click here). If you work for UNAIDS outside Geneva you can access the WHO intranet through the following link: remote. When you have entered your UNAIDS username and password, click on intranet WHO. On the WHO intranet homepage, click on information resources WHO library online information resources online journals (GIFT) - A to Z list and you will see the list of accessible journals.

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