Cardiac safety assessment with motion field imaging analysis of human iPS cell-derived cardiomyocytes is improved by an integrated evaluation with cardiac ion channel profiling.

We validated a motion field imaging (MFI) assay with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) as a model to assess multiple cardiac liabilities by comparing the guinea-pig Langendorff heart with hiPS-CMs using 4 reference compounds and 9 internal compounds. We investigated repolarization duration, beating rate (BR), conduction speed, contractility, and inhibitory profile of three cardiac ion channels: hERG, Cav1.2, and Nav1.5. For repolarization, the contraction-relaxation duration (CRDc) of hiPS-CMs was generally consistent with the QTc interval of Langendorff heart. However, 2 internal compounds shortened CRDc despite QTc prolongation in Langendorff heart. Cardiac ion channel profiling revealed that hiPS-CMs could not be used to detect QTc prolongation when the value of Cav1.2 IC50 / hERG IC50 for a compound was between 1 and 10, whereas hiPS-CMs showed responses largely consistent with Langendorff heart when Cav1.2 IC50 / hERG IC50 was below 1 or above 10. The accuracy of hiPS-CMs for the BR was not high, mainly because the BR of hiPS-CMs was increased by an inhibition of Cav1.2. The hiPS-CMs were highly sensitive to conduction speed and contractility, able to detect QRS widening caused by Nav1.5-inhibition, as well as decreased LVdP/dtmax caused by the inhibition of Cav1.2 and/or Nav1.5. In conclusion, the MFI assay with hiPS-CMs would be useful for evaluating multiple cardiac liabilities. The ion channel profile helps to interpret the results of MFI assay and correctly evaluate cardiac risks. Therefore, an integrated cardiac safety assessment with MFI and ion channel profiling is recommended.

Implementing Impact Evaluations of Malaria Control Interventions: Process, Lessons Learned, and Recommendations.

As funding for malaria control increased considerably over the past 10 years resulting in the expanded coverage of malaria control interventions, so did the need to measure the impact of these investments on malaria morbidity and mortality. Members of the Roll Back Malaria (RBM) Partnership undertook impact evaluations of malaria control programs at a time when there was little guidance in terms of the process for conducting an impact evaluation of a national-level malaria control program. The President's Malaria Initiative (PMI), as a member of the RBM Partnership, has provided financial and technical support for impact evaluations in 13 countries to date. On the basis of these experiences, PMI and its partners have developed a streamlined process for conducting the evaluations with a set of lessons learned and recommendations. Chief among these are: to ensure country ownership and involvement in the evaluations; to engage stakeholders throughout the process; to coordinate evaluations among interested partners to avoid duplication of efforts; to tailor the evaluation to the particular country context; to develop a standard methodology for the evaluations and a streamlined process for completion within a reasonable time; and to develop tailored dissemination products on the evaluation for a broad range of stakeholders. These key lessons learned and resulting recommendations will guide future impact evaluations of malaria control programs and other health programs.

Framework for Evaluating the Health Impact of the Scale-Up of Malaria Control Interventions on All-Cause Child Mortality in Sub-Saharan Africa.

Concerted efforts from national and international partners have scaled up malaria control interventions, including insecticide-treated nets, indoor residual spraying, diagnostics, prompt and effective treatment of malaria cases, and intermittent preventive treatment during pregnancy in sub-Saharan Africa (SSA). This scale-up warrants an assessment of its health impact to guide future efforts and investments; however, measuring malaria-specific mortality and the overall impact of malaria control interventions remains challenging. In 2007, Roll Back Malaria's Monitoring and Evaluation Reference Group proposed a theoretical framework for evaluating the impact of full-coverage malaria control interventions on morbidity and mortality in high-burden SSA countries. Recently, several evaluations have contributed new ideas and lessons to strengthen this plausibility design. This paper harnesses that new evaluation experience to expand the framework, with additional features, such as stratification, to examine subgroups most likely to experience improvement if control programs are working; the use of a national platform framework; and analysis of complete birth histories from national household surveys. The refined framework has shown that, despite persisting data challenges, combining multiple sources of data, considering potential contributions from both fundamental and proximate contextual factors, and conducting subnational analyses allows identification of the plausible contributions of malaria control interventions on malaria morbidity and mortality.

Availability and Quality of Size Estimations of Female Sex Workers, Men Who Have Sex with Men, People Who Inject Drugs and Transgender Women in Low- and Middle-Income Countries.

OBJECTIVE: To assess the availability and quality of population size estimations of female sex workers (FSW), men who have sex with men (MSM), people who inject drug (PWID) and transgender women. METHODS: Size estimation data since 2010 were retrieved from global reporting databases, Global Fund grant application documents, and the peer-reviewed and grey literature. Overall quality and availability were assessed against a defined set of criteria, including estimation methods, geographic coverage, and extrapolation approaches. Estimates were compositely categorized into 'nationally adequate', 'nationally inadequate but locally adequate', 'documented but inadequate methods', 'undocumented or untimely' and 'no data.' FINDINGS: Of 140 countries assessed, 41 did not report any estimates since 2010. Among 99 countries with at least one estimate, 38 were categorized as having nationally adequate estimates and 30 as having nationally inadequate but locally adequate estimates. Multiplier, capture-recapture, census and enumeration, and programmatic mapping were the most commonly used methods. Most countries relied on only one estimate for a given population while about half of all reports included national estimates. A variety of approaches were applied to extrapolate from sites-level numbers to national estimates in two-thirds of countries. CONCLUSIONS: Size estimates for FSW, MSM, PWID and transgender women are increasingly available but quality varies widely. The different approaches present challenges for data use in design, implementation and evaluation of programs for these populations in half of the countries assessed. Guidance should be further developed to recommend: a) applying multiple estimation methods; b) estimating size for a minimum number of sites; and, c) documenting extrapolation approaches.

Adoption of rapid diagnostic tests for the diagnosis of malaria, a preliminary analysis of the Global Fund program data, 2005 to 2010.

INTRODUCTION: The World Health Organization Guidelines for the Treatment of Malaria, in 2006 and 2010, recommend parasitological confirmation of malaria before commencing treatment. Although microscopy has been the mainstay of malaria diagnostics, the magnitude of diagnostic scale up required to follow the Guidelines suggests that rapid diagnostic tests (RDTs) will be a large component. This study analyzes the adoption of rapid diagnostic testing in malaria programs supported by the Global Fund to fight AIDS, Tuberculosis and Malaria (Global Fund), the leading international funder of malaria control globally. METHODS AND FINDINGS: We analyzed, for the period 2005 to 2010, Global Fund programmatic data for 81 countries on the quantity of RDTs planned; actual quantities of RDTs and artemisinin-based combination treatments (ACTs) procured in 2009 and 2010; RDT-related activities including RDTs distributed, RDTs used, total diagnostic tests including RDTs and microscopy performed, health facilities equipped with RDTs; personnel trained to perform rapid diagnostic malaria test; and grant budgets allocated to malaria diagnosis. In 2010, diagnosis accounted for 5.2% of malaria grant budget. From 2005 to 2010, the procurement plans include148 million RDTs through 96 malaria grants in 81 countries. Around 115 million parasitological tests, including RDTs, had reportedly been performed from 2005 to 2010. Over this period, 123,132 health facilities were equipped with RDTs and 137,140 health personnel had been trained to perform RDT examinations. In 2009 and 2010, 41 million RDTs and 136 million ACTs were purchased. The ratio of procured RDTs to ACTs was 0.26 in 2009 and 0.34 in 2010. CONCLUSIONS/SIGNIFICANCE: Global Fund financing has enabled 81 malaria-endemic countries to adopt WHO guidelines by investing in RDTs for malaria diagnosis, thereby helping improve case management of acute febrile illness in children. However, roll-out of parasitological diagnosis lags behind the roll-out of ACT-based treatment, and will require prioritization of investments.

Simplifying ART cohort monitoring: can pharmacy stocks provide accurate estimates of patients retained on antiretroviral therapy in Malawi?

BACKGROUND: Routine monitoring of patients on antiretroviral therapy (ART) is crucial for measuring program success and accurate drug forecasting. However, compiling data from patient registers to measure retention in ART is labour-intensive. To address this challenge, we conducted a pilot study in Malawi to assess whether patient ART retention could be determined using pharmacy records as compared to estimates of retention based on standardized paper- or electronic based cohort reports. METHODS: Twelve ART facilities were included in the study: six used paper-based registers and six used electronic data systems. One ART facility implemented an electronic data system in quarter three and was included as a paper-based system facility in quarter two only. Routine patient retention cohort reports, paper or electronic, were collected from facilities for both quarter two [April-June] and quarter three [July-September], 2010. Pharmacy stock data were also collected from the 12 ART facilities over the same period. Numbers of ART continuation bottles recorded on pharmacy stock cards at the beginning and end of each quarter were documented. These pharmacy data were used to calculate the total bottles dispensed to patients in each quarter with intent to estimate the number of patients retained on ART. Information for time required to determine ART retention was gathered through interviews with clinicians tasked with compiling the data. RESULTS: Among ART clinics with paper-based systems, three of six facilities in quarter two and four of five facilities in quarter three had similar numbers of patients retained on ART comparing cohort reports to pharmacy stock records. In ART clinics with electronic systems, five of six facilities in quarter two and five of seven facilities in quarter three had similar numbers of patients retained on ART when comparing retention numbers from electronically generated cohort reports to pharmacy stock records. Among paper-based facilities, an average of 13 4 hours was needed to calculate patient retention for cohort reporting using patient registers as compared to 2.25 hours using pharmacy stock cards. CONCLUSION: The numbers of patients retained on ART as estimated using pharmacy stock records were largely similar to estimates based on either paper registers or electronic data system. Furthermore, less time and staff effort was needed to estimate ART patient retention using pharmacy stock records versus paper-based registers. Reinforcing ARV stock management may improve the precision of estimates.

Global fund financing of tuberculosis services delivery in prisons.

INTRODUCTION: Despite concerted efforts to scale up tuberculosis control with large amounts of international financing in the last 2 decades, tuberculosis continues to be a social issue affecting the world's most marginalized and disadvantaged communities. This includes prisoners, estimated at about 10 million globally, for whom tuberculosis is a leading cause of mortality and morbidity. The Global Fund to Fight AIDS, Tuberculosis and Malaria has emerged as the single largest international donor for tuberculosis control, including funding support in delivering tuberculosis treatment for the confined population. METHODS: The Global Fund grants database, with an aggregate approved investment of $21.7 billion in 150 countries by the end of 2010, was reviewed to identify tuberculosis and human immunodeficiency virus/tuberculosis grants and activities that monitored the delivery of tuberculosis treatment and support activities in penitentiary settings. The distribution and trend of number of countries with tuberculosis prison support was mapped by year, geographic region, tuberculosis or multidrug-resistant tuberculosis burden, and prison population rate. We examined the types of grant recipients managing program delivery, their performance, and the nature and range of services provided. RESULTS: Fifty-three of the 105 countries (50%) with Global Fund-supported tuberculosis programs delivered services within prison settings. Thirty-two percent (73 of 228) of tuberculosis grants, representing $558 million of all disbursements of Global Fund tuberculosis support by the end of 2010, included output indicators related to tuberculosis services delivered in prisons. Nearly two-thirds (64%) of these grants were implemented by governments, with the remaining by civil society and other partners. In terms of services, half (36 of 73) of grants provided diagnosis and treatment and an additional 27% provided screening and monitoring of tuberculosis for prisoners. The range of services tracked was limited in scope and scale, with 69% offering only 1 type of service and less than one-fifth offering 2 types of service. CONCLUSIONS: This study is a preliminary attempt to examine Global Fund investments in the fight against tuberculosis in prison settings. Tuberculosis services delivered in prisons have increased in the last decade, but systematic information on funding levels and gaps, services provided, and cost-effective delivery models for delivering tuberculosis services in prisons are lacking.

Long-term costs and health impact of continued global fund support for antiretroviral therapy.

BACKGROUND: By the end of 2011 Global Fund investments will be supporting 3.5 million people on antiretroviral therapy (ART) in 104 low- and middle-income countries. We estimated the cost and health impact of continuing treatment for these patients through 2020. METHODS AND FINDINGS: Survival on first-line and second-line ART regimens is estimated based on annual retention rates reported by national AIDS programs. Costs per patient-year were calculated from country-reported ARV procurement prices, and expenditures on laboratory tests, health care utilization and end-of-life care from in-depth costing studies. Of the 3.5 million ART patients in 2011, 2.3 million will still need treatment in 2020. The annual cost of maintaining ART falls from $1.9 billion in 2011 to $1.7 billion in 2020, as a result of a declining number of surviving patients partially offset by increasing costs as more patients migrate to second-line therapy. The Global Fund is expected to continue being a major contributor to meeting this financial need, alongside other international funders and domestic resources. Costs would be $150 million less in 2020 with an annual 5% decline in first-line ARV prices and $150-370 million less with a 5%-12% annual decline in second-line prices, but $200 million higher in 2020 with phase out of stavudine (d4T), or $200 million higher with increased migration to second-line regimens expected if all countries routinely adopted viral load monitoring. Deaths postponed by ART correspond to 830,000 life-years saved in 2011, increasing to around 2.3 million life-years every year between 2015 and 2020. CONCLUSIONS: Annual patient-level direct costs of supporting a patient cohort remain fairly stable over 2011-2020, if current antiretroviral prices and delivery costs are maintained. Second-line antiretroviral prices are a major cost driver, underscoring the importance of investing in treatment quality to improve retention on first-line regimens.

Scaling up towards international targets for AIDS, tuberculosis, and malaria: contribution of global fund-supported programs in 2011-2015.

OBJECTIVE: The paper projects the contribution to 2011-2015 international targets of three major pandemics by programs in 140 countries funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria, the largest external financier of tuberculosis and malaria programs and a major external funder of HIV programs in low and middle income countries. DESIGN: Estimates, using past trends, for the period 2011-2015 of the number of persons receiving antiretroviral (ARV) treatment, tuberculosis case detection using the internationally approved DOTS strategy, and insecticide-treated nets (ITNs) to be delivered by programs in low and middle income countries supported by the Global Fund compared to international targets established by UNAIDS, Stop TB Partnership, Roll Back Malaria Partnership and the World Health Organisation. RESULTS: Global Fund-supported programs are projected to provide ARV treatment to 5.5-5.8 million people, providing 30%-31% of the 2015 international target. Investments in tuberculosis and malaria control will enable reaching in 2015 60%-63% of the international target for tuberculosis case detection and 30%-35% of the ITN distribution target in sub-Saharan Africa. CONCLUSION: Global Fund investments will substantially contribute to the achievement by 2015 of international targets for HIV, TB and malaria. However, additional large scale international and domestic financing is needed if these targets are to be reached by 2015.

Global Fund financing of public-private mix approaches for delivery of tuberculosis care.

OBJECTIVES: To map the extent and scope of public-private mix (PPM) interventions in tuberculosis (TB) control programmes supported by the Global Fund. METHODS: We reviewed the Global Fund's official documents and data to analyse the distribution, characteristics and budgets of PPM approaches within Global Fund supported TB grants in recipient countries between 2003 and 2008. We supplemented this analysis with data on contribution of PPM to TB case notifications in 14 countries reported to World Health Organization in 2009, for the preparation of the global TB control report. RESULTS: Fifty-eight of 93 countries and multi-country recipients of Global Fund-supported TB grants had PPM activities in 2008. Engagement with 'for-profit' private sector was more prevalent in South Asia while involvement of prison health services has been common in Eastern Europe and central Asia. In the Middle East and North Africa, involving non-governmental organizations seemed to be the focus. Average and median spending on PPM within grants was 10% and 5% respectively, ranging from 0.03% to 69% of the total grant budget. In China, India, Nigeria and the Philippines, PPM contributed to detecting more than 25% TB cases while maintaining high treatment success rates. CONCLUSION: In spite of evidence of cost-effectiveness, PPM constitutes only a modest part of overall TB control activities. Scaling up PPM across countries could contribute to expanding access to TB care, increasing case detection, improving treatment outcomes and help achieve the global TB control targets.

Sexual and reproductive health activities in HIV programmes: can we monitor progress?

BACKGROUND: Resource allocation and integration of services have been of interest recently to achieve health-related Millennium Development Goals. This paper analyses the extent to which countries receiving funding in HIV were able to invest in activities in the area of sexual and reproductive health (SRH). METHODS: The authors screened the Global Fund grants data with an aggregate investment of US$16 billion in 140 countries to identify indicators revealing typical SRH services. The analysis focused on the 'Top Ten' internationally agreed indicators and used international guidelines and frameworks to define services for SRH and opportunities for 'linkage' between HIV and SRH services. RESULTS: As of December 2008, 238 of all HIV grants (n = 252) from 133 countries included 1620 service delivery indicators related to SRH. The budgets amounted to US$9.1 billion with US$5.9 billion committed and US$4 billion disbursed. Services included (1) prevention of mother to child transmission for 445,000 HIV-positive pregnant women, (2) 5.7 million care and support services, (3) 1.2 billion condoms delivered, (4) 4.4 million episodes of sexually transmitted infections treated, (5) 61 million counselling and testing encounters, and (6) 11.6 million behavioural change communication (BCC) outreach services for people at high risk and 64.5 million BCC activities for the general population, including youth. Information on the linkage and integration of SRH-HIV services was limited. CONCLUSION: Around 94% of HIV programmes supported SRH-related activities. However, there is a need to systematically capture data on SRH-HIV service integration to understand the benefits of linking these services.

Asia can afford universal access for AIDS prevention and treatment.

This paper draws on published reports, data from the Global Fund to Fight AIDS, Tuberculosis, and Malaria and the Asian Development Bank, and analysis by the Commission on AIDS in Asia to estimate financial resources required to achieve universal access for HIV in low-income and middle-income countries of Asia. It explores optimal use of available resources to mount effective response to AIDS in Asia against an uncertain economic climate. Although there is global commitment to tackle the HIV pandemic, available financing falls short of minimum requirements to achieve universal access to prevention and treatment. To support essential HIV priorities in Asia, the Commission on AIDS in Asia estimated annual resource needs to be US$ 3.1 billion. Yet, in 2007, according to one study, estimated total public spending on AIDS in 14 major Asian countries was only US$ 0.9 billion. Hence, scarce resources need to be carefully applied to address the concentrated HIV epidemics in Asia and achieve universal coverage by prioritizing investment in high-impact interventions to maximally avert new infections and deaths, intensifying multisectoral efforts through catalytic financing that mainstreams HIV interventions into existing services, particularly for low-impact prevention programs, and ensuring countries with growing economies mobilize increased amounts of domestic funding to match international financing.

Lives saved by Global Fund-supported HIV/AIDS, tuberculosis and malaria programs: estimation approach and results between 2003 and end-2007.

BACKGROUND: Since 2003, the Global Fund has supported the scale-up of HIV/AIDS, tuberculosis and malaria control in low- and middle-income countries. This paper presents and discusses a methodology for estimating the lives saved through selected service deliveries reported to the Global Fund. METHODS: Global Fund-supported programs reported, by end-2007, 1.4 million HIV-infected persons on antiretroviral treatment (ARV), 3.3 million new smear-positive tuberculosis cases detected in DOTS (directly observed TB treatment, short course) programs, and 46 million insecticide-treated mosquito nets (ITNs) delivered. We estimated the corresponding lives saved using adaptations of existing epidemiological estimation models. RESULTS: By end-2007, an estimated 681,000 lives (95% uncertainty range 619,000-774,000) were saved and 1,097,000 (993,000-1,249,000) life-years gained by ARV. DOTS treatment would have saved 1.63 million lives (1.09-2.17 million) when compared against no treatment, or 408,000 lives (265,000-551,000) when compared against non-DOTS treatment. ITN distributions in countries with stable endemic falciparum malaria were estimated to have achieved protection from malaria for 26 million of child-years at risk cumulatively, resulting in 130,000 (27,000-232,000) under-5 deaths prevented. CONCLUSIONS: These results illustrate the scale of mortality effects that supported programs may have achieved in recent years, despite margins of uncertainty and covering only selected intervention components. Evidence-based evaluation of disease impact of the programs supported by the Global Fund with international and in-country partners must be strengthened using population-level data on intervention coverage and demographic outcomes, information on quality of services, and trends in disease burdens recorded in national health information systems.

Global Fund-supported programmes contribution to international targets and the Millennium Development Goals: an initial analysis.

OBJECTIVE: The Global Fund to Fight AIDS, Tuberculosis and Malaria is one of the largest funders to fight these diseases. This paper discusses the programmatic contribution of Global Fund-supported programmes towards achieving international targets and Millennium Development Goals, using data from Global Fund grants. METHODOLOGY: Results until June 2006 of 333 grants supported by the Global Fund in 127 countries were aggregated and compared against international targets for HIV/AIDS, tuberculosis and malaria. Progress reports to the Global Fund secretariat were used as a basis to calculate results. Service delivery indicators for antiretrovirals (ARV) for HIV/AIDS, case detection under the DOTS strategy for tuberculosis (DOTS) and insecticide-treated nets (ITNs) for malaria prevention were selected to estimate programmatic contributions to international targets for the three diseases. Targets of Global Fund-supported programmes were projected based on proposals for Rounds 1 to 4 and compared to international targets for 2009. FINDINGS: Results for Global Fund-supported programmes total 544,000 people on ARV, 1.4 million on DOTS and 11.3 million for ITNs by June 2006. Global Fund-supported programmes contributed 18% of international ARV targets, 29% of DOTS targets and 9% of ITNs in sub-Saharan Africa by mid-2006. Existing Global Fund-supported programmes have agreed targets that are projected to account for 19% of the international target for ARV delivery expected for 2009, 28% of the international target for DOTS and 84% of ITN targets in sub-Saharan Africa. CONCLUSION: Global Fund-supported programmes have already contributed substantially to international targets by mid-2006, but there is a still significant gap. Considerably greater financial support is needed, particularly for HIV, in order to achieve international targets for 2009.