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ONGOING PROJECTS

[1] WHO Outpatient Surveillance Project

Brief description: The Uganda Malaria Surveillance Project (UMSP) is running an Outpatient Surveillance Program at 21 level III/IV health facilities ‘Malaria Reference Centres (MRCs)’ located in 21 districts across the country. Data is collected using the Ministry of Health’s HMIS Form 031 (Outpatient registers) as part of strengthening HMIS. Data is then entered into a Microsoft Access electronic database at the sites and sent to the UMSP core office in Kampala. Data analysis is performed using STATA and generation of weekly and monthly surveillance reports is done. Findings of the report are disseminated on a monthly basis during the WHO Surveillance, Monitoring, Evaluation, and Operations Research Technical Working Group (SMEOR-TWG) meeting that include the National Malaria Control Program (NMCP), WHO and other stakeholders. Our reports are also shared with the District Health Management Teams of the respective districts, and the health facility In-charges of each MRC on a monthly basis for dissemination to the health workers at MRCs and in effect contribute to evidence-based decision-making such as improvement in case management of malaria.

[2] Impact of long-lasting insecticide treated bednets with and without piperonyl butoxide (PBO) on malaria indicators in Uganda: a cluster-randomised trial

Study period: January 2017 – December 2018.
Goal: Evidence of the impact of combination long-lasting insecticide treated nets (LLINs), with the synergist piperonyl butoxide (PBO) is urgently needed. In 2017, LLINs will be distributed to all Ugandan households through a mass-distribution campaign led by the Ministry of Health. LLINs with, and without, PBO will be distributed, which presents an opportunity to rigorously evaluate and compare the performance of combination LLINs (with PBO) and conventional LLINs (without PBO) on a wide-scale in Uganda, across a variety of malaria transmission intensities, vector ecologies, and insecticide resistance patterns.

Following WHO guidance for robust evaluation of PBO nets, we propose to carry out a cluster-randomised trial to compare the impact of LLINs with, and without, PBO in Uganda. The primary objective is to evaluate the impact of combination LLINs (with PBO), as compared to conventional LLINs (without PBO), on parasite prevalence, in Eastern and Western Uganda. We will test the hypothesis that parasite prevalence will be lower in intervention clusters (health sub-districts [HSDs] randomised to receive PBO nets), than in control clusters (HSDs randomised to conventional nets) overall, and stratified by region (Eastern and Western regions).

Collaborators:
• Principal Investigator: Prof Janet Hemingway
• Co-investigators: Prof Moses Kamya, Prof Sarah Staedke, Prof Grant Dorsey, Prof Martin Donnelly, Dr Yeka Adoke, Prof Hilary Ranson, Prof Anthony Mbonye, Dr Jimmy Opigo, Dr Catherine Maiteki-Sebuguzi
Funded by: The Against Malaria Foundation
Sponsored by: Liverpool School of Tropical Medicine

[3] Feasibility and acceptability of NoviGuide: a mobile health technology application for management of neonatal care in resource constrained clinical settings in sub-Saharan Africa

Study period: October 2016 – ongoing. Brief description: NoviGuide is a tablet-based software designed to guide users through the initial assessment and daily care of neonates focusing on; respiratory support, glucose, fluid and feeding mgt and infection risk and mgt. Step-by-step prompts guide users to enter data from history, physical exam and medical resources at the facility. Based on the data entered, NoviGuide makes case-specific management recommendations. It also contains a 3D animation instructional video on newborn resuscitation and additional learning resources. Collaborators: IDRC, UCSF, Global strategies and University of Connecticut. Sponsored by: Bill and Melinda gates foundation, PTBi East Africa grant. Study participants: Midwives working in Tororo District Hospital.

[4] PROMOTE-II

The purpose of the Prevention of Malaria and HIV Disease in Tororo (PROMOTE-II) program project is to evaluate promising interventions to reduce the burden of malaria and HIV among pregnant women and improve maternal child health through hypothesis based interventional studies. To achieve this overall goal, we are currently conducting 2 double blind randomized clinical trials (Birth Cohort 1 and 2) with and integrated immunology component to address the following 2 overarching questions: (1) Can DP given to pregnant women and children up to 2 years of age reduce the burden of malaria compared to current standard malaria prevention (SMP) strategies? (2) Will controlling malaria during pregnancy and the first years of life enhance antimalarial immunity? Principal Investigators are Prof Moses Kamya of Makerere University/IDRC and Drs. Diane Havlir, Grant Dorsey and Maggie Feeney of UCSF.
i) Birth Cohort 1
This randomized, double-blinded, controlled trial of 300 HIV uninfected pregnant women and the children born to them, will be the first trial to evaluate the efficacy and safety of DP for the prevention of malaria in pregnant women. It will compare 2 dosing strategies of this novel intervention with the current standard of care of IPTp with SP in an area of high transmission intensity and widespread antifolate resistance. The study interventions will be divided into two phases. In the first phase, HIV uninfected women at 12-20 weeks gestation will be randomized in equal proportions to one of three IPTp treatment arms: 1) 3 doses of SP, 2) 3 doses of DP, or 3) monthly DP. Follow-up for the pregnant women will end approximately 6 weeks after giving birth. In the second phase of the study, all children born to mothers enrolled in the study will be followed from birth until they reach 36 months of age. Children born to mothers randomized to receive 3 doses of SP during pregnancy will receive DP every 3 months between 2-24 months of age. Children born to mothers randomized to receive 3 doses of DP or monthly DP during pregnancy will receive either DP every 3 months or monthly DP between 2-24 months of age. Children will then be followed an additional year between 24-36 months of age following the interventions. Pregnant women will undergo frequent sampling using a highly sensitive PCR assay to better define the timing and frequency of malaria infection during pregnancy and the primary outcome will be based on placental histopathology to maximize the detection of placental infection throughout pregnancy. We will test the hypothesis that IPT with DP will significantly reduce the burden of malaria in pregnancy and infancy and improve the development of naturally acquired antimalarial immunity.
ii) Birth Cohort 2

Strategic interventions such as monthly DP for HIV-infected pregnant women and their children to prevent malaria represent an opportunity to improve both maternal and child health outcomes. This is a double-blinded, randomized controlled trial of 200 HIV-infected pregnant women living in Tororo, Uganda, an area of high malaria transmission. 128 HIV-infected pregnant women between 12 and 28 weeks gestation will be randomized to receive enhanced malaria chemoprevention with monthly DP versus monthly DP placebo. Their HIV-exposed children will receive the same prevention regimen from 2 to 24 months of age to which the mothers were randomized. All women will receive daily TS throughout the study per Uganda MOH guidelines. Children will also receive daily TS from 6 weeks to 24 months of age. TS will be considered a study drug only in infants and children beginning 6 weeks after cessation of breastfeeding and upon exclusion of HIV infection. Women and their children will be followed for 36 months after delivery. This study tests the hypothesis that enhanced versus standard malaria chemoprevention in HIV-infected pregnant women and their children will reduce the incidence of malaria among children from 0 to 24 months of age.

This trial will also evaluate the pharmacokinetic exposure of concomitant DP and cART during pregnancy. DP and the first-line antiretroviral efavirenz (EFV) share metabolic pathways that could potentially lead to clinically relevant drug interactions. Pregnant women will undergo intensive PK evaluations for DP and EFV during the 3rd trimester. We will compare EFV PK in women receiving DP+TS vs. pl/TS and will compare DP PK between HIV-infected women receiving EFV-based cART and HIV-uninfected pregnant women receiving the identical regimen enrolled from Birth Cohort 1 not receiving cART.

iii) Immunology Project

The primary goals of this project are: 1. To determine whether exposure to malaria antigens in utero is associated with fetal tolerance, and whether limiting such exposure prevents the development of tolerance to malaria. We will determine whether in utero exposure is associated with tolerance, as evidenced by an expansion of functionally suppressive malaria-specific Tregs in cord blood. As a secondary analysis, we will assess whether chemoprevention during pregnancy prevents the development of tolerance. 2. To prospectively evaluate the impact of in utero antigen exposure on the natural acquisition of malaria-specific cellular immunity during early childhood. We will perform longitudinal assessments of malaria-specific T cells and immunoregulatory responses that develop following natural exposure to malaria, and relate these to in utero exposure and to the incidence of malaria during the first 3 years of life. 3. To determine whether the proportion of “tolerogenic” fetal T cells present at birth (TF:TA ratio) predicts neonatal immune tolerance to malaria antigens and the subsequent development of antimalarial immunity following postnatal exposure. We will measure the TF:TA ratio in cord blood and determine its association with regulatory and effector responses to malaria in cord blood, and with the incidence of malaria and the development of malaria-specific cellular immunity during childhood.

iv) Birth Cohort 3

Study period: 2016-2018. Goal: To compare monthly sulfadoxine pyrimethamine commonly known as fansidar and monthly dihydroartemisinin-piperaquine commonly known as duocotexin for prevention of malaria in HIV-negative pregnant women, and to validate and adapt a gestational dating by metabolic profile at birth. Collaborators: University of California San Francisco, Makerere University, IDRC. Sponsored by: The National Institute of Child Health and Human Development, and the Bill and Melinda Gates Foundation

[5] MIND-IHOP Study: Mulago Inpatient Non-invasive Diagnosis of Pneumonia (MIND)-International HIV-associated Opportunistic Pneumonias (IHOP) Study

Study period: September 2006 – ongoing. Brief description: The MIND-IHOP study evaluates the epidemiology, diagnosis, and outcomes of HIV-associated pulmonary infections, primarily tuberculosis (TB) and Pneumocystis pneumonia (PCP). In 2009, the study expanded to include studies of the lung microbiome in HIV-infected persons. Collaborators: MU-UCSF Research Collaboration, UCSF, National Institutes of Health, University of North Carolina, University of Cincinnati. Sponsored by: National Heart Lung and Blood Institute (NHLBI).

[6] Understanding mobility and risk in SEARCH communities

Study period: June 2015 – May 2020. Brief description: The purpose of this 5-year study is to investigate how population mobility affects HIV transmission dynamics and HIV care cascade outcomes in eastern Africa. It leverages the Sustainable East Africa Research in Community Health (SEARCH) trial (NCT# 01864603), a 6-year study in 32 communities of 10,000 persons each in Uganda and Kenya to test the effectiveness of a “treatment as prevention” strategy for reducing community HIV incidence. This study’s aims are to measure the mobility of individuals in eastern African communities, estimate the impact of mobility on HIV incidence, and estimate the impact of mobility on HIV care cascade outcomes. The study will address critical scientific gaps in how best to measure mobility and its impact on the dual goals of preventing HIV and treating those already infected. We will translate study results into tangible strategies for addressing the challenges of mobile populations, in order to optimize HIV prevention and achieve the full potential of ART. Collaborators: MU-UCSF Research Collaboration. Sponsored by: National Institutes Health/National Institute of Mental Health.

[7] SEARCH: Sustainable East Africa Research in Community Health

Study period: April 2013, Uganda - September 2013, Kenya to 2018. Brief description: Sustainable East Africa Research in Community Health (SEARCH) Collaboration was established in Vienna in 2010 to evaluate health and economic outcomes of bold community based health interventions for communicable and non-communicable diseases (NCD). The first initiative of the SEARCH collaboration is a community cluster randomized trial in Uganda and Kenya of widespread early community wide antiretroviral therapy (ART) vs. standard of care, where primary endpoints will include both community health and community economic status. An important strength of the SEARCH Collaboration is the partnership it has built with NIH, PEPFAR, WHO, and the World Bank to draw intellectual, financial, and policy support. From the inception the SEARCH collaboration has worked with Uganda and Kenya government agencies, community leaders, the US partner implementing agencies through Advisory Boards. Study implementation will coordinate with and compliment ongoing country activities. Collaborators: MU-UCSF Research Collaboration, Infectious Diseases Research Collaboration (IDRC) and Kenya Medical Research Institute, (KEMRI).  Sponsored by: The World Bank, NIAID, PEPFAR, WHO, MOH of Kenya, Uganda; Gilead Sciences, Inc.

[8] SEARCH Randomized Trial 

Study period: April 2013, Uganda & September 2013, Kenya to 2018. Brief description: The SEARCH study is designed to inform the current debates on global health investments precipitated by a) mathematical models predicting the HIV epidemic can be halted with widespread ART; and b) the reality of diminishing resources and growing costs of existing programs. The study is designed to leverage investments in HIV to develop sustainable systems for other infectious and NCDs. By examining individual, household, and community level socio-economic outcomes, the SEARCH study will assess whether an integrated approach to addressing health problems serve as an economic development intervention as well. Unique elements of the study a) inclusion of diagnosis and linkage to care of multiple communicable (TB, malaria) and non- communicable disease (hypertension, diabetes) in study design; b) improving and building community health delivery for ART and other diseases using new and efficient care models; c) evaluations that measure the immediate, cumulative and downstream effects of the intervention in the health, education and economic sectors; and d) a focus on sustainability. Collaborators: MU-UCSF Research Collaboration, Infectious Diseases Research Collaboration (IDRC) and Kenya Medical Research Institute, (KEMRI). Sponsored by:  The World Bank, NIAID, PEPFAR, WHO, MOH of Kenya, Uganda; Gilead Sciences, Inc.

[9] ICEMR/PRISM: The International Center of Excellence for Malaria Research / Program for Resistance, Immunology, Surveillance & Modeling of Malaria in Uganda

Study period: July 2010 to June 2017. Brief description: Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) is the dedicated East Africa International Center of Excellence for Malaria Research. The International Center of Excellence for Malaria Research (ICEMR) program, created by NIAID/NIH in July 2010, established a global network of independent research centers in malaria-endemic settings to provide knowledge, tools, and evidence-based strategies to support researchers working in a variety of settings, especially within governments and healthcare institutions. The overall strategy of the multi-project PRISM program is to apply a comprehensive and iterative approach to malaria surveillance that will generate an evidence base to help maximize the impact of control interventions across a wide range of epidemiological settings. Collaborators: MU-UCSF Research Collaboration, , Infectious Diseases Research Collaboration (IDRC), MOH of Uganda, Johns Hopkins University, London School of Hygiene and Tropical Medicine (LSHTM), Liverpool School of Tropical Medicine, University of Florida, Durham University. Sponsored by: NIH (NIAID)
i) Surveillance:
    Cohorts: The Cohorts study are three concurrent, dynamic population-based cohorts to estimate the incidence of malaria and other indicators of malaria morbidity in children living in three well defined epidemiological settings of varying malaria transmission intensities. Study participants are recruited from randomly selected households located in our catchment areas and followed for two years.

    Surveys: The Surveys project conducts cross-sectional surveys in communities and primary schools twice a year for at least 2 years in the 3 different sites.  The surveys will be timed to correspond to the high and low malaria transmission seasons, when possible.  In the community surveys, 200 households will be recruited from a list randomly generated from a census database at each site.   
    Entomology: The Entomology studies, propose to estimate malaria transmission intensity, as measured by EIR, using three different methodologies including human landing catches (the gold standard), CDC light traps, and pyrethrum spray catches combined with exit trap collections.  The study will be conducted in three different study sites, Tororo, Jinja, and Kanungu, all of which were included in the original survey conducted in Uganda.

ii) Parasite and Insecticide Resistance: The Resistance project will utilize available tools to conduct efficient surveys of the prevalence of known resistance markers across Uganda, develop new tools to improve surveillance methods, search for new markers to allow us to track the development of resistance to newer drugs and insecticides and identify associations between specific interventions and the development of resistance.

iii) Immunology: The Immunology Project, in response to the need for better tools to measure exposure and the relationship between exposure and disease, the specific aims of the Immunology Project are: 1) to characterize the individual-level relationships between P. falciparum exposure, the immune response, and protection from infection and disease in Ugandan cohorts, 2) to develop and validate immunologic assays for estimating the population-level dynamics of exposure to P. falciparum in surveillance studies performed throughout Uganda, and 3) to develop and validate immunologic assays for estimating the population-level dynamics of disease in response to changing P. falciparum exposure in surveillance studies performed throughout Uganda.

[10] GAVI: Global Alliance for Vaccines Initiative - Full country evaluation 

Study period: March 2013 to 2016. Brief description: To understand and quantify the barriers to, as well as drivers of, immunization program improvement, including the contribution of the GAVI Alliance.  The scope of the evaluations will include GAVI’s support for new and underused vaccines as well as GAVI’s cash based support to countries. Collaborators: Institute of Health Metrics and Evaluation (IHME), PATH. Sponsored by: The Global Alliance Vaccines Initiative.

[11] Acceptability and feasibility of serial HIV testing during pregnancy and the postpartum period with male partner testing in Tororo, Uganda

Study Period: February 2013 to March 2016. Brief Description: Recognizing that perinatal transmission of HIV continues to be a critical public health crisis, the Joint United Nations Program on HIV/AIDS (UNAIDS) declared a country-led multinational goal to eliminate perinatal HIV infections and to improve maternal HIV care by 2015. In order to assess the acceptability and feasibility of serial HIV testing, HIV-negative pregnant women were asked to participate in repeat HIV tests integrated into routine follow up antenatal and postpartum child immunization visits. While women reported high interest in involving their male partners in HIV testing and testing was offered free of charge, actual uptake of HIV testing among men was very low.  Innovative strategies to successfully integrate male partner testing within routine antenatal and postpartum health services as part of a comprehensive HIV prevention program in sub-Saharan Africa needs to be piloted and studied. Collaborators: MU-UCSF Research Collaboration.  Sponsored by:  The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH)

[12] Fogarty International Center (FIC) Malaria Training Program [2000 – ongoing]:

Trainees are chosen from among Ugandan junior scientists with interests in malaria research- either clinical, epidemiology, or molecular research tracks. When possible, training will be linked to ongoing research projects in Uganda. Formal training will be principally at the Masters level, although some more advanced training at the PhD or postdoctoral level will also be available. Training will be available at Makerere University in Kampala, Uganda, at the University of California, San Francisco and Berkeley, and in sandwich programs involving multiple institutions. The aims of this training program include:
1) To increase the expertise in Uganda in relevant clinical, epidemiological, and molecular research on malaria,
2) To strengthen the sustainability of malaria research in Uganda,
3) To expand research interactions between Ugandan and American scientists,
4) To strengthen trainee contributions to evidence-based decision-making,
5) To optimize training through utilization of additional available resources in Uganda,
6) To strengthen research capacity in Uganda by helping trainees to integrate into Ugandan institutions and pursue independently-supported scientific careers.
Contact: Dr. Arthur Mpimbaza, Email: arthurwakg [at] yahoo [dot] com

[13] Sentinel surveillance for Acute Febrile Illness in Uganda

Study period: 2016-2019. Goal: Identify leading causes of acute febrile illness other than malaria in different geographic regions of Uganda and to build sustainable laboratory capacity and surveillance capacity with focus on vector-borne and zoonotic diseases. Collaborators: Infectious Diseases Institute (IDI), The Centers for Disease Control and Prevention (CDC), and the Uganda Virus Research Institute (UVRI). Sponsored by: CDC

[14] Prophylaxis against malaria to enhance child development (PROTECT)

Study period: 2015-2020. Goal: To determine the effect of malaria prevention in pregnant women and in their children on children's neurodevelopment and to determine the mechanisms for this effect. Collaborators: Makerere University, Indiana University, University of Minnesota, University of California San Francisco, Infectious Diseases Research Collaboration. Sponsored by: NIH

[15] END TB: Evaluation of Novel Diagnostics for Tuberculosis study

Study period: June 2013 – December 2016. Brief description: Evaluating conventional and novel algorithms for intensified case finding among PLHIV, identifying breath-based biomarkers for TB screening and diagnosis, and identifying methods to improve the performance of urine LAM assays for TB diagnosis. Collaborators: MU-UCSF Research Collaboration, Johns Hopkins University, University of Utah, Global Good. Sponsored by: NIAID, PEPFAR, and Global Good.

[16] REACT: Resistance to antimalarial artemisinin-based combination therapies

Study period: July, 2007-November, 2019. Brief description: The specific aims of the study are: (1) to assess impacts of selective pressures for resistance of malaria parasites to artemisinin-based combination therapies used for the treatment and chemoprevention of malaria, (2) to characterize phenotypes associated with diminished drug sensitivity, and (3) to identify mediators of high level drug resistance. Our overall goal is to better characterize antimalarial drug resistance and resistance determinants before the problem becomes widespread in Africa, so that monitoring of these determinants can guide efforts to circumvent the spread of resistance. Collaborators: MU-UCSF Research Collaboration. Sponsored by: NIH/NIAID

[17] PACT: Pharmacokinetics/pharmacodynamics of antimalarial artemisinin-based combination therapies

Study period: Feb., 2015-Jan., 2020. Brief description: The specific aims of the study are: (1) to define the pharmacokinetics of DHA/piperaquine when used as intermittent preventive therapy for Ugandan pregnant women and children, (2) to characterize associations between exposure to piperaquine and circulating parasitemia, placental malaria, and clinical malaria in pregnant women and children, and (3) to characterize associations between exposure to DHA and piperaquine and risk of altered drug sensitivity. Overall, our primary goal will be to optimize dosing regimens for intermittent preventive therapy with DHA/piperaquine in pregnant women and children to enable protection against malaria without selection of drug resistance. Collaborators: MU-UCSF Research Collaboration. Sponsored by: NIH/NIAID

[18] Evaluation of Photo-thermal Spectroscopy enhanced rapid diagnostic test for Plasmodium falciparum Malaria

Study period: August, 2015 to September, 2017. Brief description: evaluation of a highly sensitive lateral flow assay to detect low density malaria infections. Collaborators: MU-UCSF research collaboration. Sponsored by: Global Good, Intellectual Ventures