Project

Title: Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipeline (VSPA)

Study period:  2023 – 2028

Major Goals: 

1. To characterise ex vivo sensitivity to lead antimalarial compounds of P. falciparum field isolates. 

2. To characterise genotypes of drug sensitivity outliers to identify mediators of decreased sensitivity in field isolates to lead antimalarial compounds. 

3. To characterise phenotypes of drug sensitivity outliers to elucidate resistance mechanisms of lead antimalarial compounds.

Study site: Tolab, Laboratory Tororo, Kalongo Laboratory and Molab and Butabika Kampala Laboratories

Collaborators: Infectious Diseases Research Collaboration (IDRC), Makerere University College of Health Sciences, University of California San Francisco, Stanford University
Principal Investigators: Samuel L. Nsobya Mellissa Conard, Roland Cooper and  Philip Rosenthal  
Study Sponsor: National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID)

Title: Resistance of Malaria Parasites to Artemisinin-Based Therapies (REACT)

Study period: 2020 – 2025

Major Goals: The goals of this project are: 

(1) To assess impacts of selective pressures for resistance of malaria parasites to ACTs 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.

Study site: Tolab, Laboratory Tororo, Kalongo Laboratory and Molab and Butabika Kampala Laboratories

Collaborators: Infectious Diseases Research Collaboration (IDRC), Makerere University College of Health Sciences, University of California San Francisco, Stanford University
Principal Investigators: Samuel L. Nsobya Mellissa Conard,  Roland Cooper and Philip Rosenthal  
Study Sponsor: National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID)

Surveillance to track and characterise antimalarial resistance trends in Ugandan Plasmodium falciparum parasites (STARTUP) 

Study period: 2022-2027.

Major Goals: 

We will characterise emerging antimalarial resistance at field sites across Uganda. We will use molecular, parasitological and epidemiological approaches to understand better the extent and origins of drug resistance, the genotypes that contribute to resistance, and the epidemiological factors that facilitate the evolution of resistant parasites. We hypothesise that multiple locally derived artemisinin-resistant lineages have emerged but that only a subset of lineages with optimal fitness will expand geographically; that decreased efficacy of artemisinins will facilitate the selection of resistance to key partner drugs; and that certain ecological and epidemiological factors will be associated with the geographical and temporal spread of resistant parasites. We will test these hypotheses with the following aims.

Aim 1. Molecular characterisation of resistance to artemisinins and key partner drugs in Uganda

Aim 2. Parasitological characterisation of resistance to artemisinins and key partner drugs in Uganda

Aim 3. Characterisation of ecological and epidemiological factors associated with ACT resistance markers.

Study site: Tolab, Laboratory Tororo, Kalongo Laboratory and Molab and Butabika Kampala Laboratories

Collaborators: Infectious Diseases Research Collaboration (IDRC), University of California San Francisco, Stanford University, Makerere University College of Health Sciences
Principal Investigators: Samuel L. Nsobya Mellissa Conard, Philip Rosenthal and Roland Cooper 
Study Sponsor: National Institutes of Health (NIH)

VERSE Project:

The Vaccine Economics Research for Sustainability and Equity

Study Period: December 2022-June 2023

The Vaccine Economics Research for Sustainability and Equity (VERSE) project is a collaborative effort between Makerere University School of Public Health (MakSPH) and the Infectious Diseases Research Collaboration (IDRC). The project focuses on equity analysis using the VERSE toolkit to measure inequities in immunization coverage and other health outcomes in Kampala, Uganda. The VERSE toolkit provides a standardized model to assess, track, and address vaccine coverage inequities, monetizing the economic losses due to inequity, and evaluating the trade-offs between equity and efficiency in immunization programs.

The VERSE project aims to develop and apply the VERSE Equity Toolkit to measure and address inequities in immunization coverage in Kampala. The toolkit allows for comprehensive analysis by incorporating various factors such as socioeconomic status, education, and geographic location. The project includes data collection, analysis of vaccine coverage, and the dissemination of findings.

Objectives

• Analyze Inequities in Immunization Coverage: Utilize the VERSE toolkit to measure and analyze inequities in DPT3 and full immunization coverage in Kampala, Uganda. This analysis will focus on socioeconomic status, education level, and other relevant factors.;
• Assess Inequities in the Use of Long-Lasting Insecticidal Nets (LLINs): Apply the VERSE toolkit to evaluate the inequities in the use of LLINs before and after a nationwide mass distribution campaign in 48 districts of Uganda;
• Generate Comprehensive Equity Assessments: Produce detailed reports and technical write-ups that quantify the drivers of vaccine coverage and LLIN usage, providing a multifaceted perspective on equity and efficiency; and
• Collaborate on Manuscript Preparation: Contribute to the drafting and submission of two manuscripts detailing the findings from the analysis of immunization coverage and LLIN usage inequities.

Study Site:  Kampala

Collaborators: Infectious Diseases Research Collaboration (IDRC), Makerere University School of Public Health (MakSPH)

Study Sponsor: Makerere University School of Public Health (MakSPH)

Access Bottlenecks Costs and Equity Study

Study period: April 2012 to December 2012.

To understand the constraints to health service delivery, determinants of patient access and policies which affect both supply and demand of health care in Uganda. Collaborators: Institute of Health Metrics and Evaluation (IHME). Sponsored by: Bill and Melinda Gates Foundation

AMIS

Study period:Ongoing.

The AMIS Project Uganda is an anthropological research project aimed at better understanding the use of antimicrobials in Ugandan society. The study aims to understand the roles and context of antimicrobials in daily life in Tororo, Wakiso and Kampala districts from the perspective of health care providers, farmers and day wage urban workers. The research focuses on the ways in which antimicrobials enable particular ways of life and livelihoods and explores the context and the wider reasons for antimicrobial use in Uganda.

Objectives

• Documentary analysis of relevant literature, policy documents and public health and lay public media content and materials, to contextualize ethnographic findings.
• In-depth ethnographic fieldwork involving key informant interviews, participant observation and surveys to understand how antibiotics are intertwined in people’s lives, with a focus on why, and how, people rely on them.
• Stakeholder interviews to reach a better understanding of AMR policies and initiatives as well as ongoing research related to AMR.
• Participatory research activities carried out every 3 months to provide preliminary feedback on research findings in order to elicit feedback and discussion among participants and local public health officials.
• Health professionals online survey to assess awareness of AMR amongst trained health care workers and veterinarians. By addressing how people actually use antimicrobials, and the wide-reaching reasons for reliance on them, the study will provide a detailed account that can be used by policy makers working on antimicrobial resistance in Uganda today.

CASAMS study

Study period:Ongoing.

World Health Organization (WHO) recommends implementation of Medicines and Therapeutic Committees (MTCs) as an intervention to improve medicine management, optimize medicine use and as such contribute to reducing the development and spread of antimicrobial resistance.

Currently, there is limited information on the composition structure, activities and functions of these committees. The role of these MTCs in implementing antimicrobial stewardship programs in Uganda and other low- and middle-income countries has remained unknown or under-characterized, so are the necessary enablers, barriers and the role of contextual factors in hospitals in Uganda. Despite the importance and prospects of antimicrobial interventions in preventing, slowing down and curing antimicrobial resistance, the evidence base on how to successfully implement antibiotic stewardship in African hospitals is thin.

With support from the Commonwealth Partnership for AMS scheme, our health partnership that includes Makerere University Pharmacy Department (MakPD), Infectious Disease Research Collaboration (IDRC), London School of Hygiene and Tropical Medicine (LSHTM), University College London NHS Foundation Hospitals (UCLH), and the Manchester Exchange (TCE) will conduct a situational analysis of patterns of use antimicrobial use and assess the feasibility of and contextual factors influencing the implementation of antimicrobial stewardship interventions at Jinja hospital.

Aim:
To strengthen the antimicrobial stewardship roles and responsibility of the medicine and therapeutic committee at Jinja regional referral hospital and develop its capacity to optimize antimicrobial treatment and clinical outcomes, and infection prevention and control at patient and health facility level.

Objectives:

1. To assess the existing capacity (knowledge, behaviors, processes) and practices of antimicrobial stewardship and infection prevention and control interventions at Jinja regional referral hospital.
2. To describe patterns of use of antimicrobials and characterize antimicrobial prescription, dispensing and administration at Jinja hospital in Uganda.
3. To determine the trend of annual antibiotic consumption using DDD per 1000 inhabitants per day and hospital activity units.
4. To assess the feasibility of and the contextual factors that enable or challenge implementation of antimicrobial stewardship interventions in Uganda.

Methods:
Jinja hospital is one of sixteen regional referral hospitals in Uganda. It is a tertiary level hospital with bed capacity of 474. It is located on two campuses about a kilometer apart with the main hospital on Narambai road and pediatric hospital at Nalufenya on Jinja – Kampala highway.
Broadly, it will be a mixed-methods observational study employing quantitative surveys and a qualitative case study.

Principal Investigators-Uganda: Dr Fred Kitutu (Makerere University Pharmacy Department and IDRC).
Principal Investigators-London: Dr Clare Chandler (London School of Hygiene and Tropical Medicine.

CHAMP: The Children with HIV and Malaria Project

Study period: October 2005 to May 2009.

Brief description: The aim of this study was to study the interactions between Human Immunodeficiency Virus (HIV) infection and malaria in African children. CHAMP has led to several important discoveries about malaria and HIV. In addition with such close clinical follow-up, CHAMP has also provided an opportunity to better understand other aspects of the disease HIV causes in African children. Collaborators: MU-UCSF Research Collaboration. Sponsored by: National Institute of Health (NIH)(Even for CHAMP, we need to list the “several” important findings that we got.)

Enhanced Entomological Surveillance (EES)

Introduction

Enhanced entomological surveillance is a key tool in understanding the impact of vector control on malaria vector density, Anopheles species composition, and Plasmodium parasite transmission. The Enhanced Entomological Surveillance project (EES) was conducted in 7 districts of Koboko, Moyo, Adjumani, Kasese, Jinja, Mubende and Busia. The EES activities was concluded in August 2023. Through the EES project, target districts routinely generate data for monitoring the impact of vector control interventions on malaria vector densities, Plasmodium falciparum sporozoite infection rates, changes in species composition and patterns of insecticide resistance.

The EES project supported the existing entomological surveillance efforts in the participating districts in order to increase the scope and improve coverage of vector surveillance in Uganda.

Project summary

The Infectious Diseases Research Collaboration (IDRC) in collaboration with the Ministry of Health and in partnership with the District Local Government, was given the mandate to support the establishment of routine entomological monitoring in several districts in Uganda.

The Enhanced Entomological Surveillance (EES) was a three-year project whose main aim was to boost routine entomological surveillance in seven districts in Uganda. The project was milestone driven with 3 key phases of implementation namely; 1) project preparation, 2) project start-up, and 3) routine EES. Vector control officers (VCOs) and village health teams (VHTs) to support the entomology surveillance activities were identified, and trained on how to support the different activities of the project including mosquito collection and analysis.

In addition, this project will evaluate the impact of malaria control interventions on malaria vector densities, species composition, seasonal vector variations, malaria sporozoite infection, vector behaviour and as well monitor the development of insecticide resistance. These data will generate evidence for efficient malaria vector control in Uganda, and in areas with similar settings.

Entomological surveillance data was generated through the existing district structures, facilitated by the Vector Control Officers (VCOs) and Village Health Teams (VHTs). This data was recorded into the DHIS-2 database for district and utilization.

Study aims

The primary objectives of the EES project were as follows;

To examine the impact of current vector control interventions on malaria vector densities, vector behaviour, and species composition.

1) To examine the impact of current vector control interventions on malaria vector densities, vector behaviour, and species composition.

2) To monitor the status and intensity of insecticide resistance

3) To establish the entomological inoculation rates in the selected districts.

4) To build the capacity of districts to conduct routine entomological surveillance.

Achievements

The EES project has built the capacity of VCOs and VHTs for conducting entomological surveillance through:

1) routine mosquito collection:

2) morphological identification of malaria vectors; 3) estimating of vector densities;

4) entry of the entomological data into the District Health Information System (DHIS2) and

5) using the DHIS2 data to make reports. Utilization of entomological data for decision making at the district level is actively encouraged.

6} Tooling of the 7 districts to perform routine Entomological surveillance

EXALT PK TRIAL: Extended duration Artemether-Lumefantrine treatment for malaria in children

Study period:Ongoing.

The study is currently being conducted at Masafu General Hospital (MGH) in Busia, and its referral centers. It is a randomized open-label prospective pharmacokinetic and pharmacodynamic study of extended duration artemether-lumefantrine in HIV-infected children on EFV-based ART and HIV-uninfected children. Children are randomly assigned to 3-day or 5-day regimens for their first intensive and population study. Thereafter one is eligible for a sequential crossover (3-day followed by 5-day AL or vice versa for two episodes of malaria).

Objectives:

• To evaluate and compare the PK exposure between 5-day AL treatment and 3-day al treatment in HIV-infected children on EFV-based ART.
• To evaluate and compare the PK exposure of 3-day and 5-day AL treatment in HIV-infected children on EFV-based ART to 3-day AL treatment in HIV-uninfected children not on ART.
• To evaluate and compare the PK exposure of 3-day and 5-day AL treatment in HIV-uninfected children not on ART.
• To evaluate the pharmacodynamics of AL in the context of extended dose regimens and HIV infection.

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.

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.

Fogarty International Center (FIC) Malaria Training Program

Study period: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

Objectives

• To increase the expertise in Uganda in relevant clinical, epidemiological, and molecular research on malaria,
• To strengthen the sustainability of malaria research in Uganda,
• To expand research interactions between Ugandan and American scientists,
• To strengthen trainee contributions to evidence-based decision-making,
• To optimize training through utilization of additional available resources in Uganda,
• To strengthen research capacity in Uganda by helping trainees to integrate into Ugandan institutions and pursue independently supported scientific careers.

FIND Study: DIAGNOSTICS USE ACCELERATOR STUDY.

Study period:Ongoing.

Febrile illnesses are often under-diagnosed and over-/mistreated. Antibiotic self-treatment and over-prescription drive antimicrobial resistance (AMR), with both immediate and long-term consequences on both individuals’ health and health systems. At the same time, patients who really do need antibiotics may not get them, which can lead to avoidable morbidity and mortality. Causes of fever vary geographically and seasonally, but there are few diagnostics to inform clinical decision making. WHO guidelines exist for children only (integrated management of childhood illnesses; IMCI), and there is no validated all-age syndromic approach.

Many febrile illnesses, especially in children, present with highly non-specific and overlapping signs and symptoms that are difficult to distinguish clinically. In Africa alone, over 600 million childhood fevers occur every year. However, when faced with a patient presenting with fever, healthcare providers, especially in low-resource settings, are left with nothing but their clinical judgment to decide whether antibiotics are needed – and often fall into the habit of prescribing one ‘just in case’. The AMR Dx Use Accelerator addresses the critical steps in the decision-making process by studying the effects of providing a set of available, point-of-care diagnostic tests and algorithms to use these tests to reach a case management decision. It also studies the underpinning behaviours that make health providers prescribe and users demand antibiotics, and favour or prevent adherence to prescription.

The FIND AMR Diagnostic (Dx) Use Accelerator is a platform to evaluate a package of interventions and provide evidence to inform policy change that can positively impact management of febrile illness, reduce drug pressure selecting for AMR, and contribute to universal health coverage (UHC). It will ultimately help prepare for the introduction of new diagnostics and provide a safe environment for new antibiotics to enjoy a longer useful therapeutic lifespan.

Objectives:

1. To understand the key drivers and barriers to delivering communication about adherence to prescriptions to patients/caregivers by health workers;
2. To understand the key drivers and barriers to adherence to prescribing instructions by patients/caregivers;
3. To assess the impact of a package of interventions on clinical outcomes and antibiotic prescriptions compared with standard-of-care practices, in patients presenting with acute febrile illnesses (defined as fever with no focus or respiratory tract infection lasting for no more than 7 days) at outpatient clinics in Uganda.

The study sites are: Aduku, Kihihi, and Nagongera Health centre IVs located in Kwania, Kanungu, and Tororo districts respectively.

Collaborators:
Principal Investigators: Dr James Kapisi and Dr Heidi Hopkins
Project Coordinator: Dr Asadu Sserwanga
Funded by: Foundation for Innovative new Diagnostics (FIND) in Geneva, Switzerland.

FRESH-AIR: The Impact of Household Ventilation on Transmission of Tuberculosis among Household Contacts of Active Tuberculosis Patients in Kampala, Uganda

Study period: July 2010 to December 2011.

This pilot study tested the feasibility of an in-home measurement of ventilation using a carbon dioxide (CO2) tracer gas decay technique, a low cost method, and evaluated if household ventilation is associated with TB in household contacts of adults with pulmonary TB (PTB) in Uganda. Findings indicated that Measuring household ventilation was feasible and Ventilation rates were lower (although not statistically significant) in homes with versus without co-prevalent TB in household contacts. Collaborators: MU-UCSF Research Collaboration. Sponsored by: UCSF Center for AIDS Research (CFAR)

G11 Research Administration Project

More information on the G11 webpage

Study period:Ongoing.

Who we are
The G11 Research Administration Project (Strengthening the Research Administration Capacity at the Infectious Diseases Research Collaboration to improve oversight of grant awards) is a National Institutes of Health (NIH) funded capacity building project. The overall goal of the project is to strengthen Institutional capacity for grants acquisition and management. Institutional capacity includes the human resources, systems and standard operating procedures which are involved in grants acquisition and management.

According to https://worldreport.nih.gov/app/#!,Uganda is one of the largest recipients of NIH funding in Africa some of which provides opportunities for capacity building, however the bulk of these opportunities are skewed towards research scientists to the disadvantage of grants administrators whose role in grant acquisition and management cannot be over stated. In order to increase institutional capacity to win and manage grants it is imperative that research administrators are equipped with the right skills and knowledge for effective and efficient management of National Institute of Health (NIH) grants.

What we do
The project delivers training, mentorship and exposure in pre and post award grants management processes to research administrators in National Institutes of Health (NIH) recipient Institutions in Uganda, to equip them with the right skills and knowledge to effectively and efficiently manage NIH grants.

Specifically, the project will:

1. Provide training and to IDRC Administrators in order to build their capacity to efficiently and effectively manage grant awards.
2. Strengthen the IDRC Grants Management system through the introduction of a novel grants tracking system and resources.
3. Establish a grants administration support center for Ugandan Research Administrators. Services of the grants administration support center include:
   • Placements for Junior Research Administrators in the IDRC Grants Office
   • Training and mentorship for research administrators in Uganda through lunch time seminars
   • Provision of a regular forum through which consultation on grant management policies, innovations, challenges and opportunities in research administration are shared.

Our target audience:
Our target audience includes Research Administrators from NIH recipient Institutions in Uganda. Research Administrators refers to all personnel involved in the management of grant awards including: Grants Managers, Finance Managers, Accountants, Administrators, Human Resource Officers, Procurement staff, Regulatory Staff, Project Coordinators just to mention a few.

Global Fund Prospective Country Evaluation(PCE)

Study period:Ongoing.

PCE is a comprehensive, country-level, prospective evaluation that utilize a variety of methods in order to provide a detailed, real-time picture of the implementation, effectiveness and impact of Global Fund-supported programmes in selected countries. The goal of PCE is to generate evidence on program implementation through impact in order to accelerate progress towards strategic objectives of the Global Fund Strategy and to facilitate continuous improvement of program implementation and quality.

Objectives:

PCE will establish country evaluation platform that supports dynamic, continuous monitoring and evaluation, learning, and problem solving with the objectives of:

• Examining and analysing implementation of the Global Fund Strategic Objectives
• Providing real-time information to allow countries and the Secretariat to adapt and adjust programme implementation
• Identifying challenges that impede programme performance and opportunities to inform and improve programme quality for impact, effectiveness, and value-for-money
• Measuring programme contributions to impact
• Strengthening country M&E systems for robust measurement and
• Identifying and disseminating best practices to improve the Global Fund model.

INTEGRATED HIV/HTN Project:

Leveraging the HIV Platform for Hypertension Control in Uganda.

Study Period: March 2020-February 2025

INTEGRATED HIV/HTN (Leveraging the HIV Platform for Hypertension Control in Uganda) is a five-year project funded by the Second European and Developing Countries Clinical Trials Partnership (EDCTP2) Grant Number: CSA2018HS-2518 to test the effectiveness of an integrated HIV/HTN care model in 26 districts in south-western Uganda. This project is implemented by a consortium led by the Infectious Diseases Research Collaboration (IDRC) in collaboration with the London School of Hygiene and Tropical Medicine (LSHTM), the Uganda Heart Institute (UHI), the Ministry of Health Uganda (MoH) and Makerere University.

There is a high burden of hypertension among HIV and non-HIV-infected people in Uganda, ranging from 15-30%. Yet, the capacity to diagnose, treat and prevent hypertension (HTN) remains sub-optimal. The double jeopardy of HIV and hypertension likely increases the risk of complications such as stroke, coronary artery disease and kidney failure. Less than 5% of people with hypertension are thought to receive regular care; thus, increasing access to care will require its integration into primary health care and HIV clinics, thus reducing co-occurring hypertension-related morbidity and mortality

The project will evaluate the effectiveness of the integrated HIV and HTN care model in selected districts and health facilities in South Western Uganda. It aims at increasing awareness of hypertension, improving hypertension control and improving quality of life for HIV patients and non-infected populations in an integrated manner and ultimately contribute to reducing the overall prevalence of hypertension in Uganda.

Objectives 

• Determine the effectiveness of the integrated HIV/HTN care model on HTN screening, HTN control and dual HIV/HTN control in the HIV clinics;
• To assess the barriers and facilitators of the integrated HIV/HTN care model among National Disease Control Programs, middle-level health district managers, clinic-level PHC leaders, providers, and patients; and
• Determine the cost, cost-effectiveness and incremental gain costs of the integrated HIV/Hypertension care model approach.

Study Site:  96 districts in Ankole, Kigezi, Bunyoro- Tooro

Collaborators: Infectious Diseases Research Collaboration (IDRC), Uganda Ministry of Health (MoH), Makerere University, London School of Hygiene & Tropical Medicine (LSHTM) and Uganda Heart Institute (UHI)

Principal Investigator: Jane Kabami 

Study Sponsor: EDCTP

A Phase 2, multi-center, randomized, open-label, doseescalation study to determine safety of single (QD) and multiple (3 QD) doses of KAE609, given to adults with uncomplicated Plasmodium falciparummalaria

Study period:Ongoing.

KAE609 is a novel spiroindolone class drug with potent and fast-acting schizonticidal activity, which acts by disrupting the malaria parasite Na+ homeostasis by inhibition of the ATPase PfATP4. KAE609 has been evaluated in healthy volunteers in single doses up to 300 mg and repeated doses up to 150 mg (3-day Once daily (QD)) without any significant safety and tolerability issue. In the initial patient study, a 3-dayQD treatment of 30 mg was well tolerated. In a subsequent patient study, at a single dose of 75 mg, transient Grade 2-3 LFT elevations were however observed in 5/11 patients. In a malaria challenge studywith healthy volunteers in Australia, transient Grade 3-4 LFT elevations were observed in 3/8 subjects following a single dose of 10 mg of KAE609. Following evaluation of these events, it was concluded that hepatic toxicity of KAE609 cannot be excluded, and that an additional safety dose escalation study should be performed before exploring safety and efficacy in a fixed-dose combination of KAE609 with a long acting anti-malarial.

Purpose : This Phase 2 study aims to determine the maximum safe dose of the investigational drug KAE609 in malaria patients. The study population consists of adult malaria patients (≥ 18 years, ≥ 45 kg bodyweight) with uncomplicated symptomatic malaria caused by Plasmodium (P.) falciparum. KAE609 will be evaluated primarily for hepatic safety following administration of single and multiple doses (once a day for 3 days) in sequential cohorts with escalatingdoses. In case that safety is acceptable for all consecutive cohorts, a protocol amendment could be considered to study additional higher dose(s).

Objectives:

• To evaluate overall safety and tolerability of KAE609.
• To assess key pharmacokinetic (PK)parameters following treatment with KAE609.
• To assess the efficacy of KAE609 in patients with uncomplicated falciparummalaria.
• To assess recrudescence after single and multiple doses of KAE609.

A longitudinal cohort study of HIV-infected persons hospitalized with pneumonia in two settings: Mulago Hospital, Kampala and San Francisco General Hospital, San Francisco

Study period: October 2008 – December 2013.

Brief description: Part of the Lung HIV Study, a network of 8 research programs and a central data coordinating center whose shared goal is to study the spectrum of HIV-associated lung disease and create a specimen bank and accompanying clinical database to catalyze future studies in the field. The MIND-IHOP study evaluates the diagnosis and epidemiology of HIV-associated pulmonary infections and the human responses to those infections. Collaborators: MU-UCSF Research Collaboration. Sponsored by: National Heart Lung and Blood Institute (NHLBI)

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

Study period: September 2006 – ongoing

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).

NoviGuide Project:

Evaluating Clinical Decision Support Software in Rural Uganda. 

Study Period: September 2020 – November 2023

The NoviGuide  project was funded by the University of California San Francisco Preterm Birth Initiative  (Grant number: OPP1107312) to evaluate the acceptability and feasibility of using midwife trainers and NoviGuide in the rollout of neonatal oxygen saturation monitoring in eastern Uganda. The project was implemented by Infectious Diseases Research Collaboration (IDRC) in collaboration with Global Strategies, the creators of NoviGuide. NoviGuide is a tablet-based, clinical decision support tool designed for frontline health care professionals. NoviGuide transforms neonatal care guidelines into step-by-step guidance.

One of the leading causes of death among preterm infants is respiratory distress syndrome (RDS). In Low and Middle Income countries, the main treatment for RDS is oxygen delivered through continuous positive airway pressure or nasal prongs. Unfortunately, oxygen treatment is often implemented without saturation monitoring. Yet over-administration of oxygen therapy is dangerous and can lead to significant long-term morbidity. In addition, the implementation of pulse oximeters is complicated by individual, social and organizational factors.

In this project, we evaluated the use of midwife Trainers and NoviGuide in the implementation of neonatal oxygen saturation monitoring at four rural health facilities in eastern Uganda. First, we trained two midwives as NoviGuide Trainers. These Trainers inturn trained all the nurses and midwives on how to use NoviGuide and pulse oximeters during their care of newborns needing oxygen therapy.

Objectives

• To evaluate the acceptability and feasibility of using midwives as NoviGuide Trainers in the rollout of the NoviGuide to new clinical sites.
• To evaluate the acceptability and feasibility of using NoviGuide to facilitate the roll out of oxygen saturation monitoring in rural hospitals in eastern Uganda.
• To evaluate the acceptability and feasibility of using a digital tutorial to train newly recruited midwives on the initial set-up of NoviGuide.
• To evaluate patterns of NoviGuide use and factors that influence the use of NoviGuide by Ugandan midwives caring for newborns.

Study Site:  4 sites – Tororo General Hospital, Mulanda, Nagongera and Mukujju Health Center IVs.

Collaborators: IDRC and Global Strategies.

Principal Investigator: Dr. Mary K. Muhindo.

Study Sponsor: University of California San Francisco Preterm Birth Initiative.

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 – ongoing.

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

Pharmacokinetics of Antimalarial Medications in Ugandan Children

Study period: June 2007 to December 2008.

Brief description: This study investigated the pharmacology of artemether/lumefantrine and artesunate/amodiaquine in HIV un-infected children in Kampala, Uganda. The comparison to prior adult data suggests that LR exposure is lower in children and that AQ/DEAQ exposure is similar in children and adults. For the artemisinin drugs, differences between exposure in children and adults vary depending on which artemisinin is administered. PK distinctions between children and adults should be considered to optimize dosing strategies for these widely utilized ACT regimens. Collaborators: MU-UCSF Research Collaboration. Sponsored by: CFAR, Drug Research Unit.

Point of Care Diagnostics Studies

i) TB LAM Study

Collaborators: Global Good/ Intellectual ventures lab, IDRC, UCSF

Objectives

• Evaluating a high sensitivity, urine-based Rapid Diagnostic Test (RDT) for Tuberculosis. The aim is to increase the sensitivity and specificity of Lipoarabinomannan (LAM) assay for plasma & urine.
• Developing a Cell-Free DNA based assay for TB diagnosis in resource limited settings

Both platforms are being compared to Genexpert and sputum culture as the gold standard.

ii) Evaluation of photo-thermal spectroscopy enhanced rapid diagnostic test for plasmodium falciparum malaria

Objectives:

Evaluating a highly sensitive HRP-2 and pLDH based prototype Rapid Diagnostic Tests for malaria (mRDTs). These prototype RDTs are designed to detect low parasitemia, such as occurs in asymptomatic malaria infections. Testing is being done in low and high transmission areas, with DNA PCR/ Microscopy as the comparative gold standard.

Prevention of Malaria and HIV Disease in Tororo (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 ART.

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

PROTECT; prophylaxis against Malaria to enhance child development

Study period:2015-Ongoing.

The prophylaxis against Malaria to enhance child development (PROTECT study) focuses on how the systemic and placental changes that occur with malaria in pregnancy can adversely affect the developing fetal brain, and fetal brain injury strongly affects long-term childhood neurodevelopment and behavior .

Objectives

• To determine the effect of malaria prevention in pregnant women and their children on child neurodevelopment.
• To identify the major mechanisms by which malaria prevention in pregnant women and children affects child neurodevelopment.

Rapid VL

Study period:Ongoing.

Optimizing HIV Viral Load Monitoring and Outcomes for High-Risk Populations- the RAPID-VL study is designed to test the comparative effectiveness of a health facility-level cluster-randomized, cross-sectional, ‘before-after’ trial of a multi-component intervention (“RAPID-VL intervention”) designed to improve the processes of HIV viral load testing in South Western Uganda. The study is recruiting 2400 HIV-infected persons attending HIV health facilities in Southwestern Uganda (1200 in study Phase 1 and 1200 in study Phase 2) in 20 HIV care clinics in Southwestern Ugandan region

Objectives

• Determine the comparative effectiveness of the RAPID-VL intervention on primary outcomes of: (1) VL ordering and (2) VL turn-around time
• Identify facilitators and barriers to implementation, and perceived utility of the RAPID-VL intervention from both the patient and clinician perspectives.
• Determine the costs, cost-effectiveness, and incremental change costs of the RAPID-VL intervention.

SEARCH Youth; Strategic Antiretroviral therapy and HIV testing for youth in rural Africa

Study period:Ongoing.

The SEARCH YOUTH study was designed as an intervention that adjusts care to account for the current psychosocial and life stage of adolescents and young adults living with HIV (AYAH).THE search youth study will therefore evaluate a package of interventions designed to improve viral suppression and retention rates among adolescents and young people living with HIV (AYAH). The components of the intervention are an assessment of participants current life stage related issues, rapid viral load feedback and provision of some choice in the location and timing of their routine care visits

The study will take place in 28 public health facilities in Uganda and Kenya and will enroll 1400 young people living with HIV aged 15-24-years-old.

SEARCH-IPT

Study period:Ongoing.

The Simplified Isoniazid Preventive Therapy Strategy to Reduce TB Burden (SEARCH-IPT) is a cluster randomized trial designed to determine if a multi-component implementation intervention (SEARCH-IPT) that targets District Health Officers (DHOs) can increase Isoniazid Preventative Therapy (IPT) initiation and completion among HIV-infected persons, and decrease Tuberculosis (TB) incidence, as compared to country standard practices in Uganda.

Objectives

• Determine if the SEARCH-IPT intervention increases IPT initiation
• Evaluate the effect of the SEARCH-IPT intervention on IPT completion and TB incidence
• Evaluate for indirect effects of the SEARCH-IPT intervention on prescribing of IPT to child (≤14 years of age) household contacts of active TB cases, and HIV-infected children (12 months to 14 years of age)
• Evaluate the cost and cost-effectiveness of SEARCH-IPT

TB Screening Improves Preventive Therapy Uptake Trial (TB-SCRIPT)

Study Period: November 2020- March 2025

Overview

Tb-script is a groundbreaking research initiative to evaluate the clinical impact of Point-of-Care (POC) C-reactive protein (CRP) based TB screening on immediate and longer-term outcomes of individuals living with HIV. This pragmatic single-blinded, randomised-controlled Phase III trial is conducted at four prominent clinics in Kampala, Uganda. 

Aims of the trial. 

Overall aim: The overall objective of this randomised trial is to evaluate the effectiveness and cost-effectiveness of POC CRP-based TB screening 

Specific aims of the trial

Aim 1: Compare the impact of point-of-care C-reactive protein (POC CRP)- vs. symptom-based TB screening on 2-year patient outcomes.

Aim 2: Compare the impact of POC CRP-   vs symptom-based TB screening on TB preventive therapy (TBPT) uptake and TB case detection.

Aim 3: Compare cost, cost-effectiveness, and projected epidemiological impact of POC CRP- vs. symptom-based TB screening.

Who is funding the trial?

The National Heart Lung and Blood Institute of the National Institute of Health, USA funds the trial. 

Research outputs. 

1. Chaisson LH, Semitala FC, Mwebe S, et al. Transaminitis prevalence among HIV-infected adults eligible for tuberculosis preventive therapy. Aids. 2022;36(11):1591-5.
2. Semitala FC, Chaisson LH, Dowdy DW, et al. Tuberculosis screening improves preventive therapy uptake (TB SCRIPT) trial among people living with HIV in Uganda: a study protocol of an individual randomised controlled trial. Trials. 2022;23(1):399.
3. Chaisson LH, Semitala FC, Nangobi F, et al. Viral suppression among adults with HIV receiving routine dolutegravir-based antiretroviral therapy and three months’ weekly isoniazid-rifapentine. Aids. 2023;37(7):1097-101.

Further information can be accessed in the protocol at the reference below

Semitala FC, Chaisson LH, Dowdy DW, et al. Tuberculosis screening improves preventive therapy uptake (TB SCRIPT) trial among people living with HIV in Uganda: a study protocol of an individual randomised controlled trial. Trials. 2022;23(1):399.

Study Site: Kawaala KCCA Health Centre IV, Kitebi KCCA Health Centre III, TASO Mulago and Mulago Immune Suppression Syndrome (Mulago ISS Clinic)

Collaborators: University of California San Francisco (UCSF)

Principal Investigators: PI- Joselyn Rwebembera

Study Sponsor: National Heart Lung and Blood Institute of the National Institute of Health (NIH), USA