Although infectious diseases are often studied individually, in reality patients with infections often have other health conditions. One obvious example is HIV and TB, often found together, as HIV increases the risk of TB disease. Co-infections can interact with one another and also impact on treatment – drugs for one condition can interfere with those used to treat another.

For example, initiation of treatment of HIV/AIDS with antiretroviral drugs can lead to a sudden flare up of TB as a patient’s immune system recovers (known as immune reconstitution inflammatory syndrome, IRIS). The PredART trial, funded under the first EDCTP programme (2003-2015), showed that treatment with a widely available steroid, prednisone, significantly reduced morbidity in IRIS patients (Meintjes G et al, 2018). A follow-up trial is assessing whether prednisone can prevent IRIS developing in high-risk patients.

One in four people globally have inactive (latent) TB infections, and around 10% go on to develop active TB disease. This risk is substantially greater in certain groups, including those with type 2 diabetes. The PROTID trial, funded in 2019, is assessing whether preventive treatment of TB in diabetes patients with latent TB is practical, clinically worthwhile and cost-effective.

Awarded in 2019, the META TRIAL study will include a large-scale phase III trial to determine whether metformin, an affordable drug widely used to treat diabetes, is also effective at preventing the development of diabetes in people living with HIV at increased risk of the condition. Also funded in 2019, the VITALITY project is evaluating the potential of vitamin D and calcium carbonate supplementation to counter the weakening of bone commonly seen in children with HIV infections.

In 2019, EDCTP also funded studies of co-morbidities through a fellowship scheme organised in partnership with GlaxoSmithKline. Through this scheme, Dr Barbara Castelnuovo is setting up a cohort of older people with HIV in Uganda, to determine the health risks they face in later life. Professor Andre Kengne is aiming to identify the key risk factors for cardiometabolic disease in people living with HIV in sub-Saharan Africa, in a project spanning Cameroon, Nigeria and South Africa. A clearer understanding of the most important risk factors could underpin the design of integrated services for people living with HIV that address both infectious and non-communicable co-morbidities.

In addition, Dr George PrayGod is investigating whether impaired gut function, due to infection, is linked to the increased risk of diabetes in people living with HIV. Professor Marielle Bouyou-Akotet is exploring whether common parasitic infections affect the risk of cardiometabolic disease in urban and rural populations in a Central African country. Finally, Professor Dorothy Yeboah-Manu is assessing how diabetes affects TB disease and responses to treatment.

The annual G-FINDER report of global health research funding has highlighted EDCTP’s major contribution to combating cryptococcal infections, a leading cause of death in people with HIV.

Cryptococcus is an opportunistic fungal infection that poses a serious risk to people with advanced HIV disease. It is responsible for the deaths of up to 20% of people with HIV infections, principally because of brain infections leading to cryptococcal meningitis.

Over several years, EDCTP has developed a suite of projects having a major impact on Cryptococcus diagnosis and treatment. Of particular note, the EDCTP-funded REMSTART trial showed that a relatively low-cost intervention, based on screening for Cryptococcus infections and providing home support to encourage adherence to treatment, reduced mortality by 28%. The follow-up TRIP project is testing whether a simplified version implemented in clinics, but using mobile messaging rather than home visits, is similarly effective.

Also focusing on implementation, the DREAMM study is piloting the introduction into routine care of screening for central nervous system infections such as cryptococcal meningitis in Cameroon, Malawi and Tanzania. The project will generate important data on cost-effectiveness in routine settings, as well as on factors affecting implementation of new clinical tools and diagnostic algorithms. The activities in Cameroon are co-funded by ANRS, the French Agency for Research on AIDS and Viral Hepatitis.v

Better treatments are also required for Cryptococcus infections. The AMBITION-cm trial is a major phase III trial testing the efficacy of an improved single-dose liposomal formulation of amphotericin B (AmBisome^®). Standard amphotericin B is not widely used in resource-poor settings in part because it requires hospitalisation for at least 14 days and its toxicity profile requires costly monitoring. Liposomal amphotericin B has a much better safety profile and, if proven to be equally effective, could provide a more practical first-line treatment option.

In addition, the 5FC HIV-Crypto study, awarded in 2019, is focusing on an alternative treatment, flucytosine, which also has a challenging dosing schedule. An EDCTP-funded team is developing a new formulation of flucytosine that is easier to administer, including a sustained-release formulation, and will compare its efficacy with the current formulation.

Despite its major burden in sub-Saharan Africa, cryptococcal meningitis remains under-studied and under-funded. The 2019 G-FINDER annual report highlighted the fact that the bulk of non-US funding was routed through EDCTP, and accounted for 85% of global funding on clinical development.

The DREAMM study is piloting the introduction of new diagnostic strategies for HIV-related meningoencephalitis into routine care in Cameroon, Malawi and Tanzania. Why is this important and how will it make a significant impact in this field?

It is important to identify effective and sustainable models of care for people living with HIV presenting with meningoencephalitis, which causes up to a third of HIV-related deaths in low- and middle- income countries (LMICs) in Africa. The DREAMM project is unique in focusing on African leadership in hospital sites supported solely by the local Ministry of Health and the delivery of care for advanced HIV disease by frontline healthcare workers, including 2- and 10-week and 6-month outcome data. 

According to initial results, DREAMM interventions (implementation of diagnostic and treatment algorithms for HIV-related meningoencephalitis; open access co-designed education programmes; infectious disease and laboratory capacity building and health system strengthening) when combined appear to substantially and sustainably reduce mortality at 2 weeks. They have the potential to be scaled up in African LMICs as tools such as tests and treatments for cryptococcal meningitis become available as part of other initiatives, including the Clinton Health Access Initiative (CHAI)/Unitaid programme on advanced HIV disease.

What comes next?

We have been working hard to circumvent the challenges posed by the COVID-19 pandemic. As DREAMM is an implementation project and HIV-related deaths from meningoencephalitis sadly remain a constant, we have worked throughout the pandemic, successfully addressing a number of delays including shipment of essential medicines such as the life-saving medicine flucytosine for the treatment of cryptococcal meningitis. 

We are excited to announce the imminent opening of our final DREAMM site in Zomba, Malawi, for recruitment into the implementation phase of the project using a pan-African approach with DREAMM investigators from the University of North Carolina Project Malawi. Many of the training resources from the DREAMM project have been incorporated in the global advanced HIV disease toolkit, the development of which was led by the DREAMM Chief Investigator in close collaboration with CHAI.  Recruitment into DREAMM is scheduled to end at the end of Q1 2021, with results, including 10-week follow-up data, due in Q2/3 of 2021.

What progress was made in 2019?

The DREAMM project made significant progress in 2019, with the completion of recruitment into the final implementation phase of the project at two sites in Dar es Salaam, Tanzania, and one site in Lilongwe, Malawi. In Cameroon, the DREAMM training programme was delivered successfully in April 2019 and the implementation phase of the project started in September 2019. 

Presentations of the DREAMM project and its unique methodology were made by St George’s University of London and Institut Pasteur DREAMM investigators at AIDS Mycoses 2019 (Cape Town, South Africa), TIMM 2019 (Nice, France) and the World Health Summit 2019 (Berlin, Germany). Preparations for the training phase of DREAMM in Zomba, Malawi, were also in full swing in 2019, with this training successfully delivered in February 2020.

This study will evaluate a new course of treatment against HIV co-infection with cryptococcal meningitis. Why is it relevant to pursue this treatment and how will this make a significant impact in the field?

HIV-associated cryptococcal meningitis is a severe fungal infection of the brain which affects about 230,000 people and causes 180,000 deaths every year – accounting for approximately 15% of all HIV-related mortality. Most cases occur in sub-Saharan Africa where treatment options are limited, involving courses of toxic antifungal medication and prolonged hospital admissions. AMBITION-cm is testing a single high dose of a less toxic intravenous antifungal in the hope of providing an effective, safe, practical, and affordable first-line treatment option for this devastating disease.

What comes next?

The key goal for the fourth and final year of the project is to reach our recruitment target and complete the follow-up of all participants in order to analyse and present our main study findings. If the novel short course treatment is effective, we will work to disseminate our findings and update international guidelines. Our ultimate aim is to ensure universal access to affordable, safe and effective treatment for HIV-associated cryptococcal meningitis by providing a practical, first-line treatment option with the potential to prevent many thousands of deaths.

What progress was made in 2019?

Our main focus during 2019 was recruitment of study participants from eight hospitals across five countries in southern and eastern Africa. By the end of the year, we had recruited over 500 of our 850 participant target.

Alongside the main clinical trial, we continued to conduct a number of scientific sub-studies in the fields of immunogenetics, diagnostics, pharmacology, health economics and anthropology. We also made good progress with our training and capacity-building activities. Our AMBITION-cm PhD student, Tshepiso Mbangiwa (Botswana), moved from her initial placement at the Institut Pasteur in Paris to the University of Cape Town to commence field work. Our 2018-19 MSc scholar, Kenneth Ssebambulidde (Uganda), graduated from the MSc in the Immunology of Infectious Diseases at the London School of Hygiene and Tropical Medicine with distinction. And 2019-20 MSc scholars, Admire Hlupeni (Zimbabwe) and Janet Zambezi (Malawi), began their studies in Epidemiology and the Immunology of Infectious Diseases at the London School.

The TRIP study is implementing cryptococcal meningitis screening and a text messaging support package in Tanzania. Why is this study important and how does it connect to the REMSTART project supported under the first EDCTP programme?

The REMSTART trial identified an effective package for cryptococcal antigen (CrAg) screening and enhanced antiretroviral therapy (ART) adherence support that reduced all-cause mortality in advanced HIV disease by 28% compared to standard of care. It contributed to global health policy on the management of advanced HIV disease, as published in 2017 WHO guidelines.

The EDCTP-funded project on Translating Research into Practice (TRIP) evaluated scale-up of the evidence-based REMSTART package in 36 facilities in Tanzania.

The TRIP intervention involved implementation and evaluation of (1) cryptococcal meningitis screening using the CrAg test plus pre-emptive treatment with fluconazole and (2) weekly mobile telephone messaging as home support for one month followed by monthly telephone consultations for the following three months in communities (i.e. health facilities and the catchment populations that they serve).

What progress was made in 2019?

The TRIP study is a cluster-randomised implementation trial with participants enrolled and followed up through early and deferred arms. After 12 months of follow up, the intervention package was eventually scaled up to the deferred arm. The trial intervention package was successfully implemented in a total of 36 facilities.  

We screened 2,771 participants, identified, enrolled and followed up 78 asymptomatic CrAg-positive, 45 symptomatic CrAg-positive and 2,645 CrAg-negative individuals with advanced HIV disease. At the deferred facilities, we screened 2,893 patients, and enrolled and followed up a total of 2,756 participants. The primary endpoint is all-cause mortality at one year. Importantly, the TRIP study is identifying factors affecting implementation of the intervention, informing efforts to introduce a package of care for advanced HIV disease in rural and urban facilities in Tanzania.

We facilitated and promoted knowledge dissemination and engagement of various stakeholders, with a particular focus on policymakers at national and international levels. These included the International Advanced HIV Disease Implementation Steering Committee (two of the TRIP investigators are among the members of the committee), an initiative of the Excellence Center for Medical Mycology of the European Confederation of Medical Mycology (ECMM) (in development of guidelines on management and diagnosis of rare mould infections), the Ministry of Health through the National Aids Control Program, Health Management Councils at regional, district and facilities levels, the scientific community, and professional organisations. We also engaged with technical working teams spanning TB and HIV/AIDS programmes, implementing partners supporting the Ministry of Health on HIV/TB, and academic institutions. 

The scale up of the intervention package means that patients with advanced HIV disease (who have a remarkably high mortality) have access to diagnostics, treatment and support which may drastically improve their survival rate. The package is transforming clinical practice and treatment outcomes in HIV programmes in Tanzania and sub-Saharan Africa as a whole.

The TRIP implementation experiences and lessons learned have shown immediate impact, guiding the national plan for scaling up cryptococcal screening nationwide in Tanzania. Among the outcomes contributing to impact included:

1. A national training manual and modules for cryptococcal screening
2. A TB/HIV national monitoring tool and opportunistic infections monitoring, including cryptococcal meningitis
3. UNITAIDS-CHAI in Tanzania taking up all TRIP sites to support the Ministry of Health to continue implementing the TRIP intervention package
4. Implementing partners supporting the Ministry of Health to scale up cryptococcal screening and pre-emptive fluconazole use in 168 facilities across the country
5. Global Advanced HIV Disease Toolkit: TRIP experiences and materials contributed to the development process.

At the national level, REMSTART has influenced the updated National Guidelines for the Management of HIV and AIDS, Sixth Edition, October 2017, which includes screening for cryptococcal infection and pre-emptive treatment with fluconazole. Training modules for CrAg screening in all regional hospitals and other selected primary care facilities have been developed. During TRIP, continued efforts to increase uptake guided the national plan for scaling up cryptococcal screening.

The TRIP project is providing implementation guidelines for the UNITAIDS project on widening access to a package of life-saving medicine, through UNITAIDS CHAI Tanzania and the Ministry of Health in Tanzania. Hence, all TRIP sites will continue with the intervention under this project. The project provides access to fluconazole, flucytosine, amphotericin B and diagnostics, including point of care CD4 testing. The UNITAIDS CHAI package will be implemented in seven countries in sub-Saharan Africa.

Through the best practice and lessons learned, REMSTART and TRIP projects have demonstrated the value of engaging with policymakers and programme managers from the outset to accelerate adoption of policies at national, regional and international levels.