Significant achievements

In COMRU, the assessment of the impact of pneumococcal vaccination on carriage and invasive disease continues, and an evaluation of pre-vaccination clinical serotype distribution was completed, and a large community based-programme to improve neonatal survival was initiated (“Saving Babies Lives”).

In SMRU, studies on the prevalence of neonatal jaundice as a cause of hospital and its nature and outcome and on perinatal depression were published, and a clinical trial is underway on the prevention of vertical transmission of Hep B with Tenofovir.

MALARIA

A series of observational and treatment trials have been completed characterising increasing antimalarial drug resistance in the region and defining the relative contributions of artemisinin and ACT partner drug resistance to treatment failure.

The studies confirm the evolution over time of artemisinin resistance, with a single PfKelch mutation, C580Y, becoming dominant. A C580Y mutated, relatively fit P. falciparum lineage has now spread from western Cambodia over a large geographical area including north-eastern Thailand, southern Laos, and southern Vietnam, and during this course has acquired piperaquine resistance. Laboratory transcriptomic studies have confirmed that oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites.

BACTERIAL

The Africa Asia Programme is actively involved in SEDRIC and in the IHME-led project to assess the burden of and map antimicrobial drug resistance (AMR) globally. We are working on novel ways to collect high-quality AMR data with associated clinical outcomes and will soon start the ACORN project to assess this in Cambodia and Vietnam. Antibiotic usage was assessed in chicken farms in Thailand, and the concept of the ‘antibiotic footprint’ for food products promoted.

We continue to work on the genomics, pathobiology of and immunological response to malaria infection, melioidosis and rickettsioses. Our work in 2018 included:

• An analysis of clinical Burkholderia pseudomallei isolates demonstrated conservation of unique lipid A structure and TLR4-dependent innate immune activation;
• We produced six new complete genomes of Orientia tsutsugamushi (making eight in total) using long-read sequencing and characterised the extraordinary genomic variation in this species; and
• A molecular epidemiological study showed the prevalence of asymptomatic naturally acquired P. cynomolgi and P. knowlesi infections in humans.

BIOANALYSIS AND PHARMACOMETRICS

2018 findings influencing treatment and efficacy include:

• Co-administration of ivermectin plus dihydroartemisinin-piperaquine leads to increased concentrations of ivermectin, imparting a greater mosquito-lethal effect;
• In a study in Niger, malnutrition was significantly associated with decreased absorption of lumefantrine, leading to under-exposure and an increased risk of malaria reinfection;
• Chloroquine, dihydroartemisinin-piperaquine and artesunate-pyronaridine all significantly increase plasma primaquine concentrations; and
• In TB modelling and simulation showed inadequate rifampicin drug levels in children with the currently available dosing regimens, and the developed population pharmacokinetic model was used to suggest an optimised dose regimen.

CLINICAL TRIALS

During 2018 the Africa Asia Programme ran around 70 clinical studies – observational, case-control, pharmacokinetics/pharmacodynamic (PK/PD) and randomised controlled trial (RCTs) – at any one time. Highlights include:

• A large multinational trial testing triple artemisinin combination therapies (TACTs) for the treatment of drug resistant falciparum malaria (TRAC II) was completed in 2018, demonstrating that TACTs are well tolerated and effective at treating multi-drug resistant malaria prevalent in much of the GMS;
• These studies have been complemented by detailed drug-drug interaction studies of the components of the triple therapies in healthy volunteers. The most important finding to date – which allowed the multinational clinical trials to proceed – was to show that mefloquine did not potentiate the effects of piperaquine on ventricular repolarisation;
• A large study of the safety of single low dose primaquine, using a novel age-based dosing regimen, in G6PD deficient African children with uncomplicated falciparum malaria is underway in Kinshasa (KIMORU) and Uganda (Imperial-KEMRI-Wellcome);
• The largest ever multicentre study on primaquine radical treatment of vivax malaria (IMPROV) was completed in 2018 and offers an efficacious and tolerated double dose primaquine regimen over 7 days; and
• An RCT in Bangladesh showed a reno-protective effect of paracetamol in adult severe malaria through an anti-oxidative mechanism.

ETHICS OF RESEARCH IN RESOURCE-LIMITED COUNTRIES

Research on how to ethically involve children, pregnant women, migrants, refugees and other under-served groups in medical research continues, including initiation of the multi-centre study “In Their Own Voices: Vulnerabilities & Abilities of Women, Children, & Families in Health Research”.

Multiple publications arose from research on how to meaningfully engage communities in research, including the use of community advisory boards and innovative approaches (e.g. art and theatre) in order for the research to be responsive, ethical and ultimately to improve lives.

MEDICINE QUALITY

The LOMWRU-based medicine quality team play a global leadership role in medicine quality research. They continue to provide evidence to the Member State Mechanism of WHO on medicine quality issues, and in 2018 organised the first ever International Conference on Medicine Quality and Public Health. Accessible data on the quality of maternal health medicines, antibiotics, antidiabetics, anti-retrovirals, and anti-tuberculous drugs is being tabulated, and these are being mapped before expanding to other classes of essential medicines. A pilot WWARN/IDDO project to map national laws related to medicine quality and the definitions of different types of poor quality medicines has been completed.

The team are also evaluating multiple innovative medicine quality screening devices. With the current evidence, it is unlikely that any one device would be able to effectively monitor the quality of all medicines.

CRITICAL CARE MEDICINE IN LOW AND MIDDLE-INCOME COUNTRIES (LMIC)

The critical illness team continues to show global leadership in translating evidence-based Western Intensive Care Units (ICU) care to LMIC settings:

• The “surviving sepsis campaign” guidelines were adapted for se in resource-poor and tropical settings, in collaboration with an international group of experts;
• A low-cost registry was developed and tested in ICUs in Sri Lanka, which will be expanded to 42 ICUs across the region as part of the Wellcome Innovations critical illness flagship programme;
• Studies on improving ICU training in low and middle-income countries have been set up and are currently running in Lao PDR and Sri Lanka; and
• A study was published showing the improved performance and reduction in mortality of a large ICU training effort in India, Bangladesh and Nepal.

A series of large trials on the use of targeted mass drug administration (MDA) as a tool for malaria elimination in the region has been completed with sites in Myanmar, Cambodia, Lao PDR and Vietnam. These studies show good efficacy and acceptable safety of dihydroartemisininpiperaquine with or without low dose primaquine, and the importance of community engagement to achieve high population coverage. Social science studies were conducted to understand factors which motivate target populations for malaria control activities towards participation.

We also described the dynamics of asymptomatic parasitaemia over time, crucial for defining the contribution of the asymptomatic reservoir to malaria transmission in low transmission settings and informing policy makers.

Studies were completed assessing the safety and benefit of ivermectin in malaria control, understanding the effect of population level MDA on vector infectivity, and understanding the aspects of housing which protect against vector entrance.

A large healthy volunteer study showed that the RTS,S/AS01 vaccine was well tolerated and immunogenic, and had no interactions with DHA-piperaquine. Modelling has shown that vaccination with RTS,S is a potentially useful adjunct to MDA in elimination campaigns.

A systematic review on the risk of sudden unexplained death after dihydroartemisinin-piperaquine was completed, which showed the safety of this drug combination and informed the WHO treatment guidelines.

All departments and units of the Africa Asia Programme conduct active public engagement (PE) activities, including science cafés and Pint of Science events. In 2018, we awarded 10 bursaries for specific investigator-led projects. Other 2018 PE projects include: Village Drama Against Malaria in Cambodia; Fishy Clouds puppet theatre on AMR in Bangkok; and Fever and Antibiotic Use, a forum theatre show by MOCRU, Myanmar. Community engagement activities include the Tak Community Advisory Board (T-CAB) on the Thai-Myanmar Border and the Young Persons Advisory Group (YPAG) in Cambodia.

A number of potentially new therapeutic interventions have been uncovered:

• Use of triple artemisinin combination therapies to prevent the emergence and spread of drug resistant malaria. A large multicentre multi-country trial (TRAC II) finished recruiting in 2018, and preliminary results show that they are reasonably well tolerated and effective against multi-drug resistant malaria;
• CRP testing was shown to be effective at reducing antibiotic usage in the treatment of febrile illness. With partners we plan to develop and test rapid tests which combine CRP with disease specific tests (such as malaria, dengue, and scrub typhus). A modelling exercise has shown that this approach would be cost-effective;
• The RTS,S malaria vaccine provides short term drug-independent protection against falciparum malaria, and may be a useful tool for malaria elimination campaigns. We have assessed for the first time the immunogenicity of RTS,S in Asian adults, and whether concomitant dihydroartemisinin-piperaquine affects it. These studies have now been completed and show good immunogenicity, no significant interactions, and they inform appropriate dosing;
• Dihydroartemisinin-piperaquine was evaluated as seasonal chemoprevention in young children in Burkina Faso. Our Clinical Pharmacology Department conducted the bioanalysis and described the PK/PD properties of piperaquine using modelling and simulation, showing that young children need a relatively higher dosage compared to adults. Increased piperaquine dosage and extended coverage during the high transmission season could have a substantial impact on the incidence of malaria;
• The renoprotective effects of paracetamol were evaluated in patients with severe and moderately severe falciparum malaria in a randomised, controlled, open-label trial. The pharmacokinetic-pharmacodynamic analysis showed that higher exposure to paracetamol increased the probability of creatinine improvement, and therefore, a renoprotective effect of paracetamol;
• A comprehensive pharmacokinetic-pharmacodynamic evaluation of the endectocide ivermectin has shown that mosquitocidal effects persist beyond the elimination of the predominant component of the parent compound. This opens up the possibility of either an unidentified active metabolite, or slower elimination of the more active minor component. In either case this has firmly put ivermectin in centre stage as a potential elimination tool. WHO has endorsed this and encouraged further research to identify the active principals - which is ongoing within the pharmacology department;
• Primaquine is widely recommended but often not used. We have calculated the proportions of patients unable to receive the new 8-aminoquinoline tafenoquine and thereby shown that primaquine will still be necessary if tafenoquine is introduced for the radical cure of vivax malaria. We have shown, using a new approach combining genotyping and time to event modelling, that if primaquine is used properly it can prevent nearly all relapses. This currently requires testing for G6PD deficiency and this is relatively expensive and generally unavailable. We have modelled an ascending dose regimen that should avoid dangerous haemolytic toxicity and could therefore be used without G6PD testing. This regimen is being tested in an adaptive trial design in known G6PD deficient healthy volunteers; and
• A rapid immunochromatography test based on Hcp1 was shown to be a potential point-of-care test for serological diagnosis of melioidosis.

We currently employ 780 research physicians, scientists, technicians, nurses, field workers and support staff in 5 Units and conduct clinical research in approximately 50 study sites across Asia and Africa. Major personnel changes in 2018 include the appointment of a new COO, and the appointment of a new director of our Laos unit, LOMWRU, to replace the long-serving founding director.

The MORU Tropical Health Network continues to have a productive working relationship with the Mahidol Faculty of Tropical Medicine (FTM). At the Aug 2018 committee meeting all parties reaffirmed their commitment to the collaboration and to build on the successes of the last 39 years improving health across Asia.

An assessment of Health and Safety Management Profile (HASMAP) audit of the Programme recognized a positive culture to managing health and safety issues across the network.

In 2018 a new team was set up focused on translating MORU’s research into positive health improvements. The Institutional Translational Partnership Award (iTPA) is funded by Wellcome and also supports innovation in the Faculty of Tropical Medicine.

The healthy volunteer ward was upgraded and relocated to a more modern facility to support clinical trials.

As part of optimizing how MORU can best positively impact the health of LMIC communities through evolution of delivery models, an independent Thai foundation, The Borderland Health Foundation (BHF), was registered to house the delivery of medical assistance to humanitarian communities on the Thai-Myanmar border, but still retaining the strong link between direct assistance and research.