Achievements in fighting Malaria

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Overview

Research from MORU has directly resulted in the most important development in antimalarial chemotherapy in the past fifty years - our work has provided the biological, economic, and clinical basis for changing global antimalarial treatment recommendations to artemisinin combination therapies (ACTs) for uncomplicated falciparum malaria and injectable artesunate for severe malaria.

Our work on the Thai-Burma border, undertaken by Shoklo Malaria Research Unit (SMRU) treats more than 20,000 malaria patients each year and has enrolled more patients in antimalarial studies than any other research group. It has led the development and evaluation of artemisinin combination therapies (ACTs), and also defined the optimum methodologies for field-based assessment of antimalarial chemotherapy.

MORU has conducted the largest clinical trial in severe malaria (SEAQUAMAT) and children (AQUAMAT), which identified injectable artesunate as the superior drug to treat adult severe malaria.

An overview of all 435 antimalarial drug trials published between 1966 and 2003, showed that MORU published one tenth of all such studies and enrolled 22% of all malaria patients studied in clinical trials worldwide.

Principal achievements in antimalarial chemotherapy:

  • The largest studies of new ACTs
  • Demonstration that systematic use of ACTs reduces the incidence of falciparum malaria, and can actually help reverse resistance to mefloquine
  • Largest ever antimalarial drug trials in severe malaria (SEAQUAMAT & AQUAMAT), which showed that artesunate compared to quinine reduced mortality, by 35% in (mainly) adults with severe malaria in Asia and 23% in African children with severe malaria.
  • The combination of quinine and clindamycin was shown to be a safe and effective treatment, which may be important for treating children and pregnant women
  • The first study to accurately describe artesunate resistance in Pailin in Western Cambodia

 

Translating research into policy

The translation of our findings into policy revision on the treatments of both uncomplicated and severe falciparum malaria has been achieved through the endorsement of our research findings by the World Health Organization (WHO), and also at a National level by the conduct of relevant clinical trials in close collaboration with National Malaria Control Programmes. Our studies have also led to WHO endorsing revised methods of assessing treatment responses. ICU training programmes in India, Bangladesh and Nepal aim to implement the best care for patients with severe malaria and other severe illnesses.

In Lao PDR we demonstrated the poor efficacy of both chloroquine and sulphadoxine-pyrimethamine in Malaria treatment. This stimulated a major reassessment of the Lao national malaria treatment policy. We then conducted a trial demonstrating the effectiveness of ACTs which proved clinically superior. This has paved the way for policy change to ACTs in Lao PDR.

Our studies of antimalarial treatment in northern Burma (Myanmar) showed that chloroquine and sulfadoxine-pyrimethamine, the nationally recommended treatment, were completely ineffective. Subsequent studies of ACT effectiveness paved the way for policy change to ACTs in Burma.

Counterfeit antimalarial drugs

We have conducted and published surveys uncovering the horrendous and widespread problems of fake antimalarial drugs throughout Southeast Asia and we have provided simple methods for their detection.


Mechanisms and epidemiology of antimalarial drug resistance

  • MORU has modeled the factors which lead to antimalarial drug resistance. Patients receiving incomplete therapies of only one antimalarial drug are a major source of resistance.
  • Our comprehensive mathematical-economic model of drug resistance contributed to revised global recommendations on antimalarial drug policy.
  • Genetic studies showed that pyrimethamine-resistant malaria found in Africa first arose in SE Asia. This extraordinary capability for spread emphasises the potential for travel of highly drug resistant parasites from SE Asia to Africa.
  • We have identified the stepwise mutations in the P. vivax genes responsible for resistance to sulphadoxin-pyrimethamine.

 

Malaria in pregnancy

Shoklo Malaria Research Unit is the major source of clinical and scientific information on vivax and falciparum malaria in pregnancy in a low transmission area, and the main source of information on antimalarial drug treatment in pregnancy. SMRU contributed 8 of the 12 existing studies on antimalarial drugs in pregnancy and worked with 69% of all patients studied.

Achievements include:

  • Characterisation of the adverse impact of malaria in pregnancy on infant survival.
  • SMRU's work has contributed significantly to a WHO report endorsing artemisinins being used as antimalarials in the second and third trimesters of pregnancy.
  • Clinical evidence has demonstrated that the triple combination of artesunate-atovaquone-proguanil can be used safely to treat falciparum malaria in pregnant women that has proved clinically resistant to all other antimalarials.
  • SMRU's studies indicate that the low birth weight associated with falciparum malaria infection is due to the effects of the infection itself, rather than irreversible damage to the placenta. This emphasises the importance of prompt effective treatment of the infection.

 

Diagnosis of malaria

Assessments of new rapid tests for falciparum malaria have been carried out.
A study in Laos showed that village health volunteers were able to use rapid dipstick tests accurately with a minimum of training. We showed that PfHRP2 based tests perform better than pLDH based rapid tests for the diagnosis of severe malaria in high transmission areas in Africa. Moreover, quantitative assessment of plasma PfHRP2 can be used as a tool to distinguish severe malaria from other severe febrile illness with co-incidental peripheral blood parasitaemia.

Treatment of severe malaria

We undertook the largest ever multi-country study to compare mortality in patients with severe malaria treated with intravenous artesunate or intravenous quinine. The Southeast Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) had participating centres in Bangladesh (Chittagong), Burma (4 centres), India (Rourkela), and Indonesia (West Papua). This showed that artesunate was associated with a 35% reduction in mortality compared with quinine. After the encouraging results of SEAQUAMAT, we conducted an  even larger study in African children (AQUAMAT), to see whether artesunate can reduce the mortality from severe malaria in this critically important patient group. This study in 11 sites over 9 African countries (Mozambique, Kenya, Tanzania, Ruanda, Uganda, Nigeria, Gambia, Ghana and the Democratic Republic of Congo) showed that injectable artesunate compared to quinine reduced mortality by 23% in children with severe malaria. The results have prompted the WHO to adapt their treatment guidelines, which now recommend artesunate as the drug of choice in all patients with severe falciparum malaria, irrespective of age or epidemiological setting.

 

Pathophysiology of malaria

We re-established that obstruction of flow in the smallest blood vessels by sticky, infected red blood cells is a central reason for severe disease in falciparum malaria, using a variety of techniques. We showed in early autopsy studies in adults dying from severe malaria that in patients with cerebral malaria (coma) the number of brain vessels blocked by sticky parasitized red blood cells was higher than in patients that had severe malaria without coma. But also in living patients we directly showed for the first time the blockage of small blood vessels using a microscopic camera. We developed a model to estimate the total body parasite burden and the sequestered numbers of parasites in patients from measurements of a protein (PfHRP2) released in the patient’s blood plasma, by the sequestered parasites. Total body parasite burden is closely related to disease severity, and in contrast with the circulating peripheral blood parasitaemia, a strong predictor for mortality.  We have shown that in patients with severe falciparum malaria, both infected and uninfected red blood cells get rigid, especially when the patient is severely ill. Measures of endothelial activation also relate to disease severity, as well as measures of oxidative stress. MORU  identified that malaria parasites that cause severe disease have a greater potential to multiply because they are less selective in the red blood cell populations that they can infect. Mitochondrial DNA studies in a worldwide collection of P. falciparum isolates (in which MORU collaborated) suggested an early origin (50,000 to 100,000 years ago) and recent expansion (10,000 years ago) of the parasite P. falciparum.

 

Vivax malaria

We have demonstrated that in Thailand P. vivax frequently coexists with cryptic P. falciparum infection, and studied the complex interaction between these two species. Genotyping methods for field epidemiology and treatment studies of P. vivax have been developed.

Clinical pharmacology

Since 2000 MORU has published studies on the interactions between drugs and the human body (pharmacokinetic and pharmacodynamic studies), with a wide variety of drugs used to treat tropical infectious diseases, these include lumefantrine, mefloquine, quinine, artesunate, artemether, and dihydroartemisinin in the treatment of falciparum malaria and atovaquone and proguanil in the treatment of malaria in pregnant women.

 

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