Gilbert Kokwaro

Averting a malaria disaster

Estimates for the annual mortality from malaria range from 0·5 to 2·5 million deaths. The burden of this enormous toll, and the concomitant morbidity, is borne by the world’s poorest countries. Malaria morbidity and mortality have been held in check by the widespread availability of cheap and effective antimalarial drugs. The loss of these drugs to resistance may represent the single most important threat to the health of people in tropical countries. Chloroquine has been the mainstay of antimalarial drug treatment for the past 40 years, but resistance is now widespread and few countries are u n a f f e c t e d . 1 Pyrimethamine-sulphadoxine (PSD) is usually deployed as a successor to chloroquine. Both these antimalarials cost less than US

Genome-wide and fine-resolution association analysis of malaria in West Africa.

0.20 per adult treatment course, but the drugs required to treat multidrug-resistant falciparum malaria (quinine, mefloquine, halofantrine) are over ten times more expensive and cannot be afforded by most tropical countries— especially those in Africa, where it is estimated that more than 90% of the world’s malaria deaths occur. Resistance to chloroquine is widespread across Africa and resistance to PSD is increasing. 2 A health calamity looms within the next few years. 3 As treatments lose their effectiveness, morbidity and mortality from malaria will inevitably continue to rise. Can this disaster be prevented? Can we really “roll back malaria”, as the new Director-General of WHO has demanded? 4

WHO, the Global Fund, and medical malpractice in malaria treatment

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10−7 to P = 4 × 10−14, with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Chloroquine resistance before and after its withdrawal in Kenya

Amir Attaran and colleagues highlight a very serious public-health issue. Provision of ineffective drugs for a life-threatening disease is indefensible. There is no doubt that chloroquine is now ineffective for the treatment of falciparum malaria in nearly all tropical countries and that its usual successor sulfadoxine-pyrimethamine is falling fast to resistance. As a result malaria mortality in eastern and southern Africa where hundreds of thousands of children die each year from the infection has doubled in the past decade. We have failed to roll back malaria and we in the developed world bear the responsibility for this humanitarian disaster. Malaria is not an insoluble problem. We already have the tools (insecticides bednets highly effective drugs) to reduce substantially the terrible death toll. But we are not providing them to the people who need them desperately but who cannot pay for them. Only a tiny fraction of the millions with malaria today receive highly effective treatments. The donors must take some responsibility for this failure. Given the choice between receiving donor support for ineffective chloroquine or sulfadoxine-pyrimethamine and receiving nothing most countries have naturally opted for the former. It is not easy to protest particularly when the main donors and the representatives of international organisations both claim these drugs are still “programmatically effective”. (excerpt)

Strengthening capacity for health research in Africa

BackgroundThe spread of resistance to chloroquine (CQ) led to its withdrawal from use in most countries in sub-Saharan Africa in the 1990s. In Malawi, this withdrawal was followed by a rapid reduction in the frequency of resistance to the point where the drug is now considered to be effective once again, just nine years after its withdrawal. In this report, the polymorphisms of markers associated with CQ-resistance against Plasmodium falciparum isolates from coastal Kenya (Kilifi) were investigated, from 1993, prior to the withdrawal of CQ, to 2006, seven years after its withdrawal. Changes to those that occurred in the dihydrofolate reductase gene (dhfr) that confers resistance to the replacement drug, pyrimethamine/sulphadoxine were also compared.MethodsMutations associated with CQ resistance, at codons 76 of pfcrt, at 86 of pfmdr1, and at codons 51, 59 and 164 of dhfr were analysed using PCR-restriction enzyme methods. In total, 406, 240 and 323 isolates were genotyped for pfcrt-76, pfmdr1-86 and dhfr, respectively.ResultsFrom 1993 to 2006, the frequency of the pfcrt-76 mutant significantly decreased from around 95% to 60%, while the frequency of pfmdr1-86 did not decline, remaining around 75%. Though the frequency of dhfr mutants was already high (around 80%) at the start of the study, this frequency increased to above 95% during the study period. Mutation at codon 164 of dhf r was analysed in 2006 samples, and none of them had this mutation.ConclusionIn accord with the study in Malawi, a reduction in resistance to CQ following official withdrawal in 1999 was found, but unlike Malawi, the decline of resistance to CQ in Kilifi was much slower. It is estimated that, at current rates of decline, it will take 13 more years for the clinical efficacy of CQ to be restored in Kilifi. In addition, CQ resistance was declining before the drugs official withdrawal, suggesting that, prior to the official ban, the use of CQ had decreased, probably due to its poor clinical effectiveness.

Guidelines for Field Surveys of the Quality of Medicines: A Proposal

Health research has a key role in the development of low-income and middle-income countries. There are several current initiatives that have greatly contributed to capacity strengthening of health research in sub-Saharan Africa, including those supported by WHO and Tropical Disease Research (TDR), the Swedish International Development Agency (SIDA) and Department for Research Cooperation (SAREC), the European Union, the Bill & Melinda Gates Foundation, the International Clinical Epidemiology Network (INCLEN), the Fogarty International Centre, the National Institutes of Health (NIH), and the Wellcome Trust. However, enormous challenges remain for sub-Saharan Africa to establish a common framework for sustainable research capacity strengthening.

Artemether/lumefantrine in the treatment of uncomplicated falciparum malaria

Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines.

Chloroquine-resistant Plasmodium vivax malaria in Debre Zeit, Ethiopia.

At present, artemether/lumefantrine (AL) is the only fixed-dose artemisinin-based combination therapy recommended and pre-qualified by WHO for the treatment of uncomplicated malaria caused by Plasmodium falciparum. It has been shown to be effective both in sub-Saharan Africa and in areas with multi-drug resistant P. falciparum in southeast Asia. It is currently recommended as first-line treatment for uncomplicated malaria in several countries. However, AL has a complex treatment regimen and the issues of adherence to treatment with AL by adult patients and real-life effectiveness in resource-poor settings will be critical in determining its useful therapeutic life, especially in Africa, where the major burden of malaria is felt. There are also issues of safety of the artemisinin derivatives, including AL, which will need to be monitored as their use in resource-poor settings becomes more widespread. There are limited pharmacokinetic studies of AL in African patients, and the relationship between plasma drug concentration and efficacy in these patients is unknown. Moreover, the effects of factors such as concurrently administered drugs, malnutrition and co-infections with HIV and helminths in malaria patients are not well understood. These will need to be addressed, although a few studies on possible drug–drug interactions with commonly used drugs, such as quinine, mefloquine and ketoconazole, have been reported. This review focuses on the status of clinical pharmacology, efficacy and real-life effectiveness of AL under a variety of settings, and highlights some of the challenges that face policy makers during the deployment of AL, especially in Africa, with regards to ensuring that those who most need this therapy will not be denied access due to official inefficiency in procurement and distribution processes.

Ongoing challenges in the management of malaria

BackgroundPlasmodium vivax accounts for about 40% of all malaria infection in Ethiopia. Chloroquine (CQ) is the first line treatment for confirmed P. vivax malaria in the country. The first report of CQ treatment failure in P. vivax was from Debre Zeit, which suggested the presence of chloroquine resistance.MethodsAn in vivo drug efficacy study was conducted in Debre Zeit from June to August 2006. Eighty-seven patients with microscopically confirmed P. vivax malaria, aged between 8 months and 52 years, were recruited and treated under supervision with CQ (25 mg/kg over three days). Clinical and parasitological parameters were assessed during the 28 day follow-up period. CQ and desethylchloroquine (DCQ) blood and serum concentrations were determined with high performance liquid chromatography (HPLC) in patients who showed recurrent parasitaemia.ResultsOf the 87 patients recruited in the study, one was lost to follow-up and three were excluded due to P. falciparum infection during follow-up. A total of 83 (95%) of the study participants completed the follow-up. On enrolment, 39.8% had documented fever and 60.2% had a history of fever. The geometric mean parasite density of the patients was 7045 parasites/μl. Among these, four patients had recurrent parasitaemia on Day 28. The blood CQ plus DCQ concentrations of these four patients were all above the minimal effective concentration (> 100 ng/ml).ConclusionChloroquine-resistant P. vivax parasites are emerging in Debre Zeit, Ethiopia. A multi-centre national survey is needed to better understand the extent of P. vivax resistance to CQ in Ethiopia.

Antimalarial drug quality in Africa

This article gives an overview of some of the ongoing challenges that are faced in the prevention, diagnosis and treatment of malaria.Malaria causes approximately 881,000 deaths every year, with nine out of ten deaths occurring in sub-Saharan Africa. In addition to the human burden of malaria, the economic burden is vast. It is thought to cost African countries more than US