Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial

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Abstract

Many countries in Africa are considering a change to combination treatment for falciparum malaria because of the increase in drug resistance. However, there are few effectiveness data for these combinations. Our aim was to study the effectiveness of three drug combinations that have proven efficacious in east Africa compared with amodiaquine monotherapy. We undertook a randomised trial of antimalarial drug combinations for children (aged 4-59 months) with uncomplicated malaria in Muheza, Tanzania, an area with a high prevalence of resistance to sulfadoxine-pyrimethamine and chloroquine. Children were randomly allocated 3 days of amodiaquine (n=270), amodiaquine +sulfadoxine-pyrimethamine (n=507), or amodiaquine+artesunate (n=515), or a 3-day six-dose regimen of artemether-lumefantrine (n=519). Drugs were taken orally, at home, unobserved by medical staff. The primary endpoint was parasitological failure by day 14 assessed blind to treatment allocation. Secondary endpoints included day 28 follow-up and gametocyte carriage. Analysis was by intention to treat. Of 3158 children screened, 1811 were randomly assigned treatment and 1717 (95%) reached the 14-day follow-up. The amodiaquine group was stopped early by the data and safety monitoring board. By day 14, the parasitological failure rates were 103 of 248 (42%) for amodiaquine, 97 of 476 (20%) for amodiaquine+sulfadoxine-pyrimethamine, 54 of 491 (11%) for amodiaquine+artesunate, and seven of 502 (1%) for artemether-lumefantrine. By day 28, the parasitological failure rates were 182 of 239 (76%), 282 of 476 (61%), 193 of 472 (40%), and 103 of 485 (21%), respectively. The difference between individual treatment groups and the next best treatment combination was significant (p<0.001) in every case. Recrudescence rates by day 28, after correction by genotyping, were 48.4%, 34.5%, 11.2%, and 2.8%, respectively. The study shows how few the options are for treating malaria where there is already a high level of resistance to sulfadoxine-pyrimethamine and amodiaquine. The WHO-packaged six-dose regimen of artemether-lumefantrine is effective taken unsupervised, although cost is a major limitation.

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Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study.

Hugh Reyburn, Redepmta Mbatia, Chris Drakeley … (2004)

To study the diagnosis and outcomes in people admitted to hospital with a diagnosis of severe malaria in areas with differing intensities of malaria transmission. Prospective observational study of children and adults over the course a year. 10 hospitals in north east Tanzania. 17,313 patients were admitted to hospital; of these 4474 (2851 children aged under 5 years) fulfilled criteria for severe disease. Details of the treatment given and outcome. Altitudes of residence (a proxy for transmission intensity) measured with a global positioning system. Blood film microscopy showed that 2062 (46.1%) of people treated for malaria had Plasmodium falciparum (slide positive). The proportion of slide positive cases fell with increasing age and increasing altitude of residence. Among 1086 patients aged > or = 5 years who lived above 600 metres, only 338 (31.1%) were slide positive, while in children < 5 years living in areas of intense transmission (< 600 metres) most (958/1392, 68.8%) were slide positive. Among 2375 people who were slide negative, 1571 (66.1%) were not treated with antibiotics and of those, 120 (7.6%) died. The case fatality in slide negative patients was higher (292/2412, 12.1%) than for slide positive patients (142/2062, 6.9%) (P < 0.001). Respiratory distress and altered consciousness were the strongest predictors of mortality in slide positive and slide negative patients and in adults as well as children. In Tanzania, malaria is commonly overdiagnosed in people presenting with severe febrile illness, especially in those living in areas with low to moderate transmission and in adults. This is associated with a failure to treat alternative causes of severe infection. Diagnosis needs to be improved and syndromic treatment considered. Routine hospital data may overestimate mortality from malaria by over twofold.

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Malaria misdiagnosis: effects on the poor and vulnerable.

Mark Amexo, Rachel Tolhurst, Guy Barnish … (2004)

Effective and affordable treatment is recommended for all cases of malaria within 24 h of the onset of illness. Most cases of "malaria" (ie, fever) are self-diagnosed and most treatments, and deaths, occur at home. The most ethical and cost-effective policy is to ensure that newer drug combinations are only used for true cases of malaria. Although it is cost effective to improve the accuracy of malaria diagnosis, simple, accurate, and inexpensive methods are not widely available, particularly in poor communities where they are most needed. In a recent study in Uganda, Karin Kallander and colleagues emphasise the difficulty in making a presumptive diagnosis of malaria, and highlight the urgent need for improved diagnostic tools that can be used at community and primary-care level, especially in poorer populations (Acta Trop 2004; 90: 211-14). WHERE NEXT? Health systems need strengthening at referral and community level, so that rapid accurate diagnosis and effective treatment is available for those who are least able to withstand the consequences of illness. Indirect evidence strongly suggests that misdiagnosis of malaria contributes to a vicious cycle of increasing ill-health and deepening poverty. Much better direct evidence is needed about why and how misdiagnosis affects the poor and vulnerable.