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SummarySenegal is changing policy for case management of uncomplicated falciparum malaria, which hitherto is diagnosed clinically and treated with chloroquine or intramuscular quinine. The WHO recommends artemisinin-based combinations for treating falciparum malaria, preferably based on a parasitological diagnosis. There are no economic projections if such a policy were introduced in Senegal. We have conducted a preliminary economic assessment of such a policy change. The study took place in the chloroquine-resistant district of Oussouye in south-western Senegal. We reviewed clinic registers of the district health posts (n ¼ 5) from 1996 to 2001, and piloted artesunate combined with amodiaquine (at 4 and 10 mg/kg/day · 3 days respectively) (AS-AQ) for treating slide-proven falciparum malaria during two rainy seasons (2000 and 2001) at one health centre. These data were used to calculate current direct patient costs (clinic visit, diagnosis, drugs) of malaria treatment and project future costs for the district. The robustness of the model was tested by allowing for different drug failure rates and costs of diagnosis. During 1996-2001, the mean number of primary treatments per year was 7654 for a mean, direct cost of US$17 452 to the community. Clinical diagnosis resulted in overtreatment: 56% and 66% in the wet and dry seasons respectively. Current policy leads to substantial drug wastage and excess direct costs for the community. The direct costs of implementing AS-AQ for slide-proven malaria would be US$8150 (53% less expensive). Studies examining the public health effect and economics of deploying AS-AQ on a wider scale are underway in Senegal.

Abstract

Background

Artesunate plus amodiaquine is a coblistered ACT, given as a single daily intake. It has been suggested that, in view of the number of tablets to be taken (particularly in adults), it may be possible to improve compliance by allowing patients to divide the daily dose. The objectives of this randomized, comparative, open-label, multicentre study, conducted in Senegal and in Cameroon in 2005, was to demonstrate the non-inferiority and to compare the safety of artesunate plus amodiaquine, as a single daily intake versus two daily intakes.

Methods

A three-day treatment period and 14-day follow-up period was performed in any subject weighting more than 10 kg, presenting with a malaria paroxysm confirmed by parasitaemia ≥ 1,000/μl, after informed consent. Patients were randomly allocated into one of the two regimens, with dosage according to bodyweight range. All products were administered by an authorized person, blinded to both the investigating physician and the biologist. The primary endpoint was an adequate response to treatment on D14 (WHO definition). The two-sided 90% confidence interval of the difference was calculated on intent to treat (ITT) population; the acceptance limit for non-inferiority was 3%. The safety was evaluated by incidence of adverse events.

Results

Three-hundred and sixteen patients were included in the study. The two patient groups were strictly comparable on D0. The adequate responses to treatment were similar for the two treatment regimens on D14, PCR-corrected (99,4% in the one-daily intake group versus 99,3% in the comparative group). The statistical analyses demonstrated the non-inferiority of administering artesunate/amodiaquine as two intakes. The drug was well tolerated. The main adverse events were gastrointestinal disorders (2.5%) and pruritus (2.5%); safety profiles were similar in the two groups.

Conclusion

This pilot study confirms the efficacy and good tolerability of artesunate plus amodiaquine, administrated either in one or in two daily intakes.

Summaryobjectives Several products of artesunate plus amodiaquine (AS + AQ) are being deployed in malariaendemic countries for treating uncomplicated falciparum malaria but dosing accuracy and consequential effects on efficacy and tolerability have not been examined.methods Patients with parasitologically confirmed, uncomplicated falciparum malaria were treated and followed by research teams or local health centre staff in Casamance, Senegal. AS + AQ was given as: (i) loose combination (AS 50 mg, AQ 200 mg), dosed on body weight, or (ii) co-blistered product (AS 50 mg, AQ 153 mg) dosed by weight or age. Target doses were: (i) AS 4 (2-10) mg ⁄ kg ⁄ day and (ii) AQ 10 (7.5-15) mg ⁄ kg ⁄ day. Patients receiving therapeutic doses defined dosing accuracy. Treatmentemergent signs and symptoms (TESS) were recorded.results A total of 3277 patients were treated with loose (n = 1972, weight-dosed) or co-blistered (n = 1305, 962 age-dosed, 343 weight-dosed) AS + AQ by the research team (n = 966) or clinic staff (n = 2311). AS was dosed correctly in >99% with all regimens. Loose AQ by weight was 98% correct. The co-blister AQ overdosed 18% of patients when dosed by age and underdosed 13% by weight. Low weight was an independent risk factor for overdosing. The co-blister had significantly more TESS than the loose product [117 ⁄ 1305 (9%) vs. 41 ⁄ 1972 (2%), relative risk = 4.3 (95% CI: 3.0-6.1, P < 0.0001)]. Age-based dosing accounted for the difference. TESS occurred mostly within one day (72%) and were mild or moderate (75%).conclusion Artesunate is easier to dose than AQ. Currently available age-dosed, co-blistered AS + AQ tends to overdose AQ and is less well tolerated than loose tablets. It is not the optimal presentation of AS + AQ.

Before 2006 in Senegal, in the absence of clinical diagnosis, all fever cases were considered as malaria and treated with chloroquine. Between 2004-2006, to face the dramatic increase of Plasmodium falciparum resistance to chloroquine, the combination of amodiaquine plus sulfadoxine-pyriméthamine was recommended for treatment. In 2006, rapid diagnostic tests were introduced and the treatment with a combination of artesunate plus amodiaquine (ASAQ) became the national recommendation for malaria treatment in 2007. This coincided with a decrease of the prevalence of malaria cases and change in fever management. Since 1995 in Mlomp in Casamance, thin and thick blood smear examination has systematically been done in patients with fever and clinical signs of malaria, and treatment with ASAQ given as experimental procedure. Between 2000 and 2012, 70,892 outpatients were attending the health center, and 51.2% of them for fever. Among these fever cases, 72.4% were suspected of malaria and 27.6% were identified as bacterial and viral infections. Confirmed malaria cases decreased dramatically from 1365 in 2000 to 53 in 2012. While comparing the 2 periods 2000-2006 and 2007-2012, the number of fever cases decreased by half, the number of fever identified as non malaria doubled and malaria treatment given decreased by 86%. Improvement of fever management in Mlomp has contributed to a better identification of their cause and to a decrease of inappropriate malaria treatments.