Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa.

BACKGROUND: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. METHODS: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. RESULTS: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. CONCLUSIONS: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis.

BACKGROUND: Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. METHODS: An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. RESULTS: A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. CONCLUSION: AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

In-vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, dihydroartemisinin and quinine in an area of high chloroquine resistance in Rwanda.

Plasmodium falciparum in-vitro susceptibility to chloroquine (CQ), monodesethylamodiaquine, quinine and dihydroartemisinin was investigated in Rwandan patients with a parasitaemia of at least >or=4000/microl. The study was carried out in November-December 2003. Dihydroartemisinin was the most potent (GM IC(50)=2.6nmol/l, 95% CI 2.2-3.2) among the drugs tested. Resistance to chloroquine was 45% (33/74) and that to monodesethylamodiaquine 7% (5/74). All the tested isolates were susceptible to quinine. The mean IC(50) of monodesethylamodiaquine, quinine and dihydroartemisinin was significantly higher for chloroquine-resistant than for chloroquine-sensitive strains (P<0.05). The IC(50) of each drug was significantly and positively correlated to that of the other three drugs (P<0.005), and this correlation was higher between CQ and monodesethylamodiaquine (r=0.8). In-vitro CQ resistance is linked to that of the other drugs tested. Most worrying is the positive correlation between the IC(50) of dihydroartemisinin and the other drugs, more particularly with CQ, suggesting an increased tolerance of the parasites to all drugs.

Efficacy of amodiaquine alone and combined with sulfadoxine-pyrimethamine and of sulfadoxine pyrimethamine combined with artesunate.

The safety and the efficacy of amodiaquine (AQ) alone, AQ plus sulfadoxine-pyrimethamine (SP) (AQ plus SP), and artesunate (ART) plus SP (ART plus SP), three possible alternatives to chloroquine (CQ), were investigated in 379 Rwandan children 6-59 months old with uncomplicated Plasmodium falciparum malaria who visited one urban/peri-urban health center and two rural health centers. The three treatment regimens were well tolerated and no serious adverse effects were observed. Children treated with AQ plus SP had less clinical failures than those treated with ART plus SP (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.06-0.81, P = 0.01) or AQ alone (OR = 0.33, 95% CI = 0.07-1.10, P = 0.08). Even after new infections were excluded, AQ plus SP was still significantly more efficacious than ART plus SP (P = 0.05). At day 14, the mean packed cell volume was significantly higher in the AQ plus SP group compared with the ART plus SP group (P = 0.02) and with the AQ alone group (P = 0.01). In Rwanda, AQ plus SP has been chosen to replace CQ as a first-line treatment. However, this is considered an interim measure and new combinations, possibly co-formulated, should be identified and tested.

Tolerability of amodiaquine and sulphadoxine-pyrimethamine, alone or in combination for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan adults.

OBJECTIVE: To assess the tolerability and efficacy of amodiaquine (AQ)+sulphadoxine-pyrimethamine (SP), the first-line malaria treatment in Rwanda. METHOD: Randomized, double-blind trial in 2003 in Kigali town. A total of 351 adult patients with uncomplicated Plasmodium falciparum malaria were randomly allocated to one of the following treatments: AQ+SP, AQ or SP. We followed patients until day 14 after treatment and recorded adverse events (AEs) and clinical and parasitological outcomes. RESULTS: One hundred and eighteen patients reported at least one AE: 40% in the AQ, 39% in the AQ+SP and 21% in the SP groups. The AE was classified as possibly related to the antimalarial treatment for 86 patients. The Risk Ratio for at least one AE after treatment was significantly and about fourfold higher in patients receiving AQ or AQ+SP than in patients receiving SP. Pruritus and fatigue were significantly more frequent in patients treated with AQ or AQ+SP than in those receiving SP. Severe AEs, such as fatigue, nausea, dizziness and vomiting, were observed in four patients treated with AQ, in 10 treated with AQ+SP and in one patient treated with SP. CONCLUSION: Amodiaquine+SP is not well tolerated and a substantial proportion of patients experienced pruritus and fatigue, thus decreasing their compliance and compromising the first line treatment implementation at national level. This renders AQ-containing regimens sub-optimal; better-tolerated treatments should be identified.

Malaria infection among pregnant women attending antenatal clinics in six Rwandan districts.

OBJECTIVES: The aim of the study was to assess the knowledge, attitude and practices of pregnant women towards malaria and their association with malaria morbidity. METHODS: Cross-sectional malaria survey of 1432 pregnant women attending six health centres, each of them situated in a specific health district in Rwanda from September to October 2002. RESULTS: The overall prevalence of malaria infection was 13.6% and all infections but two were caused by Plasmodium falciparum. The six health districts were significantly different in terms of malaria prevalence, which varied between 11.5% and 15.4% in four and was <5% in the other two districts. The prevalence of anaemia and splenomegaly mirrored that of malaria infection. In three districts, the prevalence of infection was significantly higher in primigravidae than in secundigravidae and multigravidae (P = 0.01), while in two others it did not vary with parity. Bed net use was low - only 13.1% of the women had at least one bed net at home and 8.3% of them slept under it - and significantly different between districts. Most women knew that malaria might have serious consequences for their pregnancy and that insecticide-treated bed nets are useful for malaria prevention. However, the bed net market price [1525 Rwandan Francs (RFr), approximately 1.6] was much higher than that considered as affordable and acceptable (389 RFr, approximately 0.3). CONCLUSION: Malaria in pregnancy is a major problem in Rwanda, even in the districts of low transmission. Bed net use among pregnant women is low. The option of providing free insecticide-treated bed nets to pregnant women should be explored and possibly implemented; it could rapidly increase bed net use and earlier attendance to antenatal clinics with clear benefits for the women's health.

Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria.

We investigated the safety and efficacy of amodiaquine alone (AQ) and combined with artesunate (AQ + AS) in 308 Rwandan children 6-59 months old with uncomplicated Plasmodium falciparum malaria attending three sentinel sites. The two treatment regimes were well tolerated and no serious adverse events were recorded. After excluding new infections, children treated with AQ + AS had fewer clinical failures at day 28 after treatment than those treated with AQ alone: OR = 0.20 [95% CI: 0.06-0.57 (P = 0.001)]. Total (parasitological and clinical) failure was also significantly less frequent in the AQ + AS group: OR = 0.34 [95% CI: 0.17-0.67 (P = 0.001)]. When adjusting for study site, the hazard ratio for treatment failure was 0.37 [95% CI: 0.20-0.68 (P = 0.001)]. Combining AQ with AS increases the efficacy of the treatment but the apparent increase of AQ resistance observed in just a 1-year period is worrying and casts doubts on the suitability of implementing AQ + AS as first-line treatment in Rwanda. Alternative treatments should be identified and tested.