The therapeutic efficacy and effects of artemether-lumefantrine (AL) and artesunate-amodiaquine co-formulated (AAcf) or co-packaged (AAcp) on malaria-associated anemia (MAA) were evaluated in 285 children < 12 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive one of the three drug combinations. Fever and parasite clearance times were similar in all treatment groups. Mean drug-attributable fall in hematocrit (DAFH), defined as difference between hematocrit values pre- and 3 d post- initiation of treatment, was low (< 4.5%) and rates of recovery from MAA were similar with all treatments. Mean areas under curve (AUCs) of the plot of deficit in hematocrit levels from 30% versus time in anemic children were similar in all groups. All regimens were well tolerated. AL, AAcf and AAcp cleared fever and parasitemia rapidly and had similar rates of resolution of MAA after treatment in malarious Nigerian children.

BackgroundDrug resistance in Plasmodium falciparum is common in many endemic and other settings but there is no clear recommendation on when to change therapy when there is delay in parasite clearance after initiation of therapy in African children.MethodsThe factors contributing to delay in parasite clearance, defined as a clearance time > 2 d, in falciparum malaria were characterized in 2,752 prospectively studied children treated with anti-malarial drugs between 1996 and 2008.Results1,237 of 2,752 children (45%) had delay in parasite clearance. Overall 211 children (17%) with delay in clearance subsequently failed therapy and they constituted 72% of those who had drug failure, i.e., 211 of 291 children. The following were independent risk factors for delay in parasite clearance at enrolment: age less than or equal to 2 years (Adjusted odds ratio [AOR] = 2.13, 95% confidence interval [CI]1.44-3.15, P < 0.0001), presence of fever (AOR = 1.33, 95% CI = 1.04-1.69, P = 0.019), parasitaemia >50,000/ul (AOR = 2.21, 95% CI = 1.77-2.75, P < 0.0001), and enrolment before year 2000 (AOR= 1.55, 95% CI = 1.22-1.96, P < 0.0001). Following treatment, a body temperature ≥ 38°C and parasitaemia > 20000/μl a day after treatment began, were independent risk factors for delay in clearance. Non-artemisinin monotherapies were associated with delay in clearance and treatment failures, and in those treated with chloroquine or amodiaquine, with pfmdr 1/pfcrt mutants. Delay in clearance significantly increased gametocyte carriage (P < 0.0001).ConclusionDelay in parasite clearance is multifactorial, is related to drug resistance and treatment failure in uncomplicated malaria and has implications for malaria control efforts in sub-Saharan Africa.

The emergence and wide dissemination of drug-resistant malarial parasites underscore the need to prevent post-transfusion malaria. In Nigeria, as in most of sub-Saharan Africa, however, blood donors are not routinely screened for malarial infection. Recently, 391 consecutive potential blood donors in a malaria-endemic area of south-western Nigeria were each checked for malarial parasitaemia using three methods: microscopy (all samples), OptiMAL (315 samples) and/or the Clinotech Malaria Cassette (142 samples). OptiMAL detects parasite-specific lactate dehydrogenase whereas the Clinotech test detects the surface proteins of merozoites and sporozoites. Microscopy revealed parasitaemias in 79 (20.2%) of the potential donors, the levels of parasitaemia varying from 34 to 6289 asexual parasites/microl (mean=445/microl). The prevalence of malarial parasitaemia, as detected by microscopy, was significantly higher during the rainy season than in the dry season (27.3% v. 5.5%; P<0.0001). There was no significant association between patent parasitaemia and fever (i.e. an axillary temperature > or =37.5 degrees C), blood group, gender or anaemia. The corresponding prevalences of malarial parasitaemia detected using the rapid diagnostic tests were 3.8% (12/315) for OptiMAL and 57.8% (82/142) for the Clinotech. With the results of the microscopy used as the 'gold standard', OptiMAL gave a sensitivity of only 16.0% but a specificity of 98.5%. The corresponding values for the Clinotech tests were 69.2% and 50.0%, respectively. It would clearly be beneficial to include screening for malaria parasitaemia in the routine investigation of potential blood donors in Nigeria, especially during the rainy season, when the risk of transfusion-transmitted malaria appears relatively high.

BackgroundCombination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Artemether-lumefantrine (AL) and artesunate-amodiaquine (AA) are efficacious regimens that have been widely adopted in sub-Saharan Africa. However, most study designs ignore the effects of these regimens on peripheral parasitaemia in the first 24 hours of therapy. The study protocol was designed to evaluate more closely the early effects and the standard measures of efficacies of these two regimens.MethodsIn an open label, randomized controlled clinical trial, children aged 12 months to 132 months were randomized to receive AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily) or artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) for three days. Peripheral blood smears were made hourly in the first 4 hours, 8 h, 16 h, 24 h, and daily on days 2-7, and on days 7, 14, 21, 28, 35, and 42 for microscopic identification and quantification of Plasmodium falciparum.ResultsA total of 193 children were randomized to receive either AL (97) or AA (96). In children that received both medications, early response of peripheral parasitaemia showed that 42% of children who received AL and 36.7% of those who received AA had an immediate rise in peripheral parasitaemia (0-4 h after treatment) followed by a rapid fall. The rise in parasitaemia was significant and seems to suggest a mobilization of asexual parasites from the deep tissues to the periphery. Days 3, 7, 14, 28, and 42 cure rates in the per protocol (PP) population were > 90% in both groups of children. Both drug combinations were well tolerated with minimal side effects.ConclusionThe study showed the high efficacy of AL and AA in Nigerian children. In addition the study demonstrated the mobilisation of asexual parasites from the deep to the periphery in the early hours of commencing ACT treatment in a subset of patients in both study groups. It is unclear whether the early parasite dynamics discovered in this study play any role in the development of drug resistance and thus it is important to further evaluate this discovery. It may be useful for studies investigating delay in parasite clearance of artemisinin derivatives as a way of monitoring the development of resistance to artemisinin to assess the early effects of the drugs on the parasites.

Abstract. The treatment efficacy and effects of artesunate-mefloquine (AMQ) and mefloquine (MQ) on malariaassociated anemia (MAA) were evaluated in 342 children ≤ 10 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive either drug/drug combination. All children recovered clinically. Fever clearance times were similar. Parasite clearance was significantly faster with AMQ (mean ± SD = 1.4 ± 0.6 days, 95% confidence interval [CI] = 1.3-1.5, P < 0.0001), but polymerase chain reaction-corrected cure rates were similar (97% versus 94%). Gametocyte carriage rates and the drug-attributable fall in hematocrit were significantly lower with AMQ (mean ± SD = 4.8 ± 3.8%, 95% CI = 3.6-6.0, P = 0.03), but the rates of resolution of MAA were similar. Both regimens were well tolerated. AMQ clears parasitemia and reduces gametocyte carriage more rapidly and causes lesser fall in hematocrit than MQ, but both regimens are effective treatment of uncomplicated P. falciparum malaria in Nigerian children.