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A simple method to estimate antimalarial drug-related fall in hematocrit (FIH) after treatment of Plasmodium falciparum infections in the field is described. The method involves numeric estimation of the relative difference in hematocrit at baseline (pretreatment) and the first 1 or 2 days after treatment begun as numerator and the corresponding relative difference in parasitemia as the denominator, and expressing it per 1000 parasites cleared from peripheral blood. Using the method showed that FIH/1000 parasites cleared from peripheral blood (cpb) at 24 or 48 hours were similar in artemether-lumefantrine and artesunate-amodiaquine-treated children (0.09; 95% confidence interval, 0.052-0.138 vs 0.10; 95% confidence interval, 0.069-0.139%; P = 0.75) FIH/1000 parasites cpb in patients with higher parasitemias were significantly (P < 0.0001) and five- to 10-fold lower than in patients with lower parasitemias suggesting conservation of hematocrit or red cells in patients with higher parasitemias treated with artesunate-amodiaquine or artemether-lumefantrine. FIH/1000 parasites cpb were similar in anemic and nonanemic children. Estimation of FIH/1000 parasites cpb is simple, allows estimation of relatively conserved hematocrit during treatment, and can be used in both observational studies and clinical trials involving antimalarial drugs.

Artesunate-amodiaquine is among the most widely available artemisinin combination therapy used as treatment regimen for uncomplicated Plasmodium falciparum malaria. Our aim was to evaluate clinical routine markers of liver and renal functions, lipid profile levels and lipid peroxidation status in a female mammalian rat model. This was an attempt to simulate a scenario where the drugs are taken without malarial parasite infection, which is a common practice in settings where drug misuse is a common practice. Twenty female Wistar rats were randomly divided into four study groups of five animals each. Group 1 (control) received distilled water, group 2 was exposed to artesunate [2 mg/kg body weight (b.w.)], group 3 was administered with amodiaquine (6.12 mg/kg b.w.) and group 4 was co-administered with artesunate (2 mg/kg b.w.) and amodiaquine (6.12 mg/kg b.w.) for 3 days. At the end of the treatment period, animals were fasted overnight and sacrificed. Markers of liver and renal functions and lipid profile indices were evaluated in the plasma, whereas lipid peroxidation status, GSH concentration and G6PD activity were assessed in the erythrocytes. The results showed that the co-administration of artesunate and amodiaquine altered liver function markers and lipid profile indices. The drugs also induced lipid peroxidation as evidenced by the elevated level of oxidative stress marker malondialdehyde (p < 0.05). We recommend therefore that the drugs should be taken with prescription only with clinical evidence of malarial parasite infection., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objectives: Artemisinin-based combination therapies (ACTs) are essential for the effective control of falciparum malaria in endemic countries. However, in most countries, such choice has been carried out without knowing their effectiveness when deployed in real-life conditions, that is, when treatment is not directly observed. We report here the results of a study assessing the effectiveness of the two ACTs currently recommended in Burkina Faso for the treatment of uncomplicated malaria, that is, artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ)., Methods: Between September 2008 and January 2010, 340 children were randomised to one of the two study arms and followed up for 42 days. Treatment was administered according to routine practices, that is, the first dose was given by study nurses who explained to the parent/guardian how to administer the other doses at home during the following 2 days., Results: The results showed a significantly higher unadjusted adequate clinical and parasitological response in the ASAQ (58.4%) than in the AL arm (46.1%) at day 28 but these trends were similar after correction with PCR data (ASAQ (89.7%) and AL (89.8%)). New infections started to appear after day 14, first in the AL and then in the ASAQ arm but at day 42 day of follow-up we observed no difference in the occurrence of recrudescent infection., Conclusion: Despite a lower cure rate than those reported in efficacy studies in which the treatment administration was directly observed, both AL and ASAQ can still be used for the treatment of uncomplicated malaria in Burkina Faso., (© 2014 John Wiley & Sons Ltd.)

Background: Artemisinin-based combination therapy (ACT) is the recommended first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide but decreased artemisinin susceptibility, phenotypically characterized as slow parasite clearance time (PCT), has now been reported in Southeast Asia. This makes it all too important to measure the dynamics of parasite clearance in African patients treated with ACT over time, to understand trends and detect changes early enough to intervene, Methods: Individual patient data from 27 clinical trials of artesunate-amodiaquine (ASAQ) vs comparators conducted between 1999 and 2009 were analysed for parasite clearance on modified intent-to-treat (ITT) basis., Results: Overall 15,017 patients treated for uncomplicated P. falciparum malaria at 44 sites in 20 sub-Saharan African countries were included in the analysis; 51% (n=7,660) vs 49% (n=7,357) were treated with ASAQ and comparator treatments, respectively. Seventy-seven per cent (77%) were children under six years of age. The proportion of the patients treated with ASAQ with persistent parasitaemia on Day 2 was 8.6%, and 1.5% on Day 3. Risk factor for not clearing parasites on Day 2 and Day 3 calculated by multivariate logistic regression with random effect on site and controlling for treatment were: high parasitaemia before treatment was (adjusted risk ratios (AOR) 2.12, 95% CI 1.91-2.35, AOR 2.43, 95% CI 1.98-3.00, respectively); non-ACT treatment (p=0.001, for all comparisons). Anaemia (p=0.001) was an additional factor for Day 2 and young age (p=0.005) for Day 3.In patients treated with ASAQ in studies who had complete parasitaemia data every 24 hours up to Day 3 and additionally Day 7, the parasite reduction ratio was 93.9% by Day 1 and 99.9% by Day 2. Using the median parasitaemia before treatment (p0=27,125 μL) and a fitted model, the predicted PCT (pPCT = 3.614*ln (p0) - 6.135, r(2) = 0.94) in ASAQ recipients was 31 hours., Conclusion: Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ. The prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling, both for research and monitoring purposes.

Although global morbidity and mortality have decreased substantially, malaria, a parasite infection of red blood cells, still kills roughly 2000 people per day, most of whom are children in Africa. Two factors largely account for these decreases; increased deployment of insecticide-treated bednets and increased availability of highly effective artemisinin combination treatments. In large trials, parenteral artesunate (an artemisinin derivative) reduced severe malaria mortality by 22·5% in Africa and 34·7% in Asia compared with quinine, whereas adjunctive interventions have been uniformly unsuccessful. Rapid tests have been an important addition to microscopy for malaria diagnosis. Chemopreventive strategies have been increasingly deployed in Africa, notably intermittent sulfadoxine-pyrimethamine treatment in pregnancy, and monthly amodiaquine-sulfadoxine-pyrimethamine during the rainy season months in children aged between 3 months and 5 years across the sub-Sahel. Enthusiasm for malaria elimination has resurfaced. This ambitious but laudable goal faces many challenges, including the worldwide economic downturn, difficulties in elimination of vivax malaria, development of pyrethroid resistance in some anopheline mosquitoes, and the emergence of artemisinin resistance in Plasmodium falciparum in southeast Asia. We review the epidemiology, clinical features, pathology, prevention, and treatment of malaria., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The efficacy of artemisinin-based combination therapy (ACT) has been established. The objective of the present study was to compare the efficacy and safety in the Central African Republic (CAR) of three commercially available artemisinin-based combinations, artemether + lumefantrine (AL), artesunate + sulphamethoxypyrazine-pyrimethamine (AS-SMP) and artesunate + amodiaquine (AS-AQ), with those of sulphadoxine-pyrimethamine + amodiaquine (SP-AQ), which was the first-line reference treatment in the country from 2004, until it was replaced by ACT in 2006 in accordance with changes in international recommendations based on resistance identified in other regions., Methods: Children aged six to 59 months with uncomplicated Plasmodium falciparum malaria were recruited in Bangui, the capital of the CAR. The 251 patients selected were randomly assigned to receive AL (n = 60), AS-SMP (n = 58), AS-AQ (n = 68) or SP-AQ (n = 65) and were followed up for 28 days. Clinical outcome was classified according to the standard 2003 World Health Organization protocol., Results: At day 28, the cure rates in a per-protocol analysis were 92% (48/52) with AL, 93% (50/54) with AS-SMP, 93% (55/59) with AS-AQ and 100% (57/57) with SP-AQ, with no statistically significant difference between the four treatments. Defervescence was significantly faster with AS-AQ than with AL (p <0.035). Fatigue was reported significantly more frequently by patients receiving AQ than by those treated with AS-SMP or AL (p = 0.006). All the other adverse events reported were mild, and no significant difference was noted by treatment., Conclusion: The three artemisinin-bsed combinations show similar, satisfactory results, comparable to that with SP-AQ. This evaluation is the first conducted in CAR since the official introduction of ACT. It should guide the National Malaria Control Programme in choosing the appropriate ACT for treatment of uncomplicated P. falciparum malaria in the future.

Objective: To evaluate the comparative efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and artesunate-amodiaquine-chlorpheniramine (AQC) for the treatment of acute uncomplicated malaria among Southwest Nigerian children., Subjects and Methods: One hundred and sixty children aged 6 months to 14 years with acute uncomplicated malaria were randomized to AL (n = 53), ASAQ (n = 53), or AQC (n = 54). Enrollees were seen daily on days 0-3 and then on days 7, 14, 21, 28 and 42 for clinical and parasitological evaluations. Paired samples of genomic DNA at enrolment and at the time of recurrent parasitaemia were genotyped using nested PCR to distinguish between reinfection and recrudescence. Detailed haematological and biochemical evaluations were carried out in a subset of enrollees on days 0, 7 and 28 as part of a safety evaluation., Results: Of the 160 children, 144 (90%) completed the study. The mean fever clearance times and parasite clearance times for AL, ASAQ and AQC were comparable (p = 0.94 and p = 0.122, respectively). On day 14, the adequate clinical and parasitological response (ACPR) for AL and AQC was 100% and for ASAQ it was 90% (p = 0.39). The PCR-uncorrected results on days 28 and 42 and the ACPR-corrected results on day 42 were similar for all drugs (p = 0.62 and p = 0.56, respectively). AQC resulted in the best parasite clearance and haematological recovery on day 2 (p = 0.022 and p = 0.018, respectively). Biochemical parameters were not adversely affected by the three artemisinin-based combination therapies (ACTs) and these were well tolerated., Conclusion: The three ACTs were efficacious and safe, but AQC resulted in a better haematological recovery on day 2 and higher cure rates throughout the study period., (© 2014 S. Karger AG, Basel.)

The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant P. berghei SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria.

Introduction: The development and spread of Plasmodium falciparum resistance to most commonly used antimalarials remain a major challenge in the control of malaria. Constant monitoring of drug efficacy is an important tool in establishing rational antimalarial drug policies., Methodology: A randomized comparative study was conducted at the Wesley Guild Hospital, Ilesa, Nigeria between February 2010 and September 2011 comparing the efficacy and safety of artemether-lumefantrine (Coartem) and fixed dose of artesunate plus amodiaquine (Larimal) in the treatment of uncomplicated P. falciparum malaria in children betweem 6 and 144 months of age. P. falciparum malaria parasitemia was assessed by microscopy and rapid diagnostic test. Drugs were administered according to age for three days under supervision. The primary efficacy endpoint was a day 28 PCR-corrected parasitological cure., Results: A total of 182 patients were enrolled in the two treatment groups, Coartem (n = 101) and Larimal (n = 81), and tested after 28 days. In the intention-to-treat population, Coartem (n = 101) and Larimal (n = 81) had a PCR-corrected cure rate of 98% and 100% respectively, while in the per-protocol population, Coartem (n = 89) and Larimal (n = 71) both had a PCR-corrected cure rate of 100% at day 28. Although parasite and fever clearance time was faster in the Larimal group, no significant difference was observed between the two drugs. No serious adverse effects  were reported., Conclusion: Five years after being introduced in Nigeria, both Coartem and Larimal have been shown to be safe and highly effective in the treatment of uncomplicated P. falciparum malaria in children.

Background: A high prevalence of chloroquine-resistant Plasmodium vivax in Indonesia has shifted first-line treatment to artemisinin-based combination therapies, combined with primaquine (PQ) for radical cure. Which combination is most effective and safe remains to be established., Methods: We conducted a prospective open-label randomized comparison of 14 days of PQ (0.25 mg base/kg) plus either artesunate-amodiaquine (AAQ + PQ) or dihydroartemisinin-piperaquine (DHP + PQ) for the treatment of uncomplicated monoinfection P. vivax malaria in North Sumatera, Indonesia. Patients were randomized and treatments were given without prior testing for G6PD status. The primary outcome was parasitological failure at day 42. Patients were followed up to 1 year., Results: Between December 2010 and April 2012, 331 patients were included. After treatment with AAQ + PQ, recurrent infection occurred in 0 of 167 patients within 42 days and in 15 of 130 (11.5%; 95% confidence interval [CI], 6.6%-18.3%) within a year. With DHP + PQ, this was 1 of 164 (0.6%; 95% CI, 0.01%-3.4%) and 13 of 143 (9.1%; 95% CI, 4.9%-15.0%), respectively (P > .2). Intravascular hemolysis occurred in 5 patients, of which 3 males were hemizygous for the G6PD-Mahidol mutation. Minor adverse events were more frequent with AAQ + PQ., Conclusions: In North Sumatera, Indonesia, AAQ and DHP, both combined with PQ, were effective for blood-stage parasite clearance of uncomplicated P. vivax malaria. Both treatments were safe, but DHP + PQ was better tolerated., Clinical Trials Registration: NCT01288820.

National Malaria Control Program (NMCP) of Bangladesh has introduced Artemisinin Based Combination (ACT), Coartem(R) (Artemether-Lumefantrine (AL), fixed dose combination, in the confirmed cases of uncomplicated P. falciparum malaria since 2004. Despite the reduction of mortality due to malaria, the development and spread of anti-malarial drug resistance wordwide posing a threat to the health services and will make it difficult to control malaria in Bangladesh in future. We need to have an alternative to Coartem which could be Artesunate-amodiaquine (AA) in a fixed dose combination (FDC), a cheaper altenative not yet evidenced to be effective and safe to our population. In this study we compared the efficacy and safety of Artemether + Lumefantrene (FDC, Coartem) with Artesunate +Amodiaquine tablets (100/270 mg FDC) for the treatment of uncomplicated P. falciparum malaria in three high risk multi-drug resistant malaria prevalent areas of Bangladesh. It was an open label randomized controlled trial conducted between December 2008 and November 2009 in 4 upazillas in patients over the age 12 to 60 years diagnosed as a case of uncomplicated P. falciparum malaria. The outcome of the cases were measured as clinical response, parasitological response, defervescence time and parasite clearance time. Drug safety was assessed by comparing the adverse events. A total of 252 cases were randomized to receive Artesunate + Amodiaquine (AA group, 147 cases) and Artemether + Lumefantrene (AL group, 106 cases), one lost to follow up at day 28 in AA group. The distribution of the cases was comparable by age, sex and study sites. Treatment success' response was observed 100% in the AL group and AA group had 99%, two failures with AA were late treatment failures and the difference was not statistically significant (p > .1). The parasitological sensitive (S) response was observed in 97% of cases in AL group and 95% in the AA group, and was not a statistically significant difference. There was no significant difference in deffervescence time and parasite clearance time between two groups of cases. No serious adverse events were observed. The frequencies of minor adverse events were insignificantly different between the two treatment groups. The two ACT regimen, AA and AL had no significant difference in efficacy and safety for treatment of Uncomplicated Malaria in Bangladesh. However, there were few more failures with AA regimen compared to AL regimen, which was not statistically significant. Both these regimens can be used alternatively by the NMCP of Bangladesh as first-line treatment option.

Background: Artemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria. Recommendations were adapted in 2010 regarding rescue treatment in case of treatment failure. Instead of quinine monotherapy, it should be combined with an antibiotic with antimalarial properties; alternatively, another artemisinin-based combination therapy may be used. However, for informing these policy changes, no clear evidence is yet available. The need to provide the policy makers with hard data on the appropriate rescue therapy is obvious. We hypothesize that the efficacy of the same artemisinin-based combination therapy used as rescue treatment is as efficacious as quinine + clindamycin or an alternative artemisinin-based combination therapy, without the risk of selecting drug resistant strains., Design: We embed a randomized, open label, three-arm clinical trial in a longitudinal cohort design following up children with uncomplicated malaria until they are malaria parasite free for 4 weeks. The study is conducted in both the Democratic Republic of Congo and Uganda and performed in three steps. In the first step, the pre-randomized controlled trial (RCT) phase, children aged 12 to 59 months with uncomplicated malaria are treated with the recommended first-line drug and constitute a cohort that is passively followed up for 42 days. If the patients experience an uncomplicated malaria episode between days 14 and 42 of follow-up, they are randomized either to quinine + clindamycin, or an alternative artemisinin-based combination therapy, or the same first-line artemisinin-based combination therapy to be followed up for 28 additional days. If between days 14 and 28 the patients experience a recurrent parasitemia, they are retreated with the recommended first-line regimen and actively followed up for another 28 additional days (step three; post-RCT phase). The same methodology is followed for each subsequent failure. In any case, all patients without an infection at day 28 are classified as treatment successes and reach a study endpoint. The RCT phase allows the comparison of the safety and efficacy of three rescue treatments. The prolonged follow-up of all children until they are 28 days parasite-free allows us to assess epidemiological-, host- and parasite-related predictors for repeated malaria infection., Trial Registration: NCT01374581 and PACTR201203000351114.

Background: Community health workers in Dangme-West district, Ghana, treated children aged 2-59 months with fever with either artesunate-amodiaquine (AAQ) or AAQ plus amoxicillin (AAQ + AMX) within a cluster-randomized controlled trial (registration no. TDR/UNDP Trial registration A: 20189). The intervention was introduced in a stepped-wedge manner. The aim of the study was reduction of mortality. This paper reports on the reduction of morbidity, notably anaemia, severe anaemia and severe illness. Clusters of 100 children were randomized in to AAQ, AAQ + AMX and pre-intervention arms. Six months later the pre-intervention clusters were randomized in to the AAQ and AAQ + AMX arms., Methods: Data were collected in eight cross-sectional surveys. Using stratified sampling, 10 clusters were randomly selected per survey. Blood samples were taken to assess haemoglobin. Caregivers were interviewed about diseases (signs and symptoms) among their children in the preceding 14 days. Multivariate logistic regression analysis was used to determine the impact on anaemia, severe anaemia and severe illness., Results: Compared with the pre-intervention clusters, anaemia was reduced in the AAQ (OR = 0.20, 95% CI 0.12-0.33) and AAQ + AMX (OR = 0.23, 95% CI 0.15-0.36) clusters, severe anaemia was reduced in the AAQ (OR = 0.20, 95% CI 0.09-0.45) and AAQ + AMX (OR = 0.12, 95% CI 0.04-0.31) clusters and severe illness was reduced in the AAQ (OR = 0.46, 95% CI 0.26-0.80) and AAQ + AMX (OR = 0.38, 95% CI 0.22-0.63) clusters. No significant differences were found in outcome variables between the AAQ and AAQ + AMX clusters., Conclusions: Treating fever with antimalarials significantly reduced the prevalence of anaemia, severe anaemia and severe illness. We found no significant reduction in outcomes when the AAQ and AAQ+AMX clusters were compared.

Background: Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce., Methods: An open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop®) to AL (Coartem®) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured., Results: The day 42 genotyping-adjusted cure rate estimates were 97.3% [95% CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier survival estimates). The difference in day 42 cure rates was -3.1% [upper limit 95% CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 [95% CI: 0.46-0.63] (ASAQ) and 0.66 [0.57-0.73] (AL) (p = 0.017)., Conclusions: Both ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended., Trial Registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713, ISRCTN40020296.

Background: Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal., Methods: Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop®) or artemether-lumefantrine (AL, Coartem®), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28., Results: Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p < 0.001), vomiting (7.1% vs 1.6%, p < 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis)., Conclusion: Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT., Trial Registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).

Objective: The aim of this study was to evaluate the efficacy and safety of three anti-malarial combinations--artemether-lumefantrine (A-L), amodiaquine-sulfadoxine-pyrimethamine (AQ-SP), and artesunate-amodiaquine (AQ-AS)--in the treatment of uncomplicated malaria in children younger than 5 years in Bangui, Central African Republic., Methodology: This study included 186 children aged 6-59 months with uncomplicated falciparum malaria who were treated at the Bédé Combattant Hospital from July through October 2010: 63 randomized to receive A-L, 63 AQ-SP, and 60 AQ-AS. Clinical outcome was classified according to WHO criteria as early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF), or adequate clinical and parasitological response (ACPR). The occurrence of mutations in the pfcrt, pfmdr-1, dhfr and dhps genes was studied by PCR-RFLP., Results: After PCR correction, ACPR at D28 was 100% for A-L, 96.55% for AQ-SP, and 100% for AQ-AS, with no significant difference between the three combinations (p = 0.36). The 2 cases of treatment failure for AQ-SP were associated with mutations at the following resistance markers: Pfcrt 76T, PfmdrI 86Y, Dhfr 108N, and Dhps A437. There was no significant difference in the reduction of anemia, fever (p = 0.87), or parasitemia (p = 0.63) between the three combinations., Conclusion: This study demonstrates that artemisinin-based combinations are still effective and tolerated in the treatment of uncomplicated malaria in children younger than 5 years in Bangui. Treatment failures were due to new infections and mutations in resistance markers.

Little is known about resistance of Plasmodium falciparum to antimalarials in Sahelian countries. Here we investigated the drug susceptibilities of fresh isolates collected in Niger post-deployment of artemisinin-based combination therapies (ACTs). We found that the parasites remained highly susceptible to new (dihydroartemisinin, lumefantrine, pyronaridine, and piperaquine) and conventional (amodiaquine and chloroquine) antimalarial drugs. The introduction of ACTs in 2005 and their further deployment nationwide have therefore not resulted in a decrease in P. falciparum susceptibilities to these antimalarials.

Background: The ineffectiveness of artesunate and amodiaquine tablets in malaria treatment remains a health burden to WHO and governments of malaria-endemic countries, including Ghana. The proliferation of illegitimate anti-malarial drugs and its use by patients is of primary concern to international and local drug regulatory agencies because such drugs are known to contribute to the development of the malaria-resistant parasites in humans. No data exist on quality of these drugs in the fishing village communities in Ghana although the villagers are likely users of such drugs. A pilot study on the quality of anti-malarial tablets in circulation during the major fishing season at a malarious fishing village located along the coast of Tema in southern Ghana was determined., Methods: Blisterpacks of anti-malarial tablets were randomly sampled. The International Pharmacopoeia and Global Pharma Health Fund Minilab protocols were used to assess the quality of anti-malarial tablets per blisterpacks allegedly manufactured by Guilin Pharmaceutical Co Ltd, China (GPCL) and Letap Pharmaceuticals Ltd, Ghana (LPL) and sold in chemical sales outlets at Kpone-on-Sea. Ferric chloride and cobaltous thiocyanate tests confirmed the presence of active ingredients in the tablets. A confirmatory test for the active ingredient was achieved with artesunate (ICRS1409) and amodiaquine (ICRS0209) reference standards. A high performance liquid chromatography analysis confirmed the amount of artesunate found in tablets., Results: Based on the International Pharmacopoeia acceptable range of 96/98 to 102% for genuine artesunate per tablet, 10% [relative standard deviation (RSD): 3.2%] of field-selected artesunate blisterpack per tablets manufactured by GPCL, and 50% (RSD: 5.1%) of a similar package per tablet by LPL, passed the titrimetric test. However, 100% (RSD: 2.2%) of amodiaquine blisterpack per tablet by GPCL were found to be within the International Pharmacopeia acceptable range of 90 to 110% for genuine amodiaquine in tablet, whilst 17% of a similar package per tablet by LPL failed spectrophotometric testing., Conclusion: Inadequate amounts of artesunate and amodiaquine detected in the tablets suggest that both pharmaceutical companies may not be following recommended drug formulation procedures, or the active pharmaceutical ingredients might have been degraded by improper storage conditions. Thus, drugs being sold at Kpone-on-Sea, Ghana may likely be classified as substandard drugs and not suitable for malaria treatment.

The objectives of this study were: 1) to evaluate the safety and efficacy of combination artesunate (AS)/amodiaquine (AQ) therapy, and 2) to determine the difference between recrudescence and resistance. An in vivo efficacy study was conducted in Equatorial Guinea. A total of 122 children 6-59 months of age from two regional hospitals were randomized and subjected to a 28-day clinical and parasitological follow-up. A blood sample on Whatman paper was taken on Days 0, 7, 14, 21, and 28 or on any day in cases of treatment failure, with the parasite DNA then being extracted for molecular analysis purposes. A total of 4 children were excluded, and 9 cases were lost to follow-up. There were 17 cases of late parasitological failure, 3 cases of late clinical failure, and 89 cases of adequate clinical and parasitological response. The parasitological failure rate was 18.3% (20 of 109) and the success rate 81.70% (95% confidence interval [72.5-87.9%]). After molecular correction, real treatment efficacy stood at 97.3%. Our study showed the good efficacy of combination AS/AQ therapy. This finding enabled this treatment to be recommended to Equatorial Guinea's National Malaria Control Program to change the official treatment policy as of March 2008.

Single Nucleotide Polymorphisms (SNPs) in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ) as well as amodiaquine (AQ) resistance. mefloquine (MQ) and lumefantrine (LU) sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008-2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild-type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001). Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001) during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART) Combination Therapy (ACT) administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future.

The authors present a case of severe falciparum malaria diagnosed in a traveler after he returned to Rhode Island from a visit to the Dominican Republic. They then review aspects of the case pertinent to our local practice environment that make diagnosis and management especially challenging.

Background: Artemisinin combination therapy is recommended as treatment for uncomplicated Plasmodium falciparum (Pf) malaria, whereas chloroquine is still widely used for non-Pf infections. A common treatment for both vivax and falciparum malaria would be welcome., Methods: A longitudinal prospective effectiveness study of 1682 children aged 3-27 months in outpatient clinics in Papua New Guinea. The main outcome was clinical treatment failure rate following treatment with artemether/lumefantrine (AL)., Results: Among 5670 febrile episodes, 1682 (28%) had positive rapid diagnostic test (RDT) results and were treated with AL. A total of 1261 (22%) had an infection confirmed by blood slide examination. Of these, 594 Pv and 332 Pf clinical malaria cases were included in the primary effectiveness analysis. Clinical treatment failure rates at 7, 28, and 42 days were 0.2%, 2.2%, and 12.0%, respectively, for Pv and 0.3%, 1.2%, and 3.6%, respectively, for Pf. A single malaria-unrelated death occurred within 42 days following treatment with AL, in a child who was aparasitemic by blood slide at reattendance., Conclusions: AL provides a rapid clinical response against both Pf and Pv malaria, but is associated with a high rate of Pv recurrent clinical episodes between days 28 and 42. In order to prevent relapsing infections from long-lasting hypnozoites, AL should ideally be complemented with a course of primaquine. In the absence of better treatment and diagnostic options, the use of AL in young children in routine practice is an acceptable, interim option in coendemic areas where Pv is resistant to chloroquine and specific treatment for Pv hypnozoites not feasible.

Background: In sub-Saharan Africa, malaria is the leading cause of morbidity and mortality especially in children. In Senegal, seasonal malaria chemoprevention (SMC) previously referred to as intermittent preventive treatment in children (IPTc) is a new strategy for malaria control in areas of high seasonal transmission. An effectiveness study of SMC, using sulphadoxine-pyrimethamine (SP) plus amodiaquine (AQ), was conducted in central Senegal from 2008 to 2010 to obtain information about safety, feasibility of delivery, and cost effectiveness of SMC. Here are report the effect of SMC delivery on the prevalence of markers of resistance to SP and AQ., Methods: This study was conducted in three health districts in Senegal with 54 health posts with a gradual introduction of SMC. Three administrations of the combination AQ + SP were made during the months of September, October and November of each year in children aged less than 10 years living in the area. Children were surveyed in December of each year and samples (filter paper and thick films) were made in 2008, 2009 and 2010. The prevalence of mutations in the pfdhfr, pfdhps, pfmdr1 and pfcrt genes was investigated by sequencing and RTPCR in samples positive by microscopy for Plasmodium falciparum., Results: Mutations at codon 540 of pfdhps and codon 164 of pfdhfr were not detected in the study. Among children with parasitaemia at the end of the transmission seasons, the CVIET haplotypes of pfcrt and the 86Y polymorphism of pfmdr1 were more common among those that had received SMC, but the number of infections detected was very low and confidence intervals were wide. The overall prevalence of these mutations was lower in SMC areas than in control areas, reflecting the lower prevalence of parasitaemia in areas where SMC was delivered., Conclusion: The sensitivity of P. falciparum to SMC drugs should be regularly monitored in areas deploying this intervention. Overall the prevalence of genotypes associated with resistance to either SP or AQ was lower in SMC areas due to the reduced number of parasitaemia individuals.

Febrile illnesses occur frequently among HIV positive patients and these are often treated presumptively as malaria in endemic areas. Parasite-based diagnosis of malaria will eliminate unnecessary treatment, reduce drug-drug interactions and the chances for the emergence of drug resistant Plasmodium. We evaluated finger prick blood samples from 387 people living with HIV (PLWHIV) and suspected of having malaria by expert microscopy and Paracheck-Pf(TM) - a histidine-rich protein-II based malaria rapid diagnostic test. The study was conducted at the PEPFAR supported AIDS Prevention Initiative in Nigeria (APIN) Clinic of the University College Hospital Ibadan, southwest Nigeria. Outcome parameters were prevalence of malaria parasitemia, sensitivity and specificity of Paracheck-Pf as well as the positive and negative predictive values for Paracheck-Pf using microscopy of Giemsa-stained blood film as gold standard. Malaria parasites were detected in 19·1% (74/387) of enrollees by microscopy and 19·3% (74/383) by Paracheck-Pf. Geometric mean parasite density was 501/μl (range 39-749 202/μl). Sensitivity and specificity of Paracheck-Pf at all parasite densities were 55·4% and 89·3% while corresponding figures at parasite densities ≥200/μl were 90·9% and 90·3%. Sensitivity and specificity at parasite densities ≥500/μl was 97·6% and 90·3%. Positive and negative predictive values for parasite density ≥200/μl were 55·4% and 98·7%, respectively. Paracheck-Pf was found to be a useful malaria diagnostic tool at parasite densities ≥200/μl facilitating appropriate clinical management.

Background: In Burkina Faso, rapid diagnostic tests for malaria have been made recently available. Previously, malaria was managed clinically. This study aims at assessing which is the best management option of a febrile patient in a hyperendemic setting. Three alternatives are: treating presumptively, testing, or refraining from both test and treatment. The test threshold is the tradeoff between refraining and testing, the test-treatment threshold is the tradeoff between testing and treating. Only if the disease probability lies between the two should the test be used., Methods and Findings: Data for this analysis was obtained from previous studies on malaria rapid tests, involving 5220 patients. The thresholds were calculated, based on disease risk, treatment risk and cost, test accuracy and cost. The thresholds were then matched against the disease probability. For a febrile child under 5 in the dry season, the pre-test probability of clinical malaria (3.2%), was just above the test/treatment threshold. In the rainy season, that probability was 63%, largely above the test/treatment threshold. For febrile children >5 years and adults in the dry season, the probability was 1.7%, below the test threshold, while in the rainy season it was higher (25.1%), and situated between the two thresholds (3% and 60.9%), only if costs were not considered. If they were, neither testing nor treating with artemisinin combination treatments (ACT) would be recommended., Conclusions: A febrile child under 5 should be treated presumptively. In the dry season, the probability of clinical malaria in adults is so low, that neither testing nor treating with any regimen should be recommended. In the rainy season, if costs are considered, a febrile adult should not be tested, nor treated with ACT, but a possible alternative would be a presumptive treatment with amodiaquine plus sulfadoxine-pyrimethamine. If costs were not considered, testing would be recommended.

The treatment efficacy of artesunate-amodiaquine (AQ) coformulated or copackaged, and the plasma and saliva concentrations of desethylamodiaquine (DEAQ), the active metabolite of AQ, were evaluated in 120 and 7 children, respectively, with uncomplicated Plasmodium falciparum malaria treated with oral daily doses of the 2 formulations for 3 days. All children recovered clinically. Fever clearance (1.1 ± 0.2 vs 1.0 ± 0 days) and parasite clearance times (21.1 ± 10.2 vs 19.0 ± 7.0 hours) in artesunate-AQ coformulated and artesunate-AQ copackaged treated children, respectively, were similar. All children remained aparasitemic for at least 28 days. Blood and saliva samples were collected over 35 days and DEAQ in plasma and saliva was determined by high-performance liquid chromatography. DEAQ was detectable in plasma and saliva within 40 minutes of oral administration of artesunate-AQ. DEAQ concentrations 7 days after the start of therapy were 247.8 and 125.1 ng/mL in plasma and saliva, respectively. The concentration-time curves of plasma and saliva in declining phases were approximately parallel giving a similar half-life of 169.1 ± 16.4 and 142.8 ± 6.5 hours in plasma and saliva, respectively. Clearance from plasma and saliva was also similar (335.6 and 443.4 mL·h·kg, respectively). Area under concentration-time curves (AUC0-35d) for plasma and saliva were 94,744.9 and 74,004.2 ng·mL·h, respectively. In general, Saliva-plasma concentration ratio was 0.25-0.4. DEAQ concentrations in saliva may be useful for monitoring therapy and for the evaluation of the disposition of AQ in children with falciparum malaria treated with AQ-based combination.

Mixed treatment comparison (MTC) meta-analysis allows several treatments to be compared in a single analysis while utilising direct and indirect evidence. Treatment by covariate interactions can be included in MTC models to explore how the covariate modifies the treatment effects. If interactions exist, the assumptions underlying MTCs may be invalidated. For conventional pair-wise meta-analysis, important benefits regarding the investigation of such interactions, gained from using individual patient data (IPD) rather than aggregate data (AD), have been described. We aim to compare IPD MTC models including patient-level covariates with AD MTC models including study-level covariates. IPD and AD random-effects MTC models for dichotomous outcomes are specified. Three assumptions are made regarding the interactions (i.e. independent, exchangeable and common interactions). The models are applied to a dataset to compare four drugs for treating malaria (i.e. amodiaquine-artesunate, dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine and chlorproguanil-dapsone plus artesunate) using the outcome unadjusted treatment success at day 28. The treatment effects and regression coefficients for interactions from the IPD models were more precise than those from AD models. Using IPD, assuming independent or exchangeable interactions, the regression coefficient for chlorproguanil-dapsone plus artesunate versus DHAPQ was statistically significant and assuming common interactions, the common coefficient was significant; whereas using AD, no coefficients were significant. Using IPD, DHAPQ was the best drug; whereas using AD, the best drug varied. Using AD models, there was no evidence that the consistency assumption was invalid; whereas, the assumption was questionable based on the IPD models. The AD analyses were misleading., (Copyright © 2012 John Wiley & Sons, Ltd.)

Malaria and pneumonia are leading causes of childhood mortality. Home Management of fever as Malaria (HMM) enables presumptive treatment with antimalarial drugs but excludes pneumonia. We aimed to evaluate the impact of adding an antibiotic, amoxicillin (AMX) to an antimalarial, artesunate amodiaquine (AAQ + AMX) for treating fever among children 2-59 months of age within the HMM strategy on all-cause mortality. In a stepped-wedge cluster-randomized, open trial, children 2-59 months of age with fever treated with AAQ or AAQ + AMX within HMM were compared with standard care. Mortality reduced significantly by 30% (rate ratio [RR] = 0.70, 95% confidence interval [CI] = 0.53-0.92, P = 0.011) in AAQ clusters and by 44% (RR = 0.56, 95% CI = 0.41-0.76, P = 0.011) in AAQ + AMX clusters compared with control clusters. The 21% mortality reduction between AAQ and AAQ + AMX (RR = 0.79, 95% CI = 0.56-1.12, P = 0.195) was however not statistically significant. Community fever management with antimalarials significantly reduces under-five mortality. Given the lower mortality trend, adding an antibiotic is more beneficial.

Background: Zanzibar has recently undergone a rapid decline in Plasmodium falciparum transmission following combined malaria control interventions with artemisinin-based combination therapy (ACT) and integrated vector control. Artesunate-amodiaquine (ASAQ) was implemented as first-line treatment for uncomplicated P. falciparum malaria in Zanzibar in 2003. Resistance to amodiaquine has been associated with the single nucleotide polymorphism (SNP) alleles pfcrt 76T, pfmdr1 86Y, 184Y and 1246Y. An accumulation of these SNP alleles in the parasite population over time might threaten ASAQ efficacy.The aim of this study was to assess whether prolonged use of ASAQ as first-line anti-malarial treatment selects for P. falciparum SNPs associated with resistance to the ACT partner drug amodiaquine., Methods: The individual as well as the combined SNP allele prevalence were compared in pre-treatment blood samples from patients with uncomplicated P. falciparum malaria enrolled in clinical trials conducted just prior to the introduction of ASAQ in 2002-2003 (n = 208) and seven years after wide scale use of ASAQ in 2010 (n = 122)., Results: There was a statistically significant decrease of pfcrt 76T (96-63%), pfmdr1 86Y (75-52%), 184Y (83-72%), 1246Y (28-16%) and the most common haplotypes pfcrt/pfmdr1 TYYD (46-26%) and TYYY (17-8%), while an increase of pfcrt/pfmdr1 KNFD (0.4-14%) and KNYD (1-12%)., Conclusions: This is the first observation of a decreased prevalence of pfcrt 76T, pfmdr1 86Y, 184Y and 1246Y in an African setting after several years of extensive ASAQ use as first-line treatment for uncomplicated malaria. This may support sustained efficacy of ASAQ on Zanzibar, although it was unexpected considering that all these SNPs have previously been associated with amodiaquine resistance. The underlying factors of these results are unclear. Genetic dilution by imported P. falciparum parasites from mainland Tanzania, a de-selection by artesunate per se and/or an associated fitness cost might represent contributing factors. More detailed studies on temporal trends of molecular markers associated with amodiaquine resistance are required to improve the understanding of this observation.

A dose regimen of artesunate and amodiaquine based on arm span- or age range (DRAAAS), derived from a study of 1674 children, was compared with standard dose regimen of the same drugs calculated according to body weight (SDRAA) in 68 malarious children. Children on DRAAAS received 0.8-1.0 of artesunate/kg and 0.9-1.2 times amodiaquine/kg compared with those receiving SDRAA. Parasite and fever clearance and fall in hematocrit in the first 3 days were similar; both regimens were well tolerated. DRAAAS is simple and is efficacious.

Artemisinin-based combination therapies (ACTs) are the first-line treatment of uncomplicated malaria. The public health benefit and safety of repeated administration of a given ACT are poorly studied. We conducted a randomized trial comparing artemether-lumefantrine, artesunate plus amodiaquine (AS+AQ) and artesunate plus sulfadoxine-pyrimethamine (AS+SP) in patients 6 months of age and older with uncomplicated malaria in Mali from July 2005 to July 2007. The patient received the same initial treatment of each subsequent uncomplicated malaria episode except for treatment failures where quinine was used. Overall, 780 patients were included. Patients in the AS+AQ and AS+SP arms had significantly less risk of having malaria episodes; risk ratio (RR) = 0.84 (P = 0.002) and RR = 0.80 (P = 0.001), respectively. The treatment efficacy was similar and above 95% in all arms. Although all drugs were highly efficacious and well tolerated, AS+AQ and AS+SP were associated with less episodes of malaria.

A new dose regimen of artesunate and amodiaquine (NDRAA) based on age or body weight range was compared with standard dose regimen of artesunate and amodiaquine (SDRAA) calculated according to body weight and with fixed-dose artesunate-amodiaquine (FDAA) and artemether-lumefantrine (AL) in 304 children afflicted by malaria aged 15 years or younger. In initial comparison (n = 208), children on NDRAA received 1-3 times amodiaquine per kilogram of body weight and 1-1.5 times of artesunate per kilogram of body weight compared with those receiving SDRAA. Parasite but not fever clearance was significantly faster in children who received NDRAA (19.4 ± 8.4 hours vs. 24.6 ± 15.5 hours, P = 0.003). Polymerase chain reaction-uncorrected cure rates on days 28-42 were also significantly higher in children who received NDRAA (P < 0.02 in all cases). Therapeutic responses in children younger than 5 years (n = 96) treated with NDRAA, FDAA, and AL were similar. Changes in hematocrit values and reported adverse events after commencing therapy were similar in those who received NDRAA and SDRAA. All drug regimens were well tolerated. NDRAA based on age or body weight range is simple, is therapeutically superior to SDRAA calculated according to body weight, and is as efficacious as AL in children younger than 5 years.

Aim: to evaluate the safety and efficacy of a fixed combination of artemether-lumefantrine for likely use against failures of the artesunate-amodiaquine first line therapy., Methods: the study was an open label single arm uncontrolled trial. we evaluated the safety and efficacy of standard artemether-lumefantrine therapy in 59 subjects with uncomplicated malaria caused by Plasmodium falciparum on the island of Sumba in eastern Indonesia. No treatment failures occurred up to day 35. One subject had recurrent parasitemia on day 42 that showed a genotype consistent with recrudescence. The efficacy of this therapy was thus estimated to be 98.3% (95% confidence interval=95%-100%). Descriptive analysis was done using the SPSS 12 computer software., Results: two hundred and thirteen P. falciparum patients met the inclusion criteria for in vivo efficacy study, 79 were given artemether-lumefantrine and 134 were treated under another protocol with artesunate-amodiaquine or sulfadoxine-pyrimethamine. Among 79 eligible subjects, 59 successfully completed the 42-day test. As expected, the mean PCT was longer than the mean FCT, i.e. 1.34 ± 0.67 (95% CI 1.21-1.47) and 1.05 ± 0.05 (95% CI 0.95-1.15) days, respectively. On day 3 of treatment, both fever and asexual stage of P. falciparum disappeared in all subjects. Observation until Day 35 showed that all of the 59 subjects treated with artemether-lumefantrine were cured., Conclusion: the findings of this uncontrolled study suggest good safety and efficacy of artemether-lumefantrine for treatment of uncomplicated falciparum malaria on Sumba Island in the Lesser Sundas archipelago of eastern Indonesia.

This study compared the efficacy against Plasmodium falciparum gametocytes of four regimens: amodiaquine-sulfadoxine/pyrimethamine (AQ-SP) and mefloquine-artesunate (MQ-AS), with and without primaquine (PQ) administered with the second dose of the schizonticide (AQ-SP; AQ-SP-PQ; MQ-AS; MQ-AS-PQ). Efficacy was determined by thick smear on days 1, 4 and 8 after the beginning of treatment. A total of 82 patients (19-23/group) were recruited. After AQ-SP administration, gametocytemia steadily increased until day 8. With AQ-SP-PQ, a marked decline in gametocytemia was detected on days 4 and 8. MQ-AS treatment resulted in reduced gametocytemia on days 4 and 8, and with MQ-AS-PQ it was reduced even further. None of the treatments cleared gametocytemia by day 8. Currently, artemisinin-based combination therapies plus PQ are the recommended treatment option against falciparum malaria; however, further studies are required to optimize the use of PQ. Issues to be addressed include the optimal time of administration, treatment duration, optimal daily and total dose, and day of evaluation of the gametocytocidal effect. In falciparum malaria, the WHO recommends a maximum of 4days of treatment; consequently, an effective regimen must clear asexual parasites and symptoms within this time frame. The same criteria should be taken into account when evaluating the anti-gametocyte activity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The therapeutic efficacy, changes in haematocrit and declines in parasitaemias were evaluated in 56 children with uncomplicated falciparum hyperparasitaemia after oral artesunate-amodiaquine or artemether-lumefantrine. All children recovered clinically within 2 days and without progression to severe malaria. Falls in haematocrit in the first 3 days after treatment began were similar and <5%. Declines in parasitaemias were monoexponential with both treatments with an estimated half-life of 1 h.

Home management of malaria is recommended for prompt, effective antimalarial treatment in children less than five years of age. Compliance, safety, and effectiveness of the new fixed-dose artesunate-amodiaquine regimen used to treat suspected malaria were assessed in febrile children enrolled in a 24-month cohort study in two settings in Madagascar. Children with fever were asked to visit community health workers. Presumptive antimalarial treatment was given and further visits were scheduled for follow-up. The primary endpoint was the risk of clinical/parasitologic treatment failure. Secondary outcomes included fever/parasite clearance, change in hemoglobin levels, and frequency of adverse events. The global clinical cure rate was 98.4% by day 28 and 97.9% by day 42. Reported compliance was 83.4%. No severe adverse effects were observed. This study provides comprehensive data concerning the clinical cure rate obtained with artesunate-amodiaquine and evidence supporting the scaling up of home management of malaria.

The effect of antimalarial drug selection on pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from two distinct geographical locations was determined in 70 and 18 P. falciparum isolates from Nigeria and Brazil, respectively, using nested polymerase chain reaction and direct DNA sequencing approaches. All isolates from Brazil and 72% from Nigeria harbored the mutant SVMNT and CVIET pfcrt haplotype, respectively. The pfcrt CVMNT haplotype was also observed in (7%) of the Nigerian samples. One hundred percent (100%) and 54% of the parasites from Brazil and Nigeria, respectively, harbored wild-type pfmdr1Asn86. We provide first evidence of emergence of the CVMNT haplotype in West Africa. The high prevalence of pfcrt CVIET and SVMNT haplotypes in Nigeria and Brazil, respectively, is indicative of different selective pressure by chloroquine and amodiaquine. Continuous monitoring of pfcrt SVMNT haplotype is required in endemic areas of Africa, where artesunate-amodiaquine combination is used for treatment of acute uncomplicated malaria.

Background: Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv)., Methods and Findings: In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10-43, p ≤ 0.001) in children receiving SP-AQ and 12% (95% CI, -11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9-54, p = 0.012) and Pv incidence was 23% (95% CI, 0-41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4-51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, -24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p > 0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%-2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention., Conclusions: IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.

Background: Current malaria control strategies recommend (i) early case detection using rapid diagnostic tests (RDT) and treatment with artemisinin combination therapy (ACT), (ii) pre-referral rectal artesunate, (iii) intermittent preventive treatment and (iv) impregnated bed nets. However, these individual malaria control interventions provide only partial protection in most epidemiological situations. Therefore, there is a need to investigate the potential benefits of integrating several malaria interventions to reduce malaria prevalence and morbidity., Methods: A randomized controlled trial was carried out to assess the impact of combining seasonal intermittent preventive treatment in children (IPTc) with home-based management of malaria (HMM) by community health workers (CHWs) in Senegal. Eight CHWs in eight villages covered by the Bonconto health post, (South Eastern part of Senegal) were trained to diagnose malaria using RDT, provide prompt treatment with artemether-lumefantrine for uncomplicated malaria cases and pre-referral rectal artesunate for complicated malaria occurring in children under 10 years. Four CHWs were randomized to also administer monthly IPTc as single dose of sulphadoxine-pyrimethamine (SP) plus three doses of amodiaquine (AQ) in the malaria transmission season, October and November 2010. Primary end point was incidence of single episode of malaria attacks over 8 weeks of follow up. Secondary end points included prevalence of malaria parasitaemia, and prevalence of anaemia at the end of the transmission season. Primary analysis was by intention to treat. The study protocol was approved by the Senegalese National Ethical Committee (approval 0027/MSP/DS/CNRS, 18/03/2010)., Results: A total of 1,000 children were enrolled. The incidence of malaria episodes was 7.1/100 child months at risk [95% CI (3.7-13.7)] in communities with IPTc + HMM compared to 35.6/100 child months at risk [95% CI (26.7-47.4)] in communities with only HMM (aOR = 0.20; 95% CI 0.09-0.41; p = 0.04). At the end of the transmission season, malaria parasitaemia prevalence was lower in communities with IPTc + HMM (2.05% versus 4.6% p = 0.03). Adjusted for age groups, sex, Plasmodium falciparum carriage and prevalence of malnutrition, IPTc + HMM showed a significant protective effect against anaemia (aOR = 0.59; 95% CI 0.42-0.82; p = 0.02)., Conclusion: Combining IPTc and HMM can provide significant additional benefit in preventing clinical episodes of malaria as well as anaemia among children in Senegal.

Background: Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce., Methods and Findings: Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28., Conclusions: This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria., Trial Registration: ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750

Background: Chloroquine resistance (CR) decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR) conferring mutant pfcrt allele and its associated chromosomal haplotype were determined before and after the change in Gabonese national treatment guidelines from chloroquine (CQ) to artesunate plus amodiaquine (AQ) in 2003., Methods: The prevalence of the wild type pfcrt allele was assessed in 144 isolates from the years 2005 - 07 by PCR fragment restriction digest and direct sequencing. For haplotype analysis of the chromosomal regions flanking the pfcrt locus, microsatellite analysis was done on a total of 145 isolates obtained in 1995/96 (43 isolates), 2002 (47 isolates) and 2005 - 07 (55 isolates)., Results: The prevalence of the mutant pfcrt allele decreased from 100% in the years 1995/96 and 2002 to 97% in 2005 - 07. Haplotype analysis showed that in 1995/96 79% of the isolates carried the same microsatellite alleles in a chromosomal fragment spanning 39 kb surrounding the pfcrt locus. In 2002 and 2005 - 07 the prevalence of this haplotype was 62% and 58%, respectively. Pfcrt haplotype analysis showed that all wild type alleles were CVMNK., Conclusion: Four years after the withdrawal of CQ from national treatment guidelines the prevalence of the mutant pfcrt allele remains at 97%. The data suggest that the combination of artesunate plus AQ may result in continued selection for the mutant pfcrt haplotype even after discontinuance of CQ usage.

In order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with Plasmodium vivax malaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. Individual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant (n = 24) and postpartum (n = 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of P. vivax infections during pregnancy.

The therapeutic efficacies of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine during 5 years of adoption as first-line treatments were evaluated in 811 ≤ 12-year-old malarious children. Compared with artemether-lumefantrine, amodiaquine-artesunate significantly reduced the proportion of children with fever and parasitemia 1 day after treatment (day 1; P < 0.008 for both). The proportion of parasitemic children on day 2 and gametocytemia on presentation and carriage reduced significantly over the years (P < 0.000001 and P < 0.03, respectively; test for trend). Overall efficacy was 96.5% (95% confidence interval [CI] = 94.5-98.6) and remained unchanged over the years (P = 0.87; test for trend). Kinetics of parasitemias after treatments were estimated by a non-compartmental model. Declines of parasitemias were monoexponential, with a mean elimination half-life of 1.09 hours (95% CI = 1.0-1.16). Parasitemia half-lives and efficacy were similar for both regimens and in all ages. Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated falciparum malaria in Nigerian children 5 years after adoption.

Background: This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field., Case Description: In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-Aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and Sanofi-Aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop") which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and Sanofi-Aventis to ensure: 1) the adoption of this new medicine by malaria-endemic countries, 2) its appropriate usage through a broad range of information tools, and 3) the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan., Discussion and Evaluation: The partnership between DNDi and Sanofi-Aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan., Conclusions: The speed at which ASAQ Winthrop was adopted in the field shows that this drug fits the needs of patients and health authorities. It also demonstrates the power of partnerships that combine different sets of strengths and skills, and that evolve to include additional actors to meet new global health challenges for poverty-related diseases.

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.

To evaluate the effects of antimalarial drugs on Plasmodium falciparum malaria-associated anemia, we use the area under the curve (AUC) of anemia levels after treatment as an approach to combine their duration and magnitude. The method involves numeric estimation, by trapezoidal rule, of AUC from a plot of deficit in hematocrit levels from 30% (the lower threshold of normal) versus time in anemic children. Using the method, we evaluated, in randomized trials, the effects of artesunate-mefloquine versus mefloquine alone and artemether-lumefantrine versus amodiaquine-artesunate on the time course of recovery from malaria-associated anemia in 109 children. Anemia resolution times were similar (10.9 ± 6.2 [standard deviation] versus 13.3 ± 8.9 days, P = 0.2), but mean AUC was significantly lower in artesunate-mefloquine- compared with mefloquine-treated children (35.5 ± 7.1 [standard error of mean] versus 49.8 ± 11.3 %·h, P = 0.02) indicating larger exposure to anemia in mefloquine-treated children. In artemether-lumefantrine- and amodiaquine-artesunate-treated children, both anemia resolution times (8.6 ± 5.3 [standard deviation] versus 8.6 ± 4.8 days, P = 0.98) and mean AUC (57.1 ± 12.9 [standard error of mean] versus 46.3 ± 8.7 %·h, P = 0.74) were similar. Estimation of AUC appears more robust than estimation of anemia resolution time in evaluating antimalarial drug effects and can be used in both observational studies and clinical trials assessing the effects of therapies on malaria-associated anemia.

Background: Malaria is the leading cause of morbidity and mortality in post-conflict Burundi. To counter the increasing challenge of anti-malarial drug resistance and improve highly effective treatment Burundi adopted artesunate-amodiaquine (AS-AQ) as first-line treatment for uncomplicated Plasmodium falciparum malaria and oral quinine as second-line treatment in its national treatment policy in 2003. Uptake of this policy in the public, private and non-governmental (NGO) retail market sectors of Burundi is relatively unknown. This study was conducted to evaluate access to national policy recommended anti-malarials., Methods: Adapting a standardized methodology developed by Health Action International/World Health Organization (HAI/WHO), a cross-sectional survey of 70 (24 public, 36 private, and 10 NGO) medicine outlets was conducted in three regions of Burundi, representing different levels of transmission of malaria. The availability on day of the survey, the median prices, and affordability (in terms of number of days' wages to purchase treatment) of AS-AQ, quinine and other anti-malarials were calculated., Results: Anti-malarials were stocked in all outlets surveyed. AS-AQ was available in 87.5%, 33.3%, and 90% of public, private, and NGO retail outlets, respectively. Quinine was the most common anti-malarial found in all outlet types. Non-policy recommended anti-malarials were mainly found in the private outlets (38.9%) compared to public (4.2%) and NGO (0%) outlets. The median price of a course of AS-AQ was US$0.16 (200 Burundi Francs, FBu) for the public and NGO markets, and 3.5-fold higher in the private sector (US$0.56 or 700 FBu). Quinine tablets were similarly priced in the public (US$1.53 or 1,892.50 FBu), private and NGO sectors (both US$1.61 or 2,000 FBu). Non-policy anti-malarials were priced 50-fold higher than the price of AS-AQ in the public sector. A course of AS-AQ was affordable at 0.4 of a day's wage in the public and NGO sectors, whereas, it was equivalent to 1.5 days worth of wages in the private sector., Conclusions: AS-AQ was widely available and affordable in the public and NGO markets of hard-to-reach post-conflict communities in Burundi. However greater accessibility and affordability of policy recommended anti-malarials in the private market sector is needed to improve country-wide policy uptake.

Background: The Expanded Programme on Immunisation (EPI) provides an effective way of delivering intermittent preventive treatment for malaria (IPT) to infants. However, it is uncertain how IPT can be delivered most effectively to older children. Therefore, we have compared two approaches to the delivery of IPT to Gambian children: distribution by village health workers (VHWs) or through reproductive and child health (RCH) trekking teams. In rural areas, RCH trekking teams provide most of the health care to children under the age of 5 years in the Infant Welfare Clinic, and provide antenatal care for pregnant women., Methods and Findings: During the 2006 malaria transmission season, the catchment populations of 26 RCH trekking clinics in The Gambia, each with 400-500 children 6 years of age and under, were randomly allocated to receive IPT from an RCH trekking team or from a VHW. Treatment with a single dose of sulfadoxine pyrimethamine (SP) plus three doses of amodiaquine (AQ) were given at monthly intervals during the malaria transmission season. Morbidity from malaria was monitored passively throughout the malaria transmission season in all children, and a random sample of study children from each cluster was examined at the end of the malaria transmission season. The primary study endpoint was the incidence of malaria. Secondary endpoints included coverage of IPTc, mean haemoglobin (Hb) concentration, and the prevalence of asexual malaria parasitaemia at the end of malaria transmission period. Financial and economic costs associated with the two delivery strategies were collected and incremental cost and effects were compared. A nested case-control study was used to estimate efficacy of IPT treatment courses. Treatment with SP plus AQ was safe and well tolerated. There were 49 cases of malaria with parasitaemia above 5,000/µl in the areas where IPT was delivered through RCH clinics and 21 cases in the areas where IPT was delivered by VHWs, (incidence rates 2.8 and 1.2 per 1,000 child months, respectively, rate difference 1.6 [95% confidence interval (CI) -0.24 to 3.5]). Delivery through VHWs achieved a substantially higher coverage level of three courses of IPT than delivery by RCH trekking teams (74% versus 48%, a difference of 27% [95% CI 16%-38%]). For both methods of delivery, coverage was unrelated to indices of wealth, with similar coverage being achieved in the poorest and wealthiest groups. The prevalence of anaemia was low in both arms of the trial at the end of the transmission season. Efficacy of IPTc against malaria during the month after each treatment course was 87% (95% CI 54%-96%). Delivery of IPTc by VHWs was less costly in both economic and financial terms than delivery through RCH trekking teams, resulting in incremental savings of US$872 and US$1,244 respectively. The annual economic cost of delivering at least the first dose of each course of IPTc was US$3.47 and US$1.63 per child using trekking team and VHWs respectively., Conclusions: In this setting in The Gambia, delivery of IPTc to children 6 years of age and under by VHWs is more effective and less costly than delivery through RCH trekking clinics., Trial Registration: ClinicalTrials.gov NCT00376155. Please see later in the article for the Editors' Summary.