Amodiaquine-sulfadoxine-pyrimethamine Research Articles

Genetic Evaluation of Interlukin-22 Single Nucleotide Polymorphism (rs1179251) with Plasmodium falciparum Clearance among Children Less Than 10 Years in the North Region of Cameroon

IL-22 is a pro and anti-inflammatory cytokine which induces the regeneration of hepatocytes cells during the immune response. Evidence has shown that genetic polymorphisms on IL-22 gene could affect the immune response and consequently the parasite clearance and the treatment outcome of malaria. This study aimed at determining the prevalence of the SNP rs1179251 of the Interleukin-22 gene and a possible association with P. falciparum clearance among children less than 10 years old in the North region of Cameroon. A case-control study was performed on 184 conveniently collected blood samples, spotted on Whartman No 3 filter paper from the SPAQ (Sulfadoxine-Pyrimethamine + Amodiaquine) clinical trial carried out in Garoua and Yagoua in 2015, from which DNA was extracted using Chelex-100 method. Genotyping of the IL-22 gene SNPs was performed using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP). Parasite clearance was defined as the disappearance of pre-treatment parasites without subsequent recurrence, irrespective of whether recurrence is a reinfection or a recrudescing parasite. Treatment outcomes were classified according to the WHO guidelines; patients that experienced early treatment failure (ETF), and late parasitological failure (LPF) were classified as failures (56 cases), while patients that experienced adequate clinical parasitological response (ACPR) were classified as successes (128 controls). The chi square test was used to establish the association between the SNP rs1179251 and parasite clearance. A P-value less than 0.05 was considered as statistically significant. The findings revealed that the mutant allele C was the most predominant with a frequency of 74.46%, with the ancestral allele G having a frequency of 25.54%. These results showed that carriers of the mutant allele C could be 3.7 times more likely not to clear the parasites during treatment but this was not statistically significant (P=0.07, OR= 3.72). In conclusion, no association was found between the SNP rs1179251 of IL-22 gene and Plasmodium falciparum clearance. So, in spite of the importance of IL-22 gene in immune responses, the studied polymorphism does not serve a decisive role in Plasmodium falciparum clearance.

Monitoring of adverse drug reactions during seasonal malaria chemoprevention campaigns in children aged 3–59 months in Burkina Faso

Seasonal malaria chemoprevention (SMC) by mass administration of sulfadoxine pyrimethamine + amodiaquine (SPAQ) reduces the burden of malaria in children aged 3-59 months. The occurrence of adverse drug reaction (ADR) may affect the success of this intervention. There are few studies of SMC adverse event surveillance in sub-Saharan Africa, particularly in Burkina Faso, a highly endemic country. Our main objective was to characterize the ADRs reported during SMC campaigns in Burkina Faso. Secondly, we evaluated the performance of the pharmacovigilance integrated into the SMC program in order to support safe administration of SMC. This was a retrospective descriptive study of SMC individual case safety reports recorded in VigiBase® in Burkina Faso from 2014 to 2021. We used the P-method for the analysis of preventable serious adverse drug reactions and WHO criteria for assessing the performance of pharmacovigilance integrated into the SMC program. A total of 1,105 SMC individual case safety reports were registered in VigiBase® for 23,311,453 doses of SPAQ given between 2014 and 2021. No pharmacovigilance signal was detected. The number of serious cases was 101, of which 23 (22.8%) were preventable. In 38.1% of children, the occurrence of ADRs led to discontinuation of SMC treatment. Vomiting was the most frequently reported adverse drug reaction (48.0%). The proportion of children whose treatment was discontinued due to vomiting was 42.7%, while the proportion of treatment discontinuation for other ADRs was 32.8% (p = 0.01). The SMC program contributed at 46.2% to the national pharmacovigilance database. The reporting rate was 0.03 per 1,000 exposed children in 2021. The median completeness score of the ICSRs was 0.7 (IQR: 0.5-0.7), and the median time to register the ICSRs in VigiBase® was 204 (IQR: 143-333) days. Post-drug administration vomiting may interfere with the purpose of SMC. Measures to manage this adverse drug reaction should be taken to improve the success of the SMC program. Based on the information on reporting time and reporting rate, spontaneous reporting should be supported by active surveillance, including cohort event monitoring, in Burkina Faso.

A non-randomized controlled trial to assess the protective effect of SMC in the context of high parasite resistance in Uganda

BackgroundUntil recently, due to widespread prevalence of molecular markers associated with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance in east and southern Africa, seasonal malaria chemoprevention (SMC) has not been used at scale in this region. This study assessed the protective effectiveness of monthly administration of SP + AQ (SPAQ) to children aged 3–59 months in Karamoja sub-region, Uganda, where parasite resistance is assumed to be high and malaria transmission is seasonal.MethodsA two-arm quasi-experimental, open-label prospective non-randomized control trial (nRCT) was conducted in three districts. In two intervention districts, 85,000 children aged 3–59 months were targeted to receive monthly courses of SMC using SPAQ during the peak transmission season (May to September) 2021. A third district served as a control, where SMC was not implemented. Communities with comparable malaria attack rates were selected from the three districts, and households with at least one SMC-eligible child were purposively selected. A total cohort of 600 children (200 children per district) were selected and followed using passive surveillance for breakthrough confirmed malaria episodes during the five-month peak transmission season. Malaria incidence rate per person-months and number of malaria episodes among children in the two arms were compared. Kaplan–Meier failure estimates were used to compare the probability of a positive malaria test. Other factors that may influence malaria transmission and infection among children in the two arms were also assessed using multivariable cox proportional hazards regression model.ResultsThe malaria incidence rate was 3.0 and 38.8 per 100 person-months in the intervention and control groups, respectively. In the intervention areas 90.0% (361/400) of children did not experience any malaria episodes during the study period, compared to 15% (29/200) in the control area. The incidence rate ratio was 0.078 (95% CI 0.063–0.096), which corresponds to a protective effectiveness of 92% (95% CI 90.0–94.0) among children in the intervention area.ConclusionSMC using SPAQ provided high protective effect against malaria during the peak transmission season in children aged 3–59 months in the Karamoja sub-region of Uganda.

Overall and Gender-Specific Effects of Intermittent Preventive Treatment of Malaria with Artemisinin-Based Combination Therapies among Schoolchildren in Mali: A Three-Group Open Label Randomized Controlled Trial.

Intermittent preventive treatment of malaria among schoolchildren (IPTsc) reduces clinical malaria, asymptomatic parasitemia, and anemia. The effects of IPTsc by gender have not been studied longitudinally. We investigated overall IPTsc efficacy and conducted a secondary analysis to explore gender-specific differences. We enrolled schoolchildren aged 6-13 years in an open-label, rolling-cohort randomized controlled trial between September 2007 and February 2013 in Kolle, Mali. Annually, schoolchildren received two full-treatment courses of sulfadoxine-pyrimethamine (SP) plus artesunate, or amodiaquine (AQ) plus artesunate, or no malaria treatment as control. We used mixed-effects generalized linear models to estimate differences in treatment outcomes across groups with interaction terms to explore gender-specific differences associated with Plasmodium falciparum infection, hemoglobin, and grade point averages (GPA) based on standardized testing. Overall, 305 students contributed 4,564 observations. Compared with the control, SP plus artesunate and AQ plus artesunate reduced the odds of P. falciparum infection (odds ratio [OR]: 0.33, 95% CI: 0.26-0.43; OR: 0.46, 95% CI: 0.36-0.59). We found strong evidence of increased mean hemoglobin concentrations (g/dL) in the SP plus artesunate group versus control (difference +0.37, 95% CI: 0.13-0.58). Collectively, schoolchildren given AQ plus artesunate had higher mean GPA (difference +0.36, 95% CI: 0.02-0.69) relative to control. Schoolgirls, compared with schoolboys, given SP plus artesunate had greater improvement in GPA (+0.50, 95% CI: -0.02 to 1.02 versus -0.27, 95% CI: -0.71 to 0.16); interaction P = 0.048, respectively. The IPTsc decreases P. falciparum infections in schoolchildren. Treatment regimens that include longer-acting drugs may be more effective at decreasing malaria-related anemia and improving educational outcomes as observed among girls in this setting.

The Effect of Artemisinin-Based Drugs vs Non-artemisinin-based Drugs on Gametophyte Carrying in the Body After the Treatment of Uncomplicated Falciparum Malaria: A Systematic Review and Meta-analysis.

The WHO recommends Artemisinin-based combination therapy (ACTs) as the first-line treatment for malaria. This meta-analysis aims to analyze the effects of artemisinin and its derivatives as well as non-artemisinin drugs on the gametophytes in the host during the treatment of falciparum malaria. Fourteen studies were included in this analysis, and the artemisinin combination drugs involved were: artemether-lumefantrine (AL), artemisinin (AST), artemether-benflumetol (AB), dihydroartemisinin-piperaquine + trimethoprim + primaquine (CV8), amodiaquine + sulfadoxine-pyrimethamine (ASP), pyronaridine-phosphate + dihydroartemisinin (PP-DHA), dihydroartemisinin (DHA), and mefloquine + artesunate (MA), with 1702 patients. The control intervention measures involved the following: sulfadoxine-pyrimethamine (SP), mefloquine (MQ), atovaquone-proguanil (AT-PG), chloroquine + sulfadoxine-pyrimethamine (C-SP), quinine (Q), pyronaridine-phosphate (PP), pyronaridine (PN), and mefloquine + primaquine (MP), with 833 patients. The effect of ACTs was more obvious (OR = 0.37, 95%CI: 0.22–0.62, p < 0.05). In the control group of second malaria attacks, the difference between the two groups was not statistically significant (RD = 1.16, 95%CI: 0.81–1.66, p < 0.05); there was no significant difference in treatment failure during follow-up (RD = -0.01, 95%CI: 0.04–0.03, p < 0.05). There were also very few serious adverse events in both groups. ACTs showed good therapeutic effects in preventing gametocythemia but did not control the recrudescence rate and overall cure, which indicated the effectiveness of the combination of antimalarial drugs. Further research is required to explore which compatibility method is most conducive to the development of clinical malaria control.

Safety and effectiveness of antimalarial therapy in sickle cell disease: a systematic review and network meta-analysis

BackgroundAbout 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD children, there is limited data on the safety and effectiveness of the available antimalarial drugs used for prophylaxis. Also, previous systematic reviews have not provided quantitative measures of preventive effectiveness. The purpose of this research was to conduct a systematic review and meta-analysis of the available literature to determine the safety and effectiveness of antimalarial chemoprophylaxis used in SCD patients.MethodsWe searched in PubMed, Medline, CINAHL, POPLine and Cochrane library, for the period spanning January 1990 to April 2018. We considered randomized or quasi-randomized controlled trials comparing any antimalarial chemoprophylaxis to, 1) other antimalarial chemoprophylaxis, 2) placebo or 3) no intervention, in SCD patients. Studies comparing at least two treatment arms, for a minimum duration of three months, with no restriction on the number of patients per arm were reviewed. The data were extracted and expressed as odds ratios. Direct pairwise comparisons were performed using fixed effect models and the heterogeneity assessed using the I-square.ResultsSix qualified studies that highlighted the importance of antimalarial chemoprophylaxis in SCD children were identified. In total, seven different interventions (Chloroquine, Mefloquine, Mefloquine artesunate, Proguanil, Pyrimethamine, Sulfadoxine-pyrimethamine, Sulfadoxine-pyrimethamine amodiaquine) were evaluated in 912 children with SCD. Overall, the meta-analysis showed that antimalarial chemoprophylaxis provided protection against parasitemia and clinical malaria episodes in children with SCD. Nevertheless, the risk of hospitalization (OR = 0.72, 95% CI = 0.267–1.959; I2 = 0.0%), blood transfusion (OR = 0.83, 95% CI = 0.542–1.280; I2 = 29.733%), vaso-occlusive crisis (OR = 19, 95% CI = 1.713–2.792; I2 = 93.637%), and mortality (OR = 0.511, 95% CI = 0.189–1.384; I2 = 0.0%) did not differ between the intervention and placebo groups.ConclusionThe data shows that antimalarial prophylaxis reduces the incidence of clinical malaria in children with SCD. However, there was no difference between the occurrence of adverse events in children who received placebo and those who received prophylaxis. This creates an urgent need to assess the efficacy of new antimalarial drug regimens as potential prophylactic agents in SCD patients.Systematic review registrationPROSPERO (CRD42016052514).

Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

BackgroundArtemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness.MethodsA literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in sub-Saharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary endpoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions.ResultsIn total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether–lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin–piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30–2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10–2.64; 14,433 patients), and amodiaquine–sulfadoxine–pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21–3.96; 8863 patients. Artesunate–amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84–1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious.ConclusionsBased on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa.

Efficacy and safety of antimalarial combinations for treatment of uncomplicated malaria in children in Bangui, Central African Republic

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. 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. 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. 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.

Incidence of Malaria and Efficacy of Combination Antimalarial Therapies over 4 Years in an Urban Cohort of Ugandan Children

BackgroundCombination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda.Methodology/Principal FindingsChildren aged 1–10 years were enrolled from randomly selected households in 2004–05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen.Conclusions/SignificanceWith ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time.Trial Registrationisrctn.org ISRCTN37517549

Selection of Known Plasmodium falciparum Resistance-Mediating Polymorphisms by Artemether-Lumefantrine and Amodiaquine- Sulfadoxine-Pyrimethamine but Not Dihydroartemisinin- Piperaquine in Burkina Faso

Artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DP), and amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) offer excellent antimalarial efficacy but may select for parasite polymorphisms that decrease drug sensitivity. We evaluated the selection of known polymorphisms in genes encoding putative transporters (pfcrt and pfmdr1) and SP targets (pfdhfr and pfdhps) in parasites that caused new infections within 42 days of therapy for uncomplicated falciparum malaria in Burkina Faso. In 559 children in 2006, 42-day genotype-uncorrected failures were seen in 31.2% with AL, 11.8% with AQ-SP, and 7.6% with DP. After prior AL therapy, selection of wild-type sequences was seen for K76T in pfcrt (72.7% mixed or mutant results pretreatment versus 52.1% in new infections; P = 0.008) and N86Y (36.0% versus 18.7%; P = 0.025) and Y184F (66.7% versus 45.8%; P = 0.009) in pfmdr1. After prior AQ-SP therapy, selection of mutant sequences was seen for N51I (30.8% versus 61.5%; P = 0.05), C59R (28.2% versus 76.9%; P = 0.002), and S108N (30.8% versus 76.9%; P = 0.005) in pfdhfr. After prior DP therapy, selection was not seen for K76T (72.7% versus 77.8%; P = 0.96) in pfcrt or N86Y (36.0% versus 33.3%; P = 0.84), Y184F (66.7% versus 77.8%; P = 0.39), or D1246Y (9.3% versus 0%; P = 0.42) in pfmdr1. In 378 additional treatments with DP in 2007, 42-day uncorrected failure was seen in 10.9%. After prior DP, selection was again not seen for K76T (66.7% mixed or mutant results versus 59.5%; P = 0.43) in pfcrt or N86Y (38.7% versus 40.5%; P = 0.85), Y184F (67.6% versus 73.0%; P = 0.54), or D1246Y (3.6% versus 8.1%; P = 0.50) in pfmdr1. Despite its chemical similarity, piperaquine did not select for the same polymorphisms as chloroquine or AQ, suggesting different mechanisms of resistance.

Malaria: efficacy of amodiaquine-sulfadoxine-pyrimethamine, nutritional status and alellic variaton of CYP2C8 gen

Problem: Therapeutic response to antimalarials depends on multiple determinants associated with the parasite (species, mutations, parasitaemia, etc.) and the host (nutrition, genes, metabolism, etc.), but little is known about the host factors. Objectives: To evaluate in non-complicated falciparum malaria patients undergoing treatment with amodiaquine-sulfadoxine-pyrimethamine (AQ-SP), some relationships between treatment response, nutritional status and characteristics of the gen CYP2C8. Methodology: A randomly assigned, balanced, non blind, controlled clinical design. Treatment response was assessed according to WHO 1998 criteria. Analysis included anthropometry, plasma levels of retinol, ferritin and selenium, and assessment of 2C8*1 (wild), 2C8*2 (Il29F) and 2C8*3 variants of CYP2C8 (R139K y K399R).Results: 33 patients were studied, all of them evidenced adequate treatment response, 10% had retinol deficiency, 25% selenium deficiency and 40% low ferritine levels. One patient exhibited the variant Il29F of CYP2C8*2 in a heterozygous fashion, the remaining individuals were homozygous for the wild form of this gene. The mutant R139K of CYP2C8*3 was absent in all individuals. Amplification fragments obtained of K339R (CYP2C8*3 gen) were not suitable for digestion, regardless of the modifications performed. These results confirm previous findings made in 22% of 23 patients in whom some variation was observed (5 in CYP2C8*2 and 2 in CYP2C8*3). For CYP2C8*3 the mutant R139K, was observed in 2 individuals. Conclusion: only one of the 33 patients (3%) had CYP2C8*2 in a heterozygous fashion, the remaining were homozygous for the wild allele of this variant. None of the patients had the mutation R139K of the CYP2C8*3 variant. This is a novel report for Latin America.

Adherence and effectiveness of drug combination in curative treatment among children suffering uncomplicated malaria in rural Senegal

Increased Plasmodium falciparum resistance to chloroquine has prompted national malaria programs to develop new policies in several African countries. Less than a year after the introduction of amodiaquine/sulfadoxine-pyrimethamine (AQ/SP) as first-line treatment in Senegal, we examined adherence rates to therapy and its efficacy among children. The study was conducted in five dispensaries in rural Senegal. Children aged 2-10 years with a presumptive diagnosis of malaria were prescribed AQ/SP. Thick blood film analyses were carried out on days 0, 3, 7, 14 and 28. Blood and urine samples were collected on day 3 for drug level measurements. The principal caregivers were questioned on treatment adherence. Among the 289 recruited children, 144 had a parasitemia >2500/microl. The results demonstrated markedly good efficacy for the treatment, as no detectable parasitemia was observed on day 28 for 97.9% of the children. However, we noticed that 35.3% of children did not comply with the recommended doses and 62.3% did not exactly adhere to the drug schedule. Despite the good efficacy of the drugs, adherence to the therapeutic scheme was poor. Strategies to promote patient adherence would improve drug performance and thus might help to prevent the rapid emergence of drug resistance.

Low Efficacy of Amodiaquine or Chloroquine Plus Sulfadoxine-Pyrimethamine against Plasmodium falciparum and P. vivax Malaria in Papua New Guinea

Because of increasing resistance to 4-aminoquinolines in Papua New Guinea, combination therapy of amodiaquine (AQ) or chloroquine (CQ) plus sulfadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000. The purpose of this study was to monitor in vivo efficacy of the current standard combination therapy against Plasmodium falciparum and P. vivax malaria. Studies were conducted between 2003 and 2005 in the Simbu, East Sepik, and Madang Provinces in Papua New Guinea according to the revised protocol of the World Health Organization (WHO) for assessment of antimalarial drug efficacy. Children between six months and seven years of age with clinically overt and parasitologically confirmed P. falciparum or P. vivax malaria were treated according to the new policy guidelines (i.e., AQ plus SP given to patients weighing < 14 kg and CQ plus SP given to patients weighing < 14 kg). Children were monitored up to day 28 and classified according to clinical and parasitological outcome as adequate clinical and parasitological response (ACPR), early treatment failure (ETF), late clinical failure (LCF), or late parasitological failure (LPF). For P. falciparum malaria, polymerase chain reaction (PCR)-corrected treatment failure rates up to day 28 ranged between 10.3% and 28.8% for AQ plus SP and between 5.6% and 28.6% for CQ plus SP, depending on the region and the year of assessment. Overall treatment failure rate with AQ or CQ plus SP for P. vivax malaria was 12%. Our results suggest that the current first-line treatment in Papua New Guinea is not sufficiently effective. According to the new WHO guidelines for the treatment of malaria, a rate of parasitological resistance greater than 10% in the two dominant malaria species in the country justifies a change in treatment policy.

Malaria 2007—Progressing Research, Persisting Challenges

MALARIA REMAINS A LEADING CAUSE OF MORBIDity and mortality globally. An estimated 3 billion individuals live in areas of risk and the disease causes more than 1 million deaths annually. Even in the United States, where endemic malaria has been eradicated for decades, an average of 1200 cases are reported annually. The articles in this issue of JAMA on malaria address a number of important issues, including the financial and logistic challenges of implementing new technologies for disease prevention and diagnosis; improvement in understanding risk factors and disease severity, particularly in children; and treatment and surveillance approaches in the face of evolving drug resistance. The diagnosis and management of malaria in endemic areas have tremendous financial impact. As Feachem and Sabot outline in their Commentary in this issue of JAMA, there is currently a resurgence of interest in the burden of malaria and possibilities for its control. The ambitious target set by the Roll Back Malaria Partnership of 50% mortality reduction by 2010 will be challenging to accomplish and will require leadership, management, and funding. Miller and colleagues also address the challenges of achieving the targets set by the Roll Back Malaria Partnership. The authors used data available from national surveys to estimate the number of insecticide-treated bed nets needed to achieve 80% coverage of pregnant women and children. They found that although more than 53% of households had nets available, between 130 million and 264 million nets are required to achieve target coverage. In addition, once the target is achieved, maintaining this target (assuming the life span of an insecticide-treated net is 4 years) would require an additional 37 million nets annually. These findings highlight the fiscal and logistic challenges of care delivery models in the developing countries where malaria is most common. Improving access to accurate diagnosis is no less challenging, as highlighted by Hamer and colleagues. Rapid antigen-detection diagnostic tests (RDTs) are frequently championed as a potential mechanism to improve reliable diagnosis of malaria and decrease inappropriate antimalarial use. However, relatively little is known about how these tests function in real-life circumstances. In this cross-sectional study from Zambia, the use of microscopy and RDTs was considered at a time when a national campaign to increase their use was ongoing. The authors found that despite the national initiative, microscopy and RDT were underused and, when used, still resulted in a high proportion of patients receiving antimalarial therapy despite a negative test result. The authors call for a shift away from empirical treatment that ignores test results and for an increase in education of clinicians on the rational use of artemisinin-based combination therapies. Globally, children account for a substantial proportion of the annual deaths from malaria. Several articles in this issue of JAMA highlight the burden of malaria in the world’s children. Idro and colleagues studied children with falciparum malaria admitted to a Kenyan hospital over a 12year period, with a focus on improving the understanding of neurological manifestations. Almost half the children had neurological involvement, most commonly seizures. In addition, children with neurological involvement had greater mortality compared with those without, and just over 2% had lasting impairment. May and colleagues also considered severe falciparum malaria in children in their examination of the association of disease manifestations with the hemoglobin variants C, S, and -thalassemia. These investigators found that among children in Ghana with severe falciparum malaria, the hemoglobin S carrier state was negatively associated with all forms of severe malaria, consistent with older literature; the hemoglobin C carrier state was negatively associated with cerebral malaria; and -thalassemia trait was negatively associated with severe anemia due to falciparum malaria. The findings of these 2 studies add to current understanding of the pathophysiology of severe malaria in children. Given the increase in resistance to antimalarial agents, combination therapy is generally advocated as first-line treatment of malaria in Africa for both adults and children. Dorsey and colleagues compared 3 treatment regimens among children in Uganda who had uncomplicated falciparum malaria: amodiaquine sulfadoxine-pyrimethamine, amodiaquine artesunate, and artemether-lumefantrine. While the artemether-lumefantrine combination was the most efficacious, prompt delivery of treatment provided

Chloroquine or amodiaquine combined with sulfadoxine–pyrimethamine for uncomplicated malaria: a systematic review

To compare the efficacies against uncomplicated falciparum malaria of chloroquine (CQ), amodiaquine (AQ), sulfadoxine-pyrimethamine (SP) and combinations of these inexpensive drugs. We searched Medline, Embase, Cochrane CENTRAL Register of Controlled Trials, BIOSIS, Web of Science, African Index Medicus, DARE, Digital Dissertations and Current Controlled Trials for randomised or quasi-randomised controlled trials conducted between 1991 and June 2004 regardless of language and geography. We also contacted malaria experts, searched reference lists, and contacted individual authors for unreported study characteristics and additional data. Unpublished data were sought and included in the analyses. Thirteen randomised trials (n = 4248) were identified and the summary relative risks of treatment failure at 28 days were calculated. There was marginal benefit in adding CQ to SP, compared with SP monotherapy (RR = 0.74, 95% CI 0.54-1.02). Combining AQ with SP was associated with a significantly lower risk of treatment failure than SP monotherapy (RR = 0.35, 95% CI 0.15-0.82) and AQ monotherapy (RR = 0.59, 95% CI 0.42-0.83). AQ plus SP was associated with a significantly lower risk of treatment failure than CQ plus SP (RR = 0.42, 95% CI 0.25-0.72). Serious adverse events were rare and did not increase with combination therapy. Amodiaquine plus SP remains an efficacious, affordable and safe option for treating malaria in certain settings.