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BackgroundChlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure.Methods1238 children aged 6 months to 10 years with uncomplicated malaria were randomized to receive CD or artemether-lumefantrine (AL) and followed for 28 days. The first dose was supervised, subsequent doses given unsupervised at home. G6PD genotype was determined to assess the interaction between treatment and G6PD status in their effects on anaemia. The main endpoints were clinical treatment failure by day 28, incidence of severe anaemia (HbFindingsOne third of patients treated with AL, and 6% of patients treated with CD, did not complete their course of medication. 18% (109/595) of children treated with CD and 6.1% (36/587) with AL required rescue medication within 4 weeks, risk difference 12% (95%CI 8.9%-16%). 23 children developed severe anaemia (17 (2.9%) treated with CD and 6 (1.0%) with AL, risk difference 1.8%, 95%CI 0.3%-3.4%, P = 0.02). Haemoglobin concentration on day 3 was lower among children treated with CD than AL (difference 0.43 g/dL, 95% CI 0.24 to 0.62), and within the CD group was lower among those children who had higher parasite density at enrollment. Only 17 out of 1069 children who were typed were G6PD A- deficient, of these 2/9 treated with CD and 1/8 treated with AL developed severe anaemia. 5/9 treated with CD had a fall of 2 g/dL or more in haemoglobin concentration by day 3.InterpretationAL was well tolerated and highly effective and when given under operational conditions despite poor adherence to the six-dose regimen. There were more cases of severe malaria and anaemia after CD treatment although G6PD deficiency was uncommon.Trial registrationClinicaltrials.gov NCT00118794.

Summary Background Malaria is a major cause of morbidity and mortality in Africa. International effort and funding for control has been stepped up, with substantial increases from 2003 in the delivery of malaria interventions to pregnant women and children younger than 5 years in The Gambia. We investigated the changes in malaria indices in this country, and the causes and public-health significance of these changes. Methods We undertook a retrospective analysis of original records to establish numbers and proportions of malaria inpatients, deaths, and blood-slide examinations at one hospital over 9 years (January, 1999–December, 2007), and at four health facilities in three different administrative regions over 7 years (January, 2001–December, 2007). We obtained additional data from single sites for haemoglobin concentrations in paediatric admissions and for age distribution of malaria admissions. Findings From 2003 to 2007, at four sites with complete slide examination records, the proportions of malaria-positive slides decreased by 82% (3397/10861 in 2003 to 337/6142 in 2007), 85% (137/1259 to 6/368), 73% (3664/16932 to 666/11333), and 50% (1206/3304 to 336/1853). At three sites with complete admission records, the proportions of malaria admissions fell by 74% (435/2530 to 69/1531), 69% (797/2824 to 89/1032), and 27% (2204/4056 to 496/1251). Proportions of deaths attributed to malaria in two hospitals decreased by 100% (seven of 115 in 2003 to none of 117 in 2007) and 90% (22/122 in 2003 to one of 58 in 2007). Since 2004, mean haemoglobin concentrations for all-cause admissions increased by 12 g/L (85 g/L in 2000–04 to 97 g/L in 2005–07), and mean age of paediatric malaria admissions increased from 3·9 years (95% CI 3·7–4·0) to 5·6 years (5·0–6·2). Interpretation A large proportion of the malaria burden has been alleviated in The Gambia. Our results encourage consideration of a policy to eliminate malaria as a public-health problem, while emphasising the importance of accurate and continuous surveillance. Funding UK Medical Research Council.

Cally Roper and colleagues analyze the distribution of sulfadoxine resistance mutations and flanking microsatellite loci to trace the emergence and dispersal of drug-resistant Plasmodium falciparum malaria in Africa., Background Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution. Methods and Findings We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations. Conclusions Resistant dhps has emerged independently in multiple sites in Africa during the past 10–20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns., Editors' Summary Background Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year, mostly in sub-Saharan Africa. People become infected with P. falciparum when they are bitten by a mosquito that has acquired the parasite in a blood meal taken from an infected person. P. falciparum malaria, which is characterized by recurring fevers and chills, anemia (loss of red blood cells), and damage to vital organs, can be fatal within hours of symptom onset if untreated. Until recently, treatment in Africa relied on chloroquine and sulfadoxine–pyrimethamine. Unfortunately, parasites resistant to both these antimalarial drugs is now widespread. Consequently, the World Health Organization currently recommends artemisinin combination therapy for the treatment of P. falciparum malaria in Africa and other places where drug-resistant malaria is common. In this therapy, artemisinin derivatives (new fast-acting antimalarial agents) are used in combination with another antimalarial to reduce the chances of P. falciparum becoming resistant to either drug. Why Was This Study Done? P. falciparum becomes resistant to antimalarial drugs by acquiring “resistance mutations,” genetic changes that prevent these drugs from killing the parasite. A mutation in the gene encoding a protein called the chloroquine resistance transporter causes resistance to chloroquine, a specific group of mutations in the dihydrofolate reductase gene causes resistance to pyrimethamine, and several mutations in dhps, the gene that encodes dihydropteroate synthase, are associated with resistance to sulfadoxine. Scientists have discovered that the mutations causing chloroquine and pyrimethamine resistance originated in Asia and spread into Africa (probably multiple times) in the late 1970s and mid-1980s, respectively. These Asian-derived mutations are now common throughout Africa and, consequently, it is not possible to determine how they spread across the continent. Information of this sort would, however, help experts design effective measures to control the spread of drug-resistant P. falciparum. Because the mutations in dhps that cause sulfadoxine resistance only began to emerge in the mid-1990s, they haven't spread evenly across Africa yet. In this study, therefore, the researchers use genetic methods to characterize the geographical origins and contemporary distribution of dhps resistance mutations in Africa. What Did the Researchers Do and Find? The researchers analyzed dhps mutations in P. falciparum DNA from blood samples collected from patients with malaria in various African countries and searched the scientific literature for other similar studies. Together, these data show that five major variant dhps sequences (three of which contain mutations that confer various degrees of resistance to sulphadoxine in laboratory tests) are currently present in Africa, each with a unique geographical distribution. In particular, the data show that P. falciparum parasites in east and west Africa carry different resistance mutations. Next, the researchers looked for microsatellite variants in the DNA flanking the dhps gene. Microsatellites are DNA regions that contain short, repeated sequences of nucleotides. Because the number of repeats can vary and because microsatellites are inherited together with nearby genes, the ancestry of various resistance mutations can be worked out by examining the microsatellites flanking different mutant dhps genes. This analysis revealed five regional clusters in which the same resistance lineage was present at all the sites examined within the region and also showed that the resistance mutations in east and west Africa have a different ancestry. What Do These Findings Mean? These findings show that sulfadoxine-resistant P. falciparum has recently emerged independently at multiple sites in Africa and that the molecular basis for sulfadoxine resistance is different in east and west Africa. This latter result may have clinical implications because it suggests that the effectiveness of sulfadoxine as an antimalarial drug may vary across the continent. Finally, although many more samples need to be analyzed to build a complete picture of the spread of antimalarial resistance across Africa, these findings suggest that economic and transport infrastructures may have played a role in governing recent parasite dispersal across this continent by affecting human migration. Thus, coordinated malaria control campaigns across socioeconomically linked areas in Africa may reduce the African malaria burden more effectively than campaigns that are confined to national territories. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000055. This study is further discussed in a PLoS Medicine Perspective by Tim Anderson The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish) Information is available from the World Health Organization on malaria (in several languages) and on drug-resistant malaria The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish) Information is available from the Roll Back Malaria Partnership on its approach to the global control of malaria, and on malaria control efforts in specific parts of the world The WorldWide Antimalarial Resistance Network is creating an international database about antimalarial drug resistance

Objectives: In the Gambia, chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) is the first-line antimalarial treatment. Plasmodium falciparum parasites carrying mutations associated with resistance to each of these drugs were present in 2001 but did not cause a significant loss of therapeutic efficacy among children receiving the combination CQ/SP. We measured their effect on parasite transmission to Anopheles gambiae mosquitoes. Design: We conducted a single-blind, randomised, controlled trial with follow-up over 28 d. Mosquito feeding experiments were carried out 7, 10, or 14 d after treatment. Setting: The study took place in the town of Farafenni and surrounding villages in the Gambia. Participants: Participants were 500 children aged 6 mo to 10 y with uncomplicated P. falciparum malaria. Interventions: Children were randomised to receive CQ, SP, or CQ/SP. Outcome Measures: Outcomes related to transmission were determined, including posttreatment gametocyte prevalence and density. Infectiousness was assessed by membrane-feeding A. gambiae mosquitoes with blood from 70 gametocyte-positive patients. Mutations at seven loci in four genes associated with drug resistance were measured pre- and posttreatment and in the midguts of infected mosquitoes. Results: After SP treatment, the infectiousness of gametocytes was delayed, compared to the other two treatment groups, despite comparable gametocyte densities. Among bloodmeal gametocytes and the midguts of infected mosquitoes, the presence of the four-locus multidrug-resistant haplotype TYRG (consisting of mutations pfcrt-76T, pfmdr1-86Y, pfdhfr-59R, and pfdhps-437G) was associated with significantly higher oocyst burdens after treatment with the combination CQ/SP. Conclusions: Parasites with a multidrug-resistant genotype had a substantial transmission advantage after CQ/SP treatment but did not have a significant impact on in vivo efficacy of this drug combination. Protocols that include measuring transmission endpoints as well as therapeutic outcomes may be a useful strategy when monitoring the evolution of drug resistance in malaria parasites in vivo., Editorial Commentary Background: In an accompanying paper published in PLoS Clinical Trials [15], the investigators report the effects of treating uncomplicated malaria in young children in the Gambia with the combination of chloroquine and sulfadoxine-pyrimethamine, as compared to either treatment individually. As an addition to the main trial results, the researchers also wanted to find out how the different treatment regimens affected the ability of the malaria parasite to generate sexual forms (gametocytes) in the participants' blood, and to what extent the parasites are then transmitted to mosquitoes. The researchers also tested whether malaria parasites had a specific genotype, termed TYRG, comprising mutations in four distinct genes associated with resistance to chloroquine and sulfadoxine-pyrimethamine, and whether that affected transmission of the parasites back to mosquitoes. What the trial shows: In this trial it was found that children treated with chloroquine and sulfadoxine-pyrimethamine were no more or less likely to carry sexual forms of the malaria parasite compared to children treated with chloroquine, over 28 days of follow-up. Transmission of the malaria parasites back to mosquitoes also did not differ significantly between children treated with chloroquine and sulfadoxine-pyrimethamine versus chloroquine alone. Parasites bearing the TYRG genotype, associated with drug resistance, were more likely to be transmitted to mosquitoes from children treated with chloroquine/sulfadoxine-pyrimethamine than from chloroquine treated children. Strengths and limitations: The addition of data about parasite transmission within the setting of a randomized trial is valuable and can provide information about the evolution of drug resistance. However, the results may not completely represent the current situation, as the trial was originally conducted in 2001 and levels of resistance may now be higher in the Gambia. Contribution to the evidence: This follow-up study to a randomized trial provides additional evidence that treatment with chloroquine and sulfadoxine-pyrimethamine, as compared to chloroquine, does not reduce the extent to which malaria parasites can produce sexual forms and transmit them back to mosquitoes. The finding that parasites bearing the TYRG genotype are more likely than other parasites to be transmitted back to mosquitoes following chloroquine and sulfadoxine-pyrimethamine treatment is also novel.

Objectives: Treatment of Plasmodium falciparum malaria with sulfadoxine-pyrimethamine (SP) is followed by a sharp rise in the prevalence and density of gametocytes. We did a randomized trial to determine the effect of treatment of asymptomatic infections with SP or SP plus one dose of artesunate (SP+AS) on gametocyte carriage. Design: The study was a three-arm open-label randomized trial. We randomized asymptomatic carriers of P. falciparum to receive antimalarial treatment or placebo, and recorded the prevalence and density of gametocytes over the next 2 mo. Setting: The trial was conducted during the dry (low malaria transmission) season in four rural villages in Gambia. Participants: Participants were adults and children aged over 6 mo with asexual P. falciparum infection and confirmed free of clinical symptoms of malaria over a 2-d screening period. Interventions: Participants were randomized to receive a single dose of SP or SP+AS or placebo. Outcome Measures: The outcome measures were the presence of gametocytes 7 and 56 d after treatment, and the duration and density of gametocytaemia over 2 mo. Results: In total, 372 asymptomatic carriers were randomized. Gametocyte prevalence on day 7 was 10.5% in the placebo group, 11.2% in the SP group (risk difference to placebo 0.7%, 95% confidence interval −7.4% to 8.7%, p = 0.87), and 7.1% in the SP+AS group (risk difference to placebo 4.1%, 95% confidence interval −3.3% to 12%, p = 0.28). By day 56, gametocyte prevalence was 13% in the placebo group and 2% in both drug-treated groups. Gametocyte carriage (the area under the curve of gametocyte density versus time), was reduced by 71% in the SP group, and by 74% in the SP+AS group, compared to placebo. Gametocyte carriage varied with age and was greater among children under 15 than among adults. Conclusions: Treatment of asymptomatic carriers of P. falciparum with SP does not increase gametocyte carriage or density. Effective treatment of asexual parasitaemia in the dry season reduces gametocyte carriage to very low levels after 4 wk., Editorial Commentary Background: During the life cycle of the Plasmodium falciparum malaria parasite, some parasites differentiate into sexual stages (gametocytes) in the blood of infected people. Gametocytes are the transmissible stage of the parasite that can infect the mosquito when it takes a blood meal from an infected person. In people with clinical signs of malaria, treatment with commonly used antimalarial drugs such as chloroquine or sulfadoxine-pyrimethamine is often followed by a rise in the numbers of gametocytes in the blood, but it is not known to what extent this is caused by the drugs themselves. The effects of different antimalarial treatments on gametocytes have generally not been well studied in trials, and particularly not in individuals who are infected with malaria but don't show clinical signs (i.e., asymptomatic carriers). However, it is important to know the effects of different malaria drugs on gametocytes, because this will help predict how parasites are likely to evolve resistance to drugs. In particular, the effects on asymptomatic carriers are interesting because of the potential benefit of giving preventive treatments to all children or adults (whether or not they have symptoms) for malaria control. The trial from Gambia reported here was conducted in adults and children over 6 mo of age who were infected with P. falciparum malaria but free from clinical symptoms. Participants were randomized to receive either sulfadoxine-pyrimethamine, sulfadoxine-pyrimethamine and artesunate, or placebo. The researchers wanted to look at the effect of these treatments on numbers of gametocytes in the participants' blood samples seven days after treatment (the primary outcome) and then up to 56 days after treatment. What this trial shows: Seven days after treatment, the researchers found that the proportion of participants carrying malaria gametocytes in the groups treated with sulfadoxine-pyrimethamine or sulfadoxine-pyrimethamine and artesunate was similar to the proportion in the placebo group. A secondary objective of the study was to look at overall gametocyte load over 56 days following treatment, by measuring the area under the curve plotting gametocyte density against time. For this secondary objective, the researchers found that gametocyte load was highest in the placebo group, and substantially lower in the groups treated with sulfadoxine-pyrimethamine or sulfadoxine-pyrimethamine and artesunate. Therefore, there was no evidence that treatment with sulfadoxine-pyrimethamine increased gametocytes in the blood of children infected with malaria but without symptoms. Strengths and limitations: In this trial, screening tests to detect malaria infection and symptoms were done twice prior to enrolling participants into the trial, with a two-day window between tests. This procedure increased the chance of detecting individuals with clinical malaria so they could be excluded from the trial and treated for malaria. The use of a placebo arm in the trial, which adds to the strength of the study, could therefore be defended ethically. The conduct of this trial in a region with seasonal transmission of malaria limits the extent to which the findings can be generalized to other regions. Contribution to the evidence: This trial provides data on the extent to which treatment with sulfadoxine-pyrimethamine or sulfadoxine-pyrimethamine and artesunate affects gametocyte levels in people infected with malaria, but without symptoms. It had previously been thought that sulfadoxine-pyrimethamine increased gametocyte carriage, but this had not been formally tested in a placebo-controlled study. The results show that both treatments reduce overall gametocyte load to very low levels over a period of 56 days after treatment, as compared to placebo.

Objectives: In the Gambia, the combination of chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) has replaced CQ monotherapy for treatment of malaria caused by Plasmodium falciparum. We measured the efficacy of the combination CQ/SP, and the prevalence of parasites carrying alleles associated with resistance to CQ or SP. Design: We conducted a single-blind, randomised, controlled trial to compare the efficacy of CQ/SP to that of SP or CQ alone. Setting: The study took place in the town of Farafenni and surrounding villages in the Gambia. Participants: Participants were children aged 12 mo to 10 y presenting as outpatients with uncomplicated P. falciparum malaria. Interventions: 500 children were randomised to receive CQ, SP, or CQ/SP as supervised treatment and actively followed over 28 d. Outcome Measures: Primary outcome was parasitaemia at any time during follow-up. Secondary outcomes were PCR-confirmed recrudescent infections among treatment failures, and clinical failure requiring rescue medication by day 28. Pretreatment parasite isolates from 161 patients were tested for the presence of resistance-associated genetic markers. Results: The prevalence of parasitological failure by day 28 for the CQ group was 60.3%, compared to 17.6% for SP (odds ratio [OR], 0.106; 95% confidence interval [CI], 0.057–0.194; p < 0.001) and 13.9% for CQ/SP (OR versus CQ, 0.140; 95% CI, 0.078–0.250; p < 0.001). There was no difference between the SP and CQ/SP groups (OR, 1.324; 95% CI, 0.705–2.50). The projected prevalence of PCR-corrected treatment failure was 30.2, 6.06, and 3.94% in the CQ, SP, and CQ/SP groups, respectively. The pfdhfr-triple mutant and pfdhps-437G mutation were common, with prevalences of 67.4 and 51.2%, respectively. Pretreatment carriage of pfdhps-437G and of multidrug-resistant parasite genotypes was associated with treatment failure in the SP group, but not in the CQ or CQ/SP groups. Conclusions: The combination of CQ/SP was an efficacious treatment for uncomplicated malaria in Gambian children in this study, but the frequent occurrence of multidrug-resistant parasites suggests that this observed efficacy is not sustainable., Editorial Commentary Background: Throughout Africa, the readily available and cheap antimalarial drug, chloroquine, has been failing as a good first-line treatment for uncomplicated malaria. This is mainly due to the malaria parasite becoming resistant to treatment. Many African countries are now adopting newer artemisinin-based combination therapies as first-line treatment. However other countries have put interim solutions in place before introducing artemisinin-based drugs. The combination of chloroquine and sulfadoxine-pyrimethamine was officially adopted as first-line therapy in the Gambia in 2004. However, little data exists on the efficacy of this combination in that setting. It is also not known whether parasites resistant to sulfadoxine-pyrimethamine, as well as chloroquine, are common in the Gambia. In this trial, conducted in a rural town in the Gambia in 2001, the researchers randomized 500 young children presenting with uncomplicated P. falciparum malaria to receive either chloroquine, sulfadoxine-pyrimethamine, or the combination of both treatments. The researchers then looked for the presence of parasites in the blood of treated children over 28 days of follow-up. Infections following treatment were defined as either the same infection that was originally treated (a recrudescence) or a new infection. The need for rescue medication, indicating clinical failure, was also examined. What the trial shows: In this trial, both sulfadoxine-pyrimethamine and the combination of chloroquine and sulfadoxine-pyrimethamine were more effective at clearing parasites from the blood than chloroquine alone. However the combination of chloroquine and sulfadoxine-pyrimethamine appeared to be equivalent to sulfadoxine-pyrimethamine in clearing parasite infection. When the researchers distinguished parasite infections into recrudescences or new infections, they found that either treatment option containing sulfadoxine-pyrimethamine prevented a recurrence of the original infection better than treatment with chloroquine. Clinical failure was also higher amongst children treated with chloroquine than those treated with sulfadoxine-pyrimethamine alone or the combination. In children treated with chloroquine and sulfadoxine-pyrimethamine, parasite infection was found in 14% of participants at 28 days of follow-up. A number of children carried parasites predicted to be resistant to both chloroquine and sulfadoxine-pyrimethamine. However, these children were not significantly more likely to fail treatment. Strengths and limitations: The trial took place in an area where there is, to date, little data on the efficacy of the different treatment regimens studied. The trial is also part of an ongoing series of other studies, which will ultimately allow researchers to detect changes in the efficacy of different treatments over time, providing information about parasite selection and the useful therapeutic life of particular treatments. However, the loss to follow-up in this trial was high (between 25 and 32%, depending on the treatment arm) due to logistical constraints around the time of the Gambian national election. It is not possible to tell if data from the participants lost to follow-up would have changed the overall conclusions. Contribution to the evidence: This study provides additional data about the efficacy of chloroquine / sulfadoxine-pyrimethamine treatment in the Gambia, as compared to chloroquine or sulfadoxine-pyrimethamine alone. Prior evidence was not strong enough to confirm the advantage of chloroquine / sulfadoxine-pyrimethamine over chloroquine alone. The identification of parasites resistant to both chloroquine and sulfadoxine-pyrimethamine indicates that new combination drugs are needed in this part of Africa.