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Background: In Zambia, malaria is one of the leading causes of morbidity and mortality, especially among under five children and pregnant women. For the latter, the World Health Organization recommends the use of artemisinin-based combination therapy (ACT) in the second and third trimester of pregnancy. In a context of limited information on ACT, the safety and efficacy of three combinations, namely artemether-lumefantrine (AL), mefloquine-artesunate (MQAS) and dihydroartemisinin-piperaquine (DHAPQ) were assessed in pregnant women with malaria. Methods: The trial was carried out between July 2010 and August 2013 in Nchelenge district, Luapula Province, an area of high transmission, as part of a multi-centre trial. Women in the second or third trimester of pregnancy and with malaria were recruited and randomized to one of the three study arms. Women were actively followed up for 63 days, and then at delivery and 1 year post-delivery. Results: Nine hundred pregnant women were included, 300 per arm. PCR-adjusted treatment failure was 4.7% (12/258) (95% CI 2.7-8.0) for AL, 1.3% (3/235) (95% CI 0.4-3.7) for MQAS and 0.8% (2/236) (95% CI 0.2-3.0) for DHAPQ, with significant risk difference between AL and DHAPQ (p = 0.01) and between AL and MQAS (p = 0.03) treatments. Re-infections during follow up were more frequent in the AL (HR: 4.71; 95% CI 3.10-7.2; p < 0.01) and MQAS (HR: 1.59; 95% CI 1.02-2.46; p = 0.04) arms compared to the DHAPQ arm. PCR-adjusted treatment failure was significantly associated with women under 20 years [Hazard Ratio (HR) 5.35 (95% CI 1.07-26.73; p = 0.04)] and higher malaria parasite density [3.23 (95% CI 1.03-10.10; p = 0.04)], and still women under 20 years [1.78, (95% CI 1.26-2.52; p < 0.01)] had a significantly higher risk of re-infection. The three treatments were generally well tolerated. Dizziness, nausea, vomiting, headache and asthenia as adverse events (AEs) were more common in MQAS than in AL or DHAPQ (p < 0.001). Birth outcomes were not significantly different between treatment arms. Conclusion: As new infections can be prevented by a long acting partner drug to the artemisinins, DHAPQ should be preferred in places as Nchelenge district where transmission is intense while in areas of low transmission intensity AL or MQAS may be used.

Background Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to malaria control and elimination. The parasite has developed resistance to every anti-malarial drug introduced for wide-scale treatment. However, the spread of resistance may be reversible. Malawi was the first country to discontinue chloroquine use due to widespread resistance. Within a decade of the removal of drug pressure, the molecular marker of chloroquine-resistant malaria had disappeared and the drug was shown to have excellent clinical efficacy. Many countries have observed decreases in the prevalence of chloroquine resistance with the discontinuation of chloroquine use. In Zambia, chloroquine was used as first-line treatment for uncomplicated malaria until treatment failures led the Ministry of Health to replace it with artemether-lumefantrine in 2003. Specimens from a recent study were analysed to evaluate prevalence of chloroquine-resistant malaria in Nchelenge district a decade after chloroquine use was discontinued. Methods Parasite DNA was extracted from dried blood spots collected by finger-prick in pregnant women who were enrolling in a clinical trial. The specimens underwent pyrosequencing to determine the genotype of the P. falciparum chloroquine resistance transporter, the gene that is associated with CQ resistance. Results Three-hundred and two specimens were successfully analysed. No chloroquine-resistant genotypes were detected. Conclusion The study found the disappearance of chloroquine-resistant malaria after the removal of chloroquine drug pressure. Chloroquine may have a role for malaria prevention or treatment in Zambia and throughout the region in the future.

Background Plasmodium falciparum ( Pf ) resistance to anti-malarial drugs remains a major hindrance to malaria control and elimination. Pf has developed resistance to nearly all antimalarial drugs including chloroquine, the first most frequently used first-line treatment for uncomplicated malaria. In Zambia, chloroquine was used as treatment for uncomplicated malaria for a long time until Pf -developed resistance and rose to as high as 60% in some parts of the country. This prompted the Ministry of Health to effect a drug policy change in 2003. Recent reports have indicated recovery of chloroquine susceptibility in neighbouring like Malawi, Mozambique and Tanzania. To update the information on chloroquine sensitivity in Zambia we conducted a study that assessed the prevalence of mutant Pf in Nchelenge district 10 years post chloroquine withdrawal. Methods Dried blood spots for this study were collected from finger-prick blood of consenting pregnant women. Deoxyribonucleic acid (DNA) was extracted and genotyped for Pf crt-76 resistance marker using specific primers in a nested polymerase chain reaction (PCR). The PCR products obtained were then pyrosequenced and read using PyroMarkTM Q96MD software. The wild-type 3D7 and Dd2 were used as wild-type and mutated controls. Results No chloroquine resistance mutation, Pfcrt 76T was detected in any of the 302 samples that were successfully amplified. This represents a 100% prevalence of Pf that are sensitive to chloroquine in the study population. Conclusions This study demonstrates a total return of chloroquine-sensitive Pf in Nchelenge after over a decade of withdrawal of chloroquine. In combination with another drug, chloroquine could be a good substitute for the currently used artemether lumefantrine, and intermittent preventive treatment in pregnancy (IPTp) and children.

Background In Zambia, malaria is one of the leading causes of morbidity and mortality, especially among under five children and pregnant women. For the latter, WHO recommends the use of Artemisinin-based Combinations Treatments (ACTs) in the second and third trimester of pregnancy. In a context of limited information on ACTs, the safety and efficacy of three ACTs, namely artemether-lumefantrine (AL), mefloquine-artesunate (MQAS) and dihydroartemisinin-piperaquine (DHAPQ) were assessed in malaria-infected pregnant women. Methods Trial was carried out between July 2010 and August 2013 in Nchelenge district, Luapula Province, an area of high transmission, as part of multi-centre trial. Women in second or third trimester of pregnancy and with malaria were recruited and randomized to one of three study arms. Women were actively followed up for 63 days, and then at delivery and one year post-delivery. Results Nine hundred pregnant women were included, 300 per arm. PCR-adjusted treatment failure was 4.7% (12/258) (95%CI:2.7–8.0) for AL, 1.3% (3/235) (95%CI:0.4–3.7) for MQAS and 0.8% (2/236) (95%CI:0.2–3.0) for DHAPQ, with significant risk difference between AL and DHAPQ (p=0.01) and between AL and MQAS (p=0.03) treatments. New infections during follow up were more frequent in AL (Hazard Ratio (HR):4.70; 95%CI:3.18–6.94; p

The Four Artemisinin-Based Combinations (4ABC) Study Group reports a randomized, non-inferiority trial comparing the efficacy and safety of four ACTs in children with mild Plasmodium falciparum malaria from seven sub-Saharan African countries., 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 Please see later in the article for the Editors' Summary, Editors' Summary Background Malaria is a global public-health problem. Half the world's population is at risk of this mosquito-borne parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Although several parasites cause malaria, Plasmodium falciparum is responsible for most of these deaths. During the second half of the 20th century, the main treatments for malaria were inexpensive “monotherapies” such as chloroquine and sulfadoxine-pyrimethamine. Unfortunately, the malaria parasite quickly developed resistance to many of these monotherapies, and in the 1990 s, there was a widespread upsurge in P. falciparum malaria. To combat this increase, the World Health Organization (WHO) now recommends artemisinin-based combination therapy (ACT) for first-line treatment of P. falciparum malaria in all regions where there is drug-resistant malaria. In ACT, artemisinin derivatives (new, fast-acting antimalarial drugs) are used in combination with another antimalarial drug (a partner drug) to reduce the chances of P. falciparum becoming resistant to either drug. Why Was This Study Done? WHO currently recommends five ACTs—amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), artesunate-mefloquine, and artesunate-sulfadoxine-pyrimethamine—for the treatment of malaria. Its treatment guidelines state that the choice of ACT in a country or region should be based on the local level of resistance to the non-artemisinin-based partner drug in the combination. However, data on resistance levels to these partner drugs are scarce or unavailable for many sub-Saharan African countries. To help these countries make an informed choice about their national antimalarial treatment policies, in this randomized, non-inferiority trial, the researchers compare the efficacy and safety of four ACTs in African children with uncomplicated (mild) P. falciparum malaria. In a randomized trial, groups of randomly chosen patients with a specific disease are given different treatments and then followed to compare the outcomes of these interventions. A non-inferiority trial investigates whether one treatment is not worse than another treatment. What Did the Researchers Do and Find? Each of twelve sites in seven sub-Saharan African countries compared three ACTs out of ASAQ, DHAPQ, AL, and chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 young children with uncomplicated malaria were treated with ACT, actively followed up for 28 days (their parents brought them back to the site for pre-arranged check-ups), and passively followed up for six months (parents brought their children back if they developed any illnesses). At each visit, blood samples were examined for the presence of parasites, and a technique called PCR was used to determine which cases of malaria were new infections and which were recurrences of the original infection. The researchers then calculated the percentage of patients with no infection or with a new infection (the PCR-adjusted adequate clinical and parasitological response [ACPR]) and the percentage of patients with no infection (the PCR-unadjusted ACPR). For the PCR-adjusted efficacy, three pair-wise comparisons (DHAPQ versus AL, DHAPQ versus ASAQ, and ASAQ versus AL) showed non-inferiority at 28 days. That is, for example, similar percentages of patients given DHAPQ or AL (97.3% and 95.5%, respectively) had either no infection or a new infection. CD+A was less efficacious than the other three treatments. For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ and ASAQ; DHAPQ had a higher efficacy than ASAQ, but non-inferiority could not be excluded. That is, the difference in efficacy of these two drugs might have happened by chance. What Do These Findings Mean? These findings suggest that AL, ASAQ, and DHAPQ are all efficacious for the treatment of uncomplicated malaria in children; CD+A was withdrawn partway through the trial because of side effects, but these findings also suggest that it was less efficacious than the other ACTs. Importantly, the PCR-unadjusted results indicate that the risk of children becoming re-infected with malaria parasites soon after treatment was lowest for DHAPQ, followed by ASAQ, and then AL. Because these findings are based on pooled results from seven sub-Saharan African countries, they are likely to be generalizable and thus of use in setting national antimalarial drug policies throughout the region. AL and ASAQ are already included in the antimalarial drug policies of many sub-Saharan African countries, note the researchers, but these findings support the WHO recommendation that DHAPQ should also be considered for the treatment for uncomplicated P. falciparum malaria. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001119. Information is available from WHO on malaria (in several languages); the 2010 World Malaria Report provides details of the current global malaria situation; the WHO Guidelines for the Treatment of Malaria and the report Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Malaria are available The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria including fact sheets about ACTs and about malaria in Africa MedlinePlus provides links to additional information on malaria (in English and Spanish)