Search

BackgroundMalaria during pregnancy can cause serious consequences including maternal anemia and low birthweight (LBW). Routine antenatal care (ANC) in Rwanda includes malaria symptom screening at each ANC visit. This cluster randomized controlled trial investigated whether adding intermittent screening with a malaria rapid diagnostic test at each routine ANC visit and treatment of positives during pregnancy (ISTp) is more effective than routine ANC for reducing malaria prevalence at delivery.MethodsBetween September 2016 and June 2018, pregnant women initiating ANC at 14 health centers in Rwanda were enrolled into ISTp or control arms. All women received an insecticide-treated bed net at enrollment. Hemoglobin concentration, placental and peripheral parasitemia, newborn outcome, birthweight, and prematurity were assessed at delivery.ResultsNine hundred seventy-five women were enrolled in ISTp and 811 in the control group. Routine ANC plus ISTp did not significantly reduce polymerase chain reaction–confirmed placental malaria compared to control (adjusted relative risk [aRR], 0.94 [95% confidence interval {CI}, .59–1.50]; P = .799). ISTp had no impact on anemia (aRR, 1.08 [95% CI, .57–2.04]; P = .821). The mean birthweight of singleton newborns was not significantly different between arms (3054 g vs 3096 g, P = .395); however, women in the ISTp arm had a higher proportion of LBW (aRR, 1.59 [95% CI, 1.02–2.49]; P = .042).ConclusionsThis is the only study to compare ISTp to symptomatic screening at ANC in a setting where intermittent preventive treatment is not routinely provided. ISTp did not reduce the prevalence of malaria or anemia at delivery and was associated with an increased risk of LBW.Clinical Trials RegistrationNCT03508349.

Summary Background Partial artemisinin resistance is suspected if delayed parasite clearance (ie, persistence of parasitaemia on day 3 after treatment initiation) is observed. Validated markers of artemisinin partial resistance in southeast Asia, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L, have been reported in Rwanda but no association with parasite clearance has been observed. We aimed to establish the efficacy of artemether–lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes. Methods This open-label, single-arm, multicentre, therapeutic efficacy study was done in 2018 in three Rwandan sites: Masaka, Rukara, and Bugarama. Children aged 6–59 months with P falciparum monoinfection and fever were eligible and treated with a 3-day course of artemether–lumefantrine. Treatment response was monitored for 28 days using weekly microscopy screenings of blood samples for P falciparum. Mutations in Pfkelch13 and P falciparum multidrug resistance-1 (Pfmdr1) genes were characterised in parasites collected from enrolled participants. Analysis of flanking microsatellites surrounding Pfkelch13 was done to define the origins of the R561H mutations. The primary endpoint was PCR-corrected parasitological cure on day 28, as per WHO protocol. Findings 228 participants were enrolled and 224 (98·2%) reached the study endpoint. PCR-corrected efficacies were 97·0% (95% CI 88–100) in Masaka, 93·8% (85–98) in Rukara, and 97·2% (91–100) in Bugarama. Pfkelch13 R561H mutations were present in 28 (13%) of 218 pre-treatment samples and P574L mutations were present in two (1%) pre-treatment samples. 217 (90%) of the 240 Pfmdr1 haplotypes observed in the pretreatment samples, had either the NFD (N86Y, Y184F, D1246Y) or NYD haplotype. Eight (16%) of 51 participants in Masaka and 12 (15%) of 82 participants in Rukara were microscopically positive 3 days after treatment initiation, which was associated with pre-treatment presence of Pfkelch13 R561H in Masaka (p=0·0005). Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda. Interpretation We confirm evidence of emerging artemisinin partial resistance in Rwanda. Although artemether–lumefantrine remains efficacious, vigilance for decreasing efficacy, further characterisation of artemisinin partial resistance, and evaluation of additional antimalarials in Rwanda should be considered. Funding The US President's Malaria Initiative. Translation For the French translation of the abstract see Supplementary Materials section.

Background Artemisinin-based combination therapies (ACTs) have proven highly effective in reducing malaria morbidity in sub-Saharan Africa. Artemether-lumefantrine (AL) was introduced in 2005 as a first-line ACT for the treatment of uncomplicated malaria in Rwanda. Monitoring the therapeutic efficacy of ACTs is necessary to ensure effective malaria case management. Methods A comparative study on the efficacy of AL and dihydroartemisinin-piperaquine (DHP) was conducted in two sites, Masaka and Ruhuha, between September 2013 and December 2015. Clinical and parasitological responses were assessed at days 28 and 42. Results A total of 534 children were treated with AL (n=267) or DHP (n=267). After polymerase chain reaction (PCR) adjustment, 98.3% and 98.9% of children in the AL and DHP arms, respectively, achieved an adequate clinical and parasitological response (ACPR) at day 28. At day 42, PCR-adjusted ACPR proportions were 97.3% and 98.4% for AL and DHP, respectively. PCR-adjusted ACPR was 99% for both drugs at days 28 and 42 in Ruhuha. The PCR-adjusted ACPR proportions in Masaka were 97.3% for AL and 98.5% for DHP at day 28 and 95.2% for AL and 97.5% for DHP at day 42. Conclusions AL remains efficacious in Rwanda 10 y after its adoption. The probability of new infections occurring among patients in the DHP arm was significantly lower than those in the AL arm. DHP also demonstrated a greater post-treatment prophylactic effect against new infections compared with AL.

The impressive decline in child mortality that occurred in Rwanda from 1996–2000 to 2006–2010 coincided with a period of rapid increase of malaria control interventions such as indoor residual spraying (IRS); insecticide-treated net (ITN) distribution and use, and improved malaria case management. The impact of these interventions was examined through ecological correlation analysis, and robust decomposition analysis of contextual factors on all-cause child mortality. Child mortality fell 61% during the evaluation period and prevalence of severe anemia in children 6–23 months declined 71% between 2005 and 2010. These changes in malaria morbidity and mortality occurred concurrently with a substantial increase in vector control activities. ITN use increased among children under five, from 4% to 70%. The IRS program began in 2007 and covered 1.3 million people in the highest burden districts by 2010. At the same time, diagnosis and treatment with an effective antimalarial expanded nationally, and included making services available to children under the age of 5 at the community level. The percentage of children under 5 who sought care for a fever increased from 26% in 2000 to 48% in 2010. Multivariable models of the change in child mortality between 2000 and 2010 using nationally representative data reveal the importance of increasing ITN ownership in explaining the observed mortality declines. Taken as a whole, the evidence supports the conclusion that malaria control interventions contributed to the observed decline in child mortality in Rwanda from 2000 to 2010, even in a context of improving socioeconomic, maternal, and child health conditions.

Background Rapid diagnostic tests (RDTs) for histidine rich protein 2 (HRP2) are often used to determine whether persons with fever should be treated with anti-malarials. However, Plasmodium falciparum parasites with a deletion of the hrp2 gene yield false-negative RDTs and there are concerns the sensitivity of HRP2-based RDTs may fall when the intensity of transmission decreases. Methods This observational study enrolled 9226 patients at three health centres in Rwanda from April 2014 to April 2015. It then compared the sensitivity of RDTs based on HRP2 and the Plasmodium lactate dehydrogenase (pLDH) to microscopy (thick smears) for the diagnosis of malaria. PCR was used to determine whether deletions of the histidine-rich central repeat region of the hrp2 gene (exon 2) were associated with false-negative HRP2-based RDTs. Results In comparison to microscopy, the sensitivity and specificity of HRP2- and pLDH-based RDTs were 89.5 and 86.2% and 80.2 and 94.3%, respectively. When the results for both RDTs were combined, sensitivity rose to 91.8% and specificity was 85.7%. Additionally, when smear positivity fell from 46 to 3%, the sensitivity of the HRP2-based RDT fell from 88 to 67%. Of 370 samples with false-negative HRP2 RDT results for which PCR was performed, 140 (38%) were identified as P. falciparum by PCR. Of the isolates identified as P. falciparum by PCR, 32 (23%) were negative for the hrp2 gene based on PCR. Of the 32 P. falciparum isolates negative for hrp2 by PCR, 17 (53%) were positive based on the pLDH RDT. Conclusion This prospective study of RDT performance coincided with a decline in the intensity of malaria transmission in Kibirizi (fall in slide positivity from 46 to 3%). This decline was associated with a decrease in HRP2 RDT sensitivity (from 88 to 67%). While P. falciparum isolates without the hrp2 gene were an important cause of false-negative HRP2-based RDTs, most were identified by the pLDH-based RDT. Although WHO does not recommend the use of combined HRP2/pLDH testing in sub-Saharan Africa, these results suggest that combination HRP2/pLDH-based RDTs could reduce the impact of false-negative HRP2-based RDTs for detection of symptomatic P. falciparum malaria. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-1768-1) contains supplementary material, which is available to authorized users.

Four predictors were independently associated with an increased risk of death: acidosis, cerebral manifestations of malaria, elevated blood urea nitrogen, or signs of chronic illness. The standard base deficit was found to be the single most relevant predictor of death., Background. Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria. Methods. African children (

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)

Additional file 2. PCR products visualized on an agarose gel. DNA is from two thick-smear positive subjects with negative HRP2-based RDTs. Lane 1: 100 bp marker. Lane 2: PCR targeting hrp2 with DNA from subject #1 (shows amplicon of expected size of ~900 bp). Lanes 3–5: PCR with DNA from subject #2. Lane 3 shows the absence of hrp2 amplicons. Lane 4 shows results of multiplex PCR for 18S rRNA with an amplicon of 276 bp (expected size for P. falciparum). Lane 5 shows results of nested PCR with species-specific primers for P. falciparum 18S rRNA with an amplicon of the expected size of 205 bp.

Additional file 1. Primer sequences used to amplify hrp2 and P. falciparum, P. vivax, P. malariae and P. ovale 18S rRNA, expected product sizes and PCR conditions.

Additional file 2. PCR products visualized on an agarose gel. DNA is from two thick-smear positive subjects with negative HRP2-based RDTs. Lane 1: 100 bp marker. Lane 2: PCR targeting hrp2 with DNA from subject #1 (shows amplicon of expected size of ~900 bp). Lanes 3–5: PCR with DNA from subject #2. Lane 3 shows the absence of hrp2 amplicons. Lane 4 shows results of multiplex PCR for 18S rRNA with an amplicon of 276 bp (expected size for P. falciparum). Lane 5 shows results of nested PCR with species-specific primers for P. falciparum 18S rRNA with an amplicon of the expected size of 205 bp.

Additional file 1. Primer sequences used to amplify hrp2 and P. falciparum, P. vivax, P. malariae and P. ovale 18S rRNA, expected product sizes and PCR conditions.