Uncomplicated Plasmodium Falciparum Malaria Research Articles

Dihydroartemisinin–Piperaquine Combination in the Treatment of Uncomplicated Plasmodium falciparum Malaria: Update on Clinical Failures in Africa and Tools for Surveillance

Dihydroartemisinin (or artenimol)–piperaquine is one of the six artemisinin-based combination therapies recommended in uncomplicated malaria treatment. However, artemisinin partial resistance has been reported in Cambodia, Laos, Vietnam, India, and, recently, in Africa. Polymorphisms in the Pfk13 gene have been described as molecular markers of artemisinin resistance and the amplification of the plasmepsine II/III (Pfpmp2/Pfpmp3) gene has been associated with piperaquine resistance. However, some therapeutic failures with this combination remain unexplained by strains’ characterization. We provide an overview on the use of dihydroartemisinin–piperaquine in malaria treatment and discuss tools available to monitor its efficacy.

ONT sequencing identifies a high prevalence of crt sensitive, triple mutant dhfr and single mutant dhps parasites within an ANC population in Nigeria.

Malaria in pregnancy is a major public health issue, particularly among vulnerable populations in malaria-endemic sub-Saharan African countries. To mitigate its risks, WHO recommends sulphadoxine-pyrimethamine (SP) for chemoprevention and artemisinin-based combination therapy (ACT) to treat uncomplicated Plasmodium falciparum malaria. These interventions have helped to alleviate the risk associated with malaria in pregnancy; however, in the context of the emergence of SP- and ACT-resistant P. falciparum, maintained efficacy is under threat. Molecular surveillance is a reliable tool to monitor the emergence of resistance where molecular markers are known. Thus, the objective of the study was to use a multiplexed amplicon Oxford Nanopore sequencing approach to assess the molecular markers for antimalarial resistance among pregnant women in Nigeria. Dried blood spots (DBS) were collected from pregnant women who received IPTp-SP at the enrollment and follow-up visits. P. falciparum genomic DNA was extracted by the Chelex® method and Pf18S qPCR was used to detect parasite DNA in each sample. With nested PCR assays, fragments of Pfdhps, Pfdhfr, Pfmdr1, Pfcrt, Pfk13 and Pfama1 genes were amplified and multiplexed amplicon-based sequencing was conducted on the minION Oxford Nanopore Technology. In total, 251 pregnant women were enrolled in the study and 457 DBS samples were collected. P. falciparum genomic DNA was detected in 12% (56/457) of the samples, 31 at baseline and the remaining during the follow-up visits. Pfama1, pfk13, Pfdhps, Pfdhfr, Pfmdr1 and Pfcrt were successfully sequenced in a single run. Notably, k13 artemisinin resistance mutations were absent, the frequencies of Pfdhfr and Pfdhps SP resistance haplotypes, IRN for pyrimethamine resistance and ISGKA/IAGKA associated with sulphadoxine resistance were 82% (36/44) and 64% (27/42), respectively, and the Pfcrt CVIET resistant haplotype was at approximately 22% (7/32). Here a multiplexed amplicon-based ONT assay established that triple mutant Pfdfhr-IRN, double mutant Pfdhps-SG haplotypes and the chloroquine sensitive strain were prevalent among pregnant women in Nigeria.

Therapeutic efficacy of artemether–lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Arba Minch Zuria District, Gamo Zone, Southwest Ethiopia

BackgroundArtemether–lumefantrine (AL) has been the primary anti-malarial drug used to treat uncomplicated Plasmodium falciparum malaria in Ethiopia since 2004. However, there have been recent reports of AL resistance mutations in different African countries, including Ethiopia. This is concerning and requires periodic monitoring of anti-malarial drug resistance. Therefore, the current study aimed to evaluate the therapeutic efficacy of AL in treating uncomplicated P. falciparum malaria in the Arba Minch Zuria District, Gamo Zone, Southwest Ethiopia.MethodsA single-arm prospective study with a 28-day follow-up period was conducted from July to October 2022. Capillary blood samples were collected for RDT and microscopic examination. The study enrolled monoinfected P. falciparum patients aged ≥ 18 years at Ganta Sira Health Post. Sociodemographic and clinical data were recorded, and a dried blood spot (DBS) was prepared for each participant. Nested polymerase chain reaction (nPCR) genotyping of the msp-1 and msp-2 genes was only performed for recurrent cases to distinguish between recurrence and reinfection. Data entry and analysis were performed using the WHO Excel spreadsheet and SPSS version 26.ResultsA total of 89 patients were enrolled, and 67 adequately completed the 28-day follow-up period. AL showed a 100% clearance rate for fever on day 2 and asexual parasites on day 3. Gametocytes were detected in 13.5% (12/89) of the participants. The gametocyte clearance rate was 58.3% (7/12) until day 7 and 100% (12/12) until day 14. Five participants developed recurrent malaria, three of whom experienced relapse and two of whom experienced reinfection. Based on the Kaplan–Meier survival analysis, the PCR-uncorrected and PCR-corrected cumulative incidence of success were 93.7% (95% CI 85.5–97.3) and 96.2% (95% CI 85.5–98.7), respectively.ConclusionAL was efficacious in treating uncomplicated P. falciparum malaria in the study area. However, the detection of recurrent patients highlights the need for continuous efficacy studies in this area.

Therapeutic efficacy and safety of artemether-lumefantrine combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria at Teda Health Centre, Northwest Ethiopia, 2022/23

BackgroundThe emergence of Plasmodium falciparum drug resistance against artemisinin-based combination therapy has threatened malaria control efforts. Since malaria control and elimination plans are dependent on these drugs, they must remain efficacious. However, resistance to these drugs was detected in low-transmission settings and is predicted to emerge in high-transmission settings, including in unspecified areas of Ethiopia. Therefore, this study aimed to assess the therapeutic efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria.MethodsA single-arm prospective observational study was conducted at Teda Health Centre, Northwest Ethiopia, by following the 2009 World Health Organization efficacy study guidelines from September 2022 to February 2023. Patients with uncomplicated falciparum malaria were conveniently selected and treated with a standard dose of artemether-lumefantrine, along with a single low dose of primaquine. Then clinical and parasitological responses and haemoglobin levels were assessed during the 28-day scheduled follow-up. Blood films were examined and asexual parasites were quantified; axillary temperature was measured; and drug adverse events were assessed throughout the follow-up. Finally, the drug efficacy (adequate clinical and parasitological response) was determined by Kaplan–Meier and per-protocol analyses. The data were analysed using the WHO Excel spreadsheet and SPSS version 25 software.ResultsThe success rates of PCR uncorrected and corrected Kaplan–Meier analysis on day 28 were 95.8% (95% CI 87.5–98.6) and 97.3% (95% CI 89.4–99.3), respectively. The per-protocol PCR uncorrected and corrected adequate clinical and parasitological responses were 95.5% (95% CI 87.5–99.1) and 97% (95% CI 89.5–99.6), respectively. On day-3, 97% of study participants were free of asexual parasitaemia, and all of them were fever-free on day-2. All of the gametocyte-positive patients at baseline were found to be negative for gametocytes on day-2. Moreover, the baseline mean hemoglobin of 13.10 g/dl increased slightly on day-14 to 13.27 g/dl but significantly on day-28 to 13.69 g/dl in a paired sample t test. All adverse events reported were mild.ConclusionArtemether-lumefantrine continued to be an efficacious and safe drug for the treatment of uncomplicated Plasmodium falciparum malaria at the Teda Health Centre.Trial registration: unique ID# PACTR202309773069812 at https://pactr.samrc.ac.za on September 1, 2023.

New guidelines reduce the risk of hospitalization for adult patients with uncomplicated Plasmodium falciparum malaria: An observational, multicenter, retrospective French study

ObjectivesWe aimed to evaluate the impact of malaria declaration year (before or after 2017) on the frequency of hospitalization in metropolitan France of patients with uncomplicated non-vomiting P.falciparum malaria. Patients and methodsAn observational, multicenter, retrospective study was carried out, using the database from the French National Reference Centre for Malaria. Descriptive analysis and multivariate analysis by logistic regression were performed using the multiple imputation by chained equation method to handle missing data. ResultsMore than 2000 (2184) uncomplicated non-vomiting P.falciparum malaria cases were recorded. Our multivariate analysis showed an association between the year 2018 and reduced risk of hospitalization (OR: 0.89; 95% CI: 0.81–0.97). ConclusionCompared to 2016, during 2018 we observed a trend toward ambulatory care for patients presenting with uncomplicated non-vomiting P.falciparum malaria.

The effect of single low-dose primaquine treatment for uncomplicated Plasmodium falciparum malaria on haemoglobin levels in Ethiopia: a longitudinal cohort study

BackgroundTo interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing. However, due to the risk of haemolysis in patients with G6PD deficiency (G6PDd), PQ use is uncommon. Thus, this study aimed to assess the safety of a single low dose of PQ administered to patients with G6PD deficiency.MethodsAn observational cohort study was conducted with patients treated for uncomplicated P. falciparum malaria with either single-dose PQ (0.25 mg/kg) (SLD PQ) + ACT or ACT alone. Microscopy-confirmed uncomplicated P. falciparum malaria patients visiting public health facilities in Arjo Didessa, Southwest Ethiopia, were enrolled in the study from September 2019 to November 2022. Patients with uncomplicated P. falciparum malaria were followed up for 28 days through clinical and laboratory diagnosis, such as measurements of G6PD levels and haemoglobin (Hb) concentrations. G6PD levels were measured by a quantiative CareSTART™ POCT S1 biosensor machine. Patient interviews were also conducted, and the type and frequency of clinical complaints were recorded. Hb data were taken on days (D) 7, 14, 21, and 28 following treatment with SLD-PQ + ACT or ACT alone.ResultsA total of 249 patients with uncomplicated P. falciparum malaria were enrolled in this study. Of these, 83 (33.3%) patients received ACT alone, and 166 (66.7%) received ACT combined with SLD-PQ treatment. The median age of the patients was 20 (IQR 28–15) years. G6PD deficiency was found in 17 (6.8%) patients, 14 males and 3 females. There were 6 (7.2%) and 11 (6.6%) phenotypic G6PD-deficient patients in the ACT alone and ACT + SLD-PQ arms, respectively. The mean Hb levels in patients treated with ACT + SLD-PQ were reduced by an average of 0.45 g/dl (95% CI = 0.39 to 0.52) in the posttreatment phase (D7) compared to a reduction of 0.30 g/dl (95% CI = 0.14 to − 0.47) in patients treated with ACT alone (P = 0.157). A greater mean Hb reduction was observed on day 7 in the G6PDd ACT + SLD-PQ group (− 0.60 g/dL) than in the G6PDd ACT alone group (− 0.48 g/dL); however, there was no statistically significant difference (P = 0.465). Overall, D14 losses were 0.10 g/dl (95% CI = − 0.00 to 0.20) and 0.05 g/dl (95% CI = − 0.123 to 0.22) in patients with and without SLD-PQ, respectively (P = 0.412).ConclusionsThis study’s findings indicate that using SLD-PQ in combination with ACT is safe for uncomplicated P. falciparum malaria regardless of the patient's G6PD status in Ethiopian settings. Caution should be taken in extrapolating this finding in other settings with diverse G6DP phenotypes.

Therapeutic efficacy and tolerability of artemether–lumefantrine for uncomplicated Plasmodium falciparum malaria in Niger, 2020

BackgroundMonitoring therapeutic efficacy is important to ensure the efficacy of artemisinin-based combination therapy (ACT) for malaria. The current first-line treatment for uncomplicated malaria recommended by the National Malaria Control Program in Niger is artemether–lumefantrine (AL). In 2020, an in vivo study was carried out to evaluate clinical and parasitological responses to AL as well as the molecular resistance to the drug in three sentinel sites: Agadez, Tessaoua and Gaya, in Niger.MethodsA multi-center, single-arm trial was conducted according to the 28-day World Health Organization (WHO) 2009 therapeutic efficacy study protocol. Children between 6 months and 15 years with confirmed uncomplicated Plasmodium falciparum infection and 1000–200,000 asexual parasites/μL of blood were enrolled and followed up for 28 days. Uncorrected and PCR-corrected efficacy results at day 28 were calculated, and molecular correction was performed by genotyping the msp1, msp2, and glurp genes. The pfk13, pfdhfr, pfdhps, pfcrt and pfmdr genes were analyzed by PCR and Sanger sequencing. The Kaplan–Meier curve assessed parasite clearance.ResultsA total of 255 patients were enrolled in the study. The adequate clinical and parasitological response after PCR correction was 98.9% (95% CI 96.4–101.0%), 92.2% (85.0–98.5%) and 97.1% (93.1–101.0%) in Gaya, Tessaoua and Agadez, respectively. No adverse events were observed. Ten mutations (SNP) were found, including 7 synonyms (K248K, G690G, E691E, E612E, C469C, G496G, P718P) and 3 non-synonyms (N594K, R255K, V714S). Two mutations emerged: N594K and V714S. The R255K mutation detected in Southeast Asia was also detected. The pfdhpsK540E and pfdhfrI164L mutations associated with high levels of resistance are absent. There is a reversal of chloroquine resistance.ConclusionThe study findings indicate that AL is effective and well tolerated for the treatment of uncomplicated malaria in three sites in Niger. The emergence of a pfk13 mutation requires additional testing such as the Ring Stage Assay and CRISPR/Cas9 to confirm the role of these emerging mutations.Trial registration NCT05070520, October 7, 2021.

Artemether–lumefantrine with or without single-dose primaquine and sulfadoxine–pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali

Artemether-lumefantrine is widely used for uncomplicated Plasmodium falciparum malaria; sulfadoxine-pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We aimed to determine the efficacy of artemether-lumefantrine with and without primaquine and sulfadoxine-pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes. In this phase 2, single-blind, randomised clinical trial conducted in Ouelessebougou, Mali, asymptomatic individuals aged 10-50 years with P falciparum gametocytaemia were recruited from the community and randomly assigned (1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine with a single dose of 0·25mg/kg primaquine, sulfadoxine-pyrimethamine plus amodiaquine, or sulfadoxine-pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were masked to group allocation. Participants were not masked to group allocation. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. The primary outcome was the median within-person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether-lumefantrine groups) or day 7 (sulfadoxine-pyrimethamine plus amodiaquine groups) after treatment, assessed by direct membrane feeding assay. All participants who received any trial drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT05081089. Between Oct 13 and Dec 16, 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). The median age of participants was 13 (IQR 11-20); 37(46%) of 80 participants were female and 43 (54%) were male. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100·0% (IQR 100·0-100·0; n=19; p=0·0011) with artemether-lumefantrine and 100·0% (100·0-100·0; n=19; p=0·0001) with artemether-lumefantrine with primaquine. Only two individuals who were infectious at baseline infected mosquitoes on day 2 after artemether-lumefantrine and none at day 5. By contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·6% (IQR 0·0-100·0; n=20; p=0·013) with sulfadoxine-pyrimethamine plus amodiaquine and 100% (100·0-100·0; n=19; p<0·0001) with sulfadoxine-pyrimethamine plus amodiaquine with tafenoquine. No grade 3-4 or serious adverse events occurred. These data support the effectiveness of artemether-lumefantrine alone for preventing nearly all mosquito infections. By contrast, there was considerable post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine; therefore, the addition of a transmission-blocking drug might be beneficial in maximising its community impact. Bill & Melinda Gates Foundation.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019

BackgroundArtemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania.MethodsThis was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy.ResultsA total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported.ConclusionThis study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).

Efficacy of artesunate-amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria in mainland Tanzania

BackgroundDiversification of artemisinin-based combination therapy (ACT) is suggested as one of the strategies that can be used to contain artemisinin resistance. Artesunate-amodiaquine (ASAQ) is one of the artemisinin-based combinations that can be used in the diversification strategy as an alternative first-line treatment for uncomplicated malaria in mainland Tanzania. There is however limited data on the efficacy of ASAQ in mainland Tanzania. This study assessed the efficacy of ASAQ for treatment of uncomplicated Plasmodium falciparum malaria in selected sentinel sites for therapeutic efficacy studies in mainland Tanzania.MethodsBetween December 2018 and March 2020, children aged between 6 months and 10 years, attending at Nagaga, Mkuzi, and Mlimba primary health facilities, and with suspected uncomplicated malaria infection were screened for eligibility to participate in the study. Malaria infection was screened using microscopy. Children with uncomplicated P. falciparum monoinfection and who fulfilled all other inclusion criteria, and had none of the exclusion criteria, according to the World Health Organization (WHO) guidelines, were treated with ASAQ. Follow-up visits were scheduled on days 0, 1, 2, 3, 7, 14, 21, and 28 or on any day of recurrent infection for clinical and laboratory assessment. Polymerase chain reaction (PCR)-corrected cure rate on day 28 was the primary outcome.ResultsA total of 264 children, 88 in each of the three study sites (Mlimba, Mkuzi and Nagaga health facilities) were enrolled and treated with ASAQ. The ASAQ PCR-corrected cure rate was 100% at all the three study sites. None of the participants had early treatment failure or late clinical failure. Furthermore, none of the participants had a serious adverse event.ConclusionASAQ was highly efficacious for the treatment of uncomplicated P. falciparum malaria in mainland Tanzania, therefore, it can be deployed as an alternative first-line treatment for uncomplicated malaria as part of diversification strategy to contain the spread of partial artemisinin resistance in the country.

Dihydroartemisinin-piperaquine treatment failure of uncomplicated Plasmodium falciparum malaria infection in a traveller.

We report a late dihydroartemisinin–piperaquine treatment failure of uncomplicated Plasmodium falciparum malaria infection in a traveller without evidence of drug resistance. The correct treatment intake was confirmed, isolates drugs susceptibility was confirmed by RSA-PSA and chemosusceptibility. No molecular markers associated with resistance to artemisinin derivatives or piperaquine were identified.

Therapeutic response to four artemisinin-based combination therapies in Angola, 2021.

Monitoring antimalarial efficacy is important to detect the emergence of parasite drug resistance. Angola conducts in vivo therapeutic efficacy studies (TESs) every 2 years in its fixed sentinel sites in Benguela, Lunda Sul, and Zaire provinces. Children with uncomplicated Plasmodium falciparum malaria were treated with artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DP), or artesunate-pyronaridine (ASPY) and followed for 28 (AL and ASAQ) or 42 days (DP and ASPY) to assess clinical and parasitological response to treatment. Two drugs were sequentially assessed in each site in February-July 2021. The primary indicator was the Kaplan-Meier estimate of the PCR-corrected efficacy at the end of the follow-up period. A total of 622 patients were enrolled in the study and 590 (95%) participants reached a study endpoint. By day 3, ≥98% of participants were slide-negative in all study sites and arms. After PCR correction, day 28 AL efficacy was 88.0% (95% CI: 82%-95%) in Zaire and 94.7% (95% CI: 90%-99%) in Lunda Sul. For ASAQ, day 28 efficacy was 92.0% (95% CI: 87%-98%) in Zaire and 100% in Lunda Sul. Corrected day 42 efficacy was 99.6% (95% CI: 99%-100%) for ASPY and 98.3% (95% CI: 96%-100%) for DP in Benguela. High day 3 clearance rates suggest no clinical evidence of artemisinin resistance. This was the fourth of five rounds of TES in Angola showing a corrected AL efficacy <90% in a site. For Zaire, AL has had an efficacy <90% in 2013, 2015, and 2021. ASAQ, DP, and ASPY are appropriate choices as artemisinin-based combination therapies in Angola.

Effectiveness of artemether-lumefantrine for treating uncomplicated malaria in low- and high-transmission areas of Ghana.

Artemisinin-based combination therapy (ACT) has been effective in the supervised treatment of uncomplicated malaria in Ghana. Since ACT usage is primarily unsupervised, this study aimed to determine the effectiveness of artemether-lumefantrine (AL) for treating malaria patients in two transmission settings in Ghana. Eighty-four individuals with uncomplicated Plasmodium falciparum malaria were recruited from Lekma Hospital (LH) in Accra (low-transmission area; N = 28), southern Ghana, and King's Medical Centre (KMC) in Kumbungu (high-transmission area; N = 56), northern Ghana. Participants were followed up for 28days after unsupervised treatment with AL. The presence of asexual parasites was determined by microscopic examination of Giemsa-stained blood smears. Plasmodium species identification was confirmed using species-specific primers targeting the 18S rRNA gene. Parasite recrudescence or reinfection was determined by genotyping the Pfmsp 1 and Pfmsp 2 genes. After AL treatment, 3.6% (2/56) of the patients from KMC were parasitaemic on day 3 compared to none from the LH patients. One patient from KMC with delayed parasite clearance on day 3 remained parasite-positive by microscopy on day 7 but was parasite-free by day 14. While none of the patients from LH experienced parasite recurrence during the 28-day follow-up, three and two patients from KMC had recurrent parasitaemia on days 21 and 28, respectively. Percentage reduction in parasite densities from day 1, 2, and 3 for participants from the KMC was 63.2%, 89.5%, and 84.5%. Parasite densities for participants from the LH reduced from 98.2%, 99.8% on day 1, and 2 to 100% on day 3. The 28-day cumulative incidence rate of treatment failure for KMC was 12.8% (95% confidence interval: 1.9-23.7%), while the per-protocol effectiveness of AL in KMC was 89.47%. All recurrent cases were assigned to recrudescence after parasite genotyping by Pfmsp 1 and Pfmsp 2. While AL is efficacious in treating uncomplicated malaria in Ghana, when taken under unsupervised conditions, it showed an 89.4% PCR-corrected cure rate in northern Ghana, which is slightly below the WHO-defined threshold.

Seasonal Malaria Chemoprevention Therapy in Children Up To 9 Years of Age: Protocol for a Cluster-Randomized Trial Study.

Seasonal malaria chemoprevention (SMC) is recommended by the World Health Organization for the sub-Sahel region in sub-Saharan Africa for preventing malaria in children 3 months old to younger than 5 years. Since 2016, the Malian National Malaria Control Program has deployed SMC countrywide during its high malaria transmission season at a rate of 4 monthly cycles annually. The standard SMC regimen includes sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ). Resistance against SP is suspected to be rising across West Africa; therefore, assessing the effectiveness of an alternative antimalarial drug for SMC is needed to provide a second-line regimen when it is ultimately needed. It is not well understood whether SMC effectively prevents malaria in children aged 5 years or older. The primary goal of the study is to compare 2 SMC regimens (SP-AQ and dihydroartemisinin-piperaquine [DHA-PQ]) in preventing uncomplicated Plasmodium falciparum malaria in children 3 months to 9 years old. Secondly, we will assess the possible use of DHA-PQ as an alternative SMC drug in areas where resistance to SP or AQ may increase following intensive use. The study design is a 3-arm cluster-randomized design comparing the SP-AQ and DHA-PQ arms in 2 age groups (younger than 5 years and 5-9 years) and a control group for children aged 5-9 years. Standard SMC (SP-AQ) for children younger than 5 years was provided to the control arm, while SMC with SP-AQ was delivered to children aged 3 months to 9 years (arm 2), and SMC with DHA-PQ will be implemented in study arm 3 for children up to 9 years of age. The study was performed in Mali's Koulikoro District, a rural area in southwest Mali with historically high malaria transmission rates. The study's primary outcome is P falciparum incidence for 2 SMC regimens in children up to 9 years of age. Should DHA-PQ provide an acceptable alternative to SP-AQ, a plausible second-line prevention option would be available in the event of SP resistance or drug supply shortages. A significant byproduct of this effort included bolstering district health information systems for rapid identification of severe malaria cases. The study began on July 1, 2019. Through November 2022, a total of 4556 children 3 months old to younger than 5 years were enrolled. Data collection ended in spring 2023, and the findings are expected to be published later in early 2024. Routine evaluation of antimalarial drugs is needed to establish appropriate SMC age targets. The study goals here may impact public health policy and provide alternative therapies in the event of drug shortages or resistance. ClinicalTrials.gov NCT04149106, https://clinicaltrials.gov/ct2/show/NCT04149106. DERR1-10.2196/51660.

Efficacy and safety of Artemisinin Combination Therapy for the treatment of uncomplicated Plasmodium falciparum malaria across international borders of India

Background &amp; objectives: Malaria due to Plasmodium falciparum (Pf) remains a major public threat in India. Artemisinin-based combination therapy (ACT) has been the country’s first-line drug for uncomplicated Pf malaria. In 2013-2014, Artesunate plus sulfadoxine (AS+SP) was replaced by Artemether Lumefantrine (AL) as the first- line antimalarial in North East (NE) states of the country which are endemic for Pf malaria. Regular monitoring of antimalarial drugs is of utmost importance to achieve the goal of elimination. This study aimed to assess the efficacy and safety of ACT for treating uncomplicated Pf malaria in the NE states of India. Methods: A prospective study of 28-day follow-up was conducted to monitor the efficacy and safety of AL from 2018-2019 in four districts, Udalgiri, Meghalaya, Lawngtlai, and Dhalai of NE, India. The clinical and parasitological response and the polymorphism analysis of the Pfdhps, P/dhfr, and Pfkelch 13 gene were evaluated. Results: A total of 234 patients were enrolled in the study out of 216 patients who completed the follow-up to 28 days. One-hundred percent adequate clinical and parasitological responses (ACPR) were observed with polymerase chain reaction (PCR) correction. The genotype results suggest no recrudescence in the treatment-failure patients. The classical single nucleotide polymorphisms (SNP) in the Pfdhfr gene was S108N (94.9%), followed by C59R (91.5%), whereas, in the Pfdhps gene, the common SNP was A437G (79.6%), followed by S3436A. No associated or validated mutations were found in the propeller region of the PfKelch13 gene. Interpretation &amp; conclusion: AL was efficacious and safe in uncomplicated P. falciparum malaria in North East India. In contrast, mutations in the genes responsible for sulfadoxine and pyrimethamine resistance have been fixed in northeast India’s population.

Effects of Momordica charantia (MC) Extract on Clinical Symptoms, Parasite Account, Thrombocytes, Total Bilirubin and Direct Bilirubin in Patients with Uncomplicated Plasmodium falciparum Malaria: A Case Report

Clinical symptoms during the treatment of uncomplicated P. falciparum malaria have been reported in several studies. Parasite density in the blood is associated with clinical symptoms, platelet, and bilirubin count. A 52-year-old male, weighing 52 kg, was given one capsule containing 325 mg bitter melon (Momordica charantia) extract for 3 days of treatment. Patients were followed up for 28 days, days 1,2,3,4,7,14,21,28, and peripheral blood microscopic examination and clinical symptoms were carried out. Measurement of platelets, total bilirubin, direct bilirubin D0, D14 and D28. Naranjo Scale, adverse events measurements were taken on D7, no signs of severe malaria, no comorbidities, no history of malaria, blood pressure 110/80 mmHg, peripheral blood parasite examination on D0 found P. falciparum parasites of 31,714/µL, D0 platelet value of 94x10 /mm3, D0 total bilirubin value of 1.3 mg% and D0 direct bilirubin value of 0.6 mµ/mL. On D1 parasite count was 2,400/µL, D2 was 372/µL, D3, D4, D7, D14, D21, D28 no asexual parasites were found again. Clinical symptoms that arose on D0 were nausea, no appetite, sweating, chills, sleep disturbance, dizziness, headache, and weakness with a body temperature of 37°C. After D3 of bitter melon extract treatment, no clinical symptoms were found again. Naranjo scale score based on nurse and pharmacist agreement was 6 (probable) at D7 for the adverse events of nausea and vomiting. There were no reported adverse events such as nausea, vomiting, diarrhea, abdominal pain, cough, sleep disturbance, dizziness, headache and weakness on D2 treatment. Bitter melon extract is effective for uncomplicated malaria P. falciparum, reduces clinical symptoms, and is safe.

Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low-dose primaquine or placebo

BackgroundSingle low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status.MethodsThis randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months–11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status.Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively.ResultsOne thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status.The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo).ConclusionsIn these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa.Trial registrationThe trial is registered at ISRCTN 11594437.

Artesunate-mefloquine therapy for uncomplicated Plasmodium falciparum malaria: an updated systematic review and meta-analysis of efficacy and safety.

To provide a continuous update on the safety and efficacy of artesunate-mefloquine (ASMQ) compared with other artemisinin combination therapy (ACT) schemes used in the treatment of uncomplicated malaria caused by Plasmodium falciparum, this study updated and expanded the results of the systematic literature review published in 2016. Only randomised controlled clinical trials published from 1 January 2001 to 12 June 2023 from five databases were included in this study. The results related to efficacy, expressed through RR, were summarized in meta-analyses, performed according to the compared ACTs and with the intention-to-treat and per-protocol analyses. The results related to safety were synthesized in a descriptive manner. Thirty-two studies were included, of which 24 had been analysed in the 2016 review and eight new ones were added. Although the methodological quality of most studies was considered moderate, the body of evidence gathered indicates that ASMQ continues to be safe and effective for the treatment of uncomplicated infections caused by P. falciparum compared with other ACTs. However, the inclusion of two new studies, which identified failure rates exceeding 10%, suggests a possible reduction in the efficacy of ASMQ in the analysed locations. The incidence of serious adverse effects, such as seizure, encephalopathy and cardiac arrhythmia, was infrequent in both the ASMQ group and the comparison groups. After including new evidence, ASMQ is still recommended as a first-line treatment of uncomplicated malaria caused by P. falciparum, although local aspects need to be considered.

Modeling policy interventions for slowing the spread of artemisinin-resistant pfkelch R561H mutations in Rwanda

Artemisinin combination therapies (ACTs) are highly effective at treating uncomplicated Plasmodium falciparum malaria, but the emergence of the new pfkelch13 R561H mutation in Rwanda, associated with delayed parasite clearance, suggests that interventions are needed to slow its spread. Using a Rwanda-specific spatial calibration of an individual-based malaria model, we evaluate 26 strategies aimed at minimizing treatment failures and delaying the spread of R561H after 3, 5 and 10 years. Lengthening ACT courses and deploying multiple first-line therapies (MFTs) reduced treatment failures after 5 years when compared to the current approach of a 3-d course of artemether–lumefantrine. The best among these options (an MFT policy) resulted in median treatment failure counts that were 49% lower and a median R561H allele frequency that was 0.15 lower than under baseline. New approaches to resistance management, such as triple ACTs or sequential courses of two different ACTs, were projected to have a larger impact than longer ACT courses or MFT; these were associated with median treatment failure counts in 5 years that were 81–92% lower than the current approach. A policy response to currently circulating artemisinin-resistant genotypes in Africa is urgently needed to prevent a population-wide rise in treatment failures.

Pyronaridine: a review of its clinical pharmacology in the treatment of malaria.

Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based combination therapy (ACT) for both uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Pyronaridine-artesunate, available as a tablet and paediatric granule formulations, is being adopted in regions where malaria treatment outcome is challenged by increasing chloroquine resistance. Pyronaridine is an old antimalarial agent that has been used for more than 50 years as a blood schizonticide, which exerts its antimalarial activity by interfering with the synthesis of the haemozoin pigment within the Plasmodium digestive vacuole. Pyronaridine exhibits a high blood-to-plasma distribution ratio due to its tendency to accumulate in blood cells. This feature is believed to play a crucial role in its pharmacokinetic (PK) properties and pharmacological activity. The PK characteristics of pyronaridine include rapid oral absorption, large volumes of distribution and low total body clearance, resulting in a long terminal apparent half-life. Moreover, differences in PK profiles have been observed between healthy volunteers and malaria-infected patients, indicating a potential disease-related impact on PK properties. Despite a long history, there is only limited knowledge of the clinical PK and pharmacodynamics of pyronaridine, particularly in special populations such as children and pregnant women. We here provide a comprehensive overview of the clinical pharmacology of pyronaridine in the treatment of malaria.