Efficacy of Three Antimalarial Regimens for Uncomplicated Plasmodium Falciparum Malaria in Cambodia, 2009 – 2011: A Randomized Control Trial

Background: Antimalarial resistance remains an important public health challenge in Cambodia. The effectiveness of three therapies for uncomplicated Falciparum malaria were evaluated in Oddar Meanchey province in Northern Cambodia from 2009 – 2011.Methods: In this randomized, open-label, parallel group controlled trial, 211 subjects at least 5 years old with uncomplicated Falciparum malaria were treated with directly observed therapy. Over 3 days, 63 received artesunate-mefloquine (AS/MQ), 77 received dihydroartemisinin-piperaquine (DHA/PPQ), and 71 received atovaquone-proguanil (ATQ/PG). Subjects were followed for 42 days or until recurrent parasitemia. Genotyping of msp1, msp2, and glurp among individual parasite isolates distinguished recrudescence from reinfection. Pfmdr1 copy number was measured by real-time PCR and half-maximal parasite inhibitory concentrations (IC50) was measured in vitro by 48-hour isotopic hypoxanthine incorporation assay.Results: The primary outcome of per-protocol PCR-adjusted efficacy at 42 days was analyzed for 190 (90.0%) of the enrolled subjects. PCR-adjusted efficacy (95% confidence interval) at 42 days was 80.6% (70.8 – 90.5%) for AS/MQ, 97.2% (93.3 – 100%) for DHA/PPQ, and 92.9% (86.1 – 99.6%) for ATQ/PG. On day 3, 59.3% remained parasitemic. At baseline, 46.9% had microscopic P. falciparum gametocytemia. Both recurrences in the DHA/PPQ arm lost Pfmdr1 copy number amplification at recrudescence. All four recurrences in the ATQ/PG arm were wild-type for cytochrome bc1. One subject withdrew from the ATQ/PG arm due to drug allergy.Conclusions: This previously unpublished study was conducted at the epicenter of substantial multi-drug resistance that emerged soon thereafter. Occurring early in the national transition from AS/MQ to DHA/PPQ, both DHA/PPQ and ATQ/PG had acceptable efficacy against uncomplicated falciparum malaria. However, efficacy of AS/MQ was only 80% with apparent mefloquine resistance based on elevated Pfmdr1 copy number and IC50. By 2009, there was already significant evidence of artemisinin resistance not previously reported at the Northern Cambodia-Thai border. This study suggests the basis for early development of significant DHA/PPQ failures within 3 years of introduction. Artemisinin resistance likely occurred on the Northern border concurrently with that reported along the Western border in Pailin.Trial Registration: This legacy trial was conducted prior to International Committee of Medical Journal Editors’ requirements for preregistration on ClinicalTrials.gov. The full protocol has been provided.

Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria and prevalence of molecular markers associated with artemisinin and partner drug resistance in Uganda

Background In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019. Methods This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trail was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

Background The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether–lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. Methods This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether–lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. Results Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether–lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether–lumefantrine. Cipargamin was well tolerated with no safety concerns. Conclusions This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin. Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202

Delayed Parasite Clearance Rates and Low Clinical and Parasitological Responses Following Treatment of Uncomplicated Falciparum Malaria With Artemether-lumefantrine in Ethiopian- Sudan Border, Western Ethiopia

BackgroundThe appearance of artemisinin-resistant parasites in Africa is catastrophic as many cases and deaths from malaria are usually reported in the continent. This study was the first to evaluate the status of artemether-lumefantrine (AL) efficacy, seventeen years after the introduction of this drug in the study area. This study aimed to assess PCR- corrected clinical and parasitological responses at 28 days following AL treatment.MethodsSixty uncomplicated falciparum malaria patients were enrolled, treated with standard doses of AL, and monitored for 28 days with clinical and parasitological assessments from September 15 to December 15, 2020. Molecular analysis was done on dried blood spots collected from each patient from day 0 and on follow-up days 1, 2, 3, 7, 14, 21, and 28. Descriptive statistics and binary logistic regressions were done using SPSS 20.0 statistical software. A p-value of less or equal to 0.05 was considered significant.ResultsSixty patients enrolled in the study, ten were lost to follow-up; and the results were analyzed for 50 patients. All of the patients were fever-free on day 3. But, two patients febrile on day 1 became febrile on day 7 of the follow-up period. Day 3 parasites positivity rate was zero and 60 % using microscopy and PCR, respectively. Parasite clearance on day 3 was more among patients ≥ 15 years as compared with < 15 years (AOR= 6.71, P=0.021). 14 of 50 patients tested were parasite positive on day 7 by PCR. In addition, 7 patients had persisted parasitemia by PCR from day 0 to day 28 of the follow-up. The PCR-corrected adequate clinical and parasitological response (ACPR) rate was 59.2 %. PCR adjusted AL treatment failures was 40.8% and it was noted as 0 early treatment failure, 10.2% late clinical failures, and 30.6% late parasitological failures. Recrudescence and new infection rate within 28 days was7/50(14%) and1/50 (2%) respectively.Conclusionartemisinin resistance is suspected in the study area as parasite positivity rate on day 3 was greater than 10%. A slow parasitological clearance was followed by low-density parasitemia persistence and recrudescences. AL treatment failure was greater than the 10% threshold for treatments in use as per WHO. These findings suggest probably a decreased sensitivity of the parasite for the artemisinin component and the partner drug and highlight the need for prompt reassessment of the efficacy of AL and other factors that may contribute to low parasite susceptibility to the drug.

Efficacy of Quinine Plus Clindamycin Versus Artemether-Lumefantrine For The Treatment of Uncomplicated Plasmodium Falciparum Malaria In Kenyan Children (CLINDAQUINE): An Open-Label Randomised Trial

Background: World Health Organisation recommends quinine plus clindamycin as first-line treatment of malaria in the first trimester of pregnancy and as a second-line treatment for uncomplicated falciparum malaria when artemisinin-based drug combinations are not available. We compared the efficacy of quinine plus clindamycin with that of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in children below 5 years of age. Methods: An open-label, phase 3, randomised trial was conducted in western Kenya. Children aged 6-59 months with uncomplicated falciparum malaria were randomly assigned (1:1) via a computer-generated randomization list to receive 3 days of twice a day treatment with either oral quinine (20mg/kg/day) plus clindamycin (20mg/kg/day) or artemether-lumefantrine tablets (artemether 20mg, lumefantrine 120mg). The primary outcome was a PCR-corrected rate of adequate clinical and parasitological response (ACPR) on day 28 in the per-protocol population. Results: A total of 384 children were enrolled and randomised, 192 to quinine plus clindamycin and 192 to artemether-lumefantrine. A total of 353 (92%) children were analysed. The PCR-corrected ACPR rate was 44.0% (80 children) in the quinine plus clindamycin group and 97.1% (166 children) in the artemether-lumefantrine group (treatment difference -53.1%, 95% CI -43.5% to -62.7%). At 72h after starting treatment, 50.3% (94 children) in the quinine plus clindamycin group were still parasitemic compared with 0.5% (1 child) in the artemether-lumefantrine group. Three serious adverse events occurred in the quinine plus clindamycin group. Conclusions: We found no evidence to support the use of quinine plus clindamycin in the treatment of uncomplicated falciparum malaria in children under 5 years of age in Kenya, where artemether-lumefantrine is still effective. Trial Registration: This trial is registered with the Pan-African Clinical Trials Registry, ACTR20129000419241.

Efficacy of dihydroartemisinin-piperaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria among children in Africa: a systematic review and meta-analysis of randomized control trials

Background Emergence of Plasmodium falciparum resistance to artemisinin and its derivatives poses a threat to the global effort to control malaria. The emergence of anti-malarial resistance has become a great public health challenge and continues to be a leading threat to ongoing malaria control efforts. The aim of this review was to synthesize available evidence on the efficacy of dihydroartemisinin-piperaquine (DHA-PQ) compared to artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria among children in Africa. Methods A systematic literature search was done to identify relevant articles from online databases PubMed/ MEDLINE, Embase, and Cochrane Central Register of Controlled Trials’ database (CENTRAL) for retrieving randomized control trials comparing efficacy of DHA-PQ and AL for treatment of uncomplicated falciparum malaria in African children. The search was performed from August 2020 to April 2021. Using Rev-Man software (V5.4.1), R-studio and Comprehensive Meta-analysis software version 3, the extracted data from eligible studies were pooled as risk ratio (RR) with 95% confidence interval (CI). Results In this review, 25 studies which involved a total of 13,198 participants were included. PCR-unadjusted treatment failure in children aged between 6 months and 15 years was significantly lower in the DHA-PQ treatment arm on day 28 than that of AL (RR 0.14, 95% CI 0.08–0.26; participants = 1302; studies = 4; I2 = 0%, high quality of evidence). Consistently, the PCR-adjusted treatment failure was significantly lower with DHA-PQ treatment group on day 28 (RR 0.45, 95% CI 0.29–0.68; participants = 8508; studies = 16; I2 = 51%, high quality of evidence) and on day 42 (RR 0.60, 95% CI 0.47–0.78; participants = 5959; studies = 17; I2 = 0%, high quality of evidence). However, the efficacy was ≥ 95% in both treatment groups on day 28. Conclusion From this review, it can be concluded that DHA-PQ reduces new infection and recrudescence on days 28 and 42 more than AL. This may trigger DHA-PQ to become a first-line treatment option.

Hematological Parameters and Key Cytokines in Patients With Uncomplicated Falciparum Malaria in Hodeidah, Yemen

Immunity to malaria has a major role in controlling disease and pathogenesis with cytokine production being involved in almost each phase of the immune response. The present study aimed to assess hematological variables and to measure plasma levels of TNFα, IFNg and IL10, their ratios, and their relation to parasitemia among patients with uncomplicated falciparum malaria in Hodeidah, Yemen. Forty patients with uncomplicated P. falciparum monoinfection and 40 healthy age and sex matched controls were enrolled in the study. Parasitological diagnosis was confirmed, and parasite density estimated. Hematologic parameters, the presence of gametocytes, and plasma cytokine levels were determined. Results revealed lower Hb levels, RBC, lymphocyte and platelet counts and higher neutrophil and reticulocyte counts among patients compared to controls. TNFα, IFNg and IL10 were higher in patients than controls. A relatively higher IL10 production was demonstrated by the significantly lower TNFα/IL10 and IFNg/IL10 ratios in patients than controls. TNFα and IL10 correlated positively with parasite density. Reticulocyte count was higher and IFNg level was lower in the presence of gametocytes. Conclusively, uncomplicated falciparum malaria is associated with the ability to regulate the production of the pro-inflammatory and anti-inflammatory cytokines. This mediates parasite clearance while simultaneously avoiding severe pathology.

Correction to: Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria

An amendment to this paper has been published and can be accessed via the original article.

Efficacy and Safety of Artemether-Lumefantrine for Treatment of Uncomplicated P. Falciparum malaria in Ethiopia: A Systematic Review and Meta-Analysis

Background: Anti-malarial drug resistance, in particular resistance to Plasmodium falciparum, challenges the treatment and control of malaria. In Ethiopia, the first-line treatment of uncomplicated falciparum malaria has been changed from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (AL) in 2004. To maximize efficacy of anti-malarial drugs and ensure adequate treatment outcomes; monitoring drug efficacy regularly is vital to establish rational malaria treatment guidelines. This systematic review and meta-analysis is performed to obtain an overall stronger evidence to guide management of uncomplicated falciparum malaria from the existing literature in Ethiopia after policy changes in 2004.Methods: A systematic literature search was performed using the preferred reporting items for systematic review and meta-analysis (PRISMA) from published therapeutic efficacy studies conducted in Ethiopia from 2004 to 2020. The search was performed from Pubmed, Google Scholar and Clinical trial registry databases to identify literature. Two reviewers independently assessed study eligibility and extracted data. While computing the efficacy of AL, polymerase chain reaction (PCR)-corrected cure rate (adequate clinical and parasitological response, ACPR) at 28th day was considered as the primary endpoint. Meta-analysis was computed using OpenMeta-Analysis software to calculate the pooled ACPR. Statistical heterogeneity was evaluated with the Cochran chi-square test (X2) test and inverse variance index (I2). Publication bias was analyzed using funnel plots and Egger’s test statistics. The review protocol is registered in PROSPERO, number CRD42020201859.Results: Out of studies screened, fifteen studies fulfilled the inclusion criteria, and were included in final analysis with a total number of 1523 participants. Treatment success of AL for uncomplicated falciparum malaria in all combined studies was 98.4% [(95% CI 97.6–99.1), P< 0.001]. Polymerase chain reaction (PCR)-corrected AL treatment success rate of 98.7% [(95% CI 97.7-99.6), P<0.001)]. The efficacy of AL with PCR-corrected cure rates ranging from 95.0 to 99.4% in per-protocol analysis, and 88.8 to 97.4% in intention-to-treat analysis. Based on the analysis, Cochrane chi-square test (X2) test and inverse variance index (I2) indicated that the included studies with heterogeneity (X2=20.48, (df=14), P=0.116 and I2=31.65%). The highest parasite positivity rate at day-3 was 5.7%. Adverse events ranged from mild to serious but were not directly attributed to the drug.Conclusion: The present review has shown that AL is efficacious and safe for treatment of uncomplicated malaria in Ethiopia. However, few therapeutic efficacy studies were conducted in Ethiopia after treatment guideline was revised in 2004. AL has been used more than a decade in the study population without other alternative artemisinin-based combination therapy in Ethiopia and considering that the potential evolution of drug resistance is of a great concern, regular and continuous monitoring of its efficacy is warranted.