Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: A systematic review of clinical studies from two malaria endemic regions – India and sub-Saharan Africa

Arya, Aditi; Foko, Loick Pradel Kojom; Chaudhry, Shewta; Sharma, Amit; Singh, Vineeta

doi:10.1016/j.ijpddr.2020.11.006

Cited by 57 publications

(65 citation statements)

References 123 publications

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“…However, in high transmission areas like Africa, the detection of minor clones with amplified Pfpm2 in polyclonal infections (MOI > 1) are challenging. Single Nucleotide Polymorphisms (SNP) in the Plasmodium chloroquine resistance transporter ( Pfcrt ) and Plasmodium multi drug resistance 1 ( Pfmdr-1 ) have been suspected to be associated with resistance to ACT partner drugs, lumefantrine and amodiaquine [ 21 , 22 ], but robust molecular markers have not yet been validated [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers

Koko¹,

Warsame

Vonhm

et al. 2022

Malar J

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Background Artesunate–amodiaquine (ASAQ) and Artemether–lumefantrine (AL) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in Liberia. Intermittent preventive treatment with sulfadoxine/pyrimethamine is also recommended for pregnant women. The therapeutic efficacy of Artesunate–amodiaquine and Artemether–lumefantrine, and the frequency of molecular markers associated with anti-malarial drug resistance were investigated. Methods The therapeutic efficacy of ASAQ and AL was evaluated using the standard World Health Organization protocol (WHO. Methods for Surveillance of Antimalarial Drug Efficacy. Geneva: World Health Organization; 2009. https://www.who.int/malaria/publications/atoz/9789241597531/en/). Eligible children were recruited and monitored clinically and parasitologically for 28 days. Polymorphisms in the Pfkelch 13, chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr-1), dihydrofolate reductase (Pfdhfr), and dihydropteroate synthase (Pfdhps) genes and copy number variations in the plasmepsin-2 (Pfpm2) gene were assessed in pretreatment samples. Results Of the 359 children enrolled, 180 were treated with ASAQ (89 in Saclepea and 91 in Bensonville) and 179 with AL (90 in Sinje and 89 in Kakata). Of the recruited children, 332 (92.5%) reached study endpoints. PCR-corrected per-protocol analysis showed ACPR of 90.2% (95% CI: 78.6–96.7%) in Bensonville and 92.7% (95% CI: 83.4.8–96.5%) in Saclepea for ASAQ, while ACPR of 100% was observed in Kakata and Sinje for AL. In both treatment groups, only two patients had parasites on day 3. No artemisinin resistance associated Pfkelch13 mutations or multiple copies of Pfpm2 were found. Most samples tested had the Pfcrt 76 T mutation (80/91, 87.9%), while the Pfmdr-1 86Y (40/91, 44%) and 184F (47/91, 51.6%) mutations were less frequent. The Pfdhfr triple mutant (51I/59R/108 N) was the predominant allele (49.2%). For the Pfdhps gene, it was the 540E mutant (16.0%), and the 436A mutant (14.3%). The quintuple allele (51I/59R/108 N-437G/540E) was detected in only one isolate (1/357). Conclusion This study reports a decline in the efficacy of ASAQ treatment, while AL remained highly effective, supporting the recent decision by NMCP to replace ASAQ with AL as first-line treatment for uncomplicated falciparum malaria. No association between the presence of the mutations in Pfcrt and Pfmdr-1 and the risk of parasite recrudescence in patients treated with ASAQ was observed. Parasites with signatures known to be associated with artemisinin and piperaquine resistance were not detected. The very low frequency of the quintuple Pfdhfr/Pfdhps mutant haplotype supports the continued use of SP for IPTp. Monitoring of efficacy and resistance markers of routinely used anti-malarials is necessary to inform malaria treatment policy. Trial registration ACTRN12617001064392.

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Section: Introductionmentioning

confidence: 99%

Artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers

Koko¹,

Warsame

Vonhm

et al. 2022

Malar J

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“…Several molecular and epidemiological studies have used blood spots on filter paper and Giemsa-stained blood smears as a DNA source [ 22 – 24 ]. Long-term storage of DBS allows for retrospective studies to determine changes in infecting malaria species and the progression of drug resistance over time [ 25 , 26 ]. Moreover, anti-malarial drug resistance 2 is becoming a major issue, emerging as a result of parasite mutation rate, the overall parasite load, strength of the drugs selected, treatment compliance and poor adherence to malaria treatment guidelines, among other factors [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular identification and anti-malarial drug resistance profile of Plasmodium falciparum from patients attending Kisoro Hospital, southwestern Uganda

Manirakiza

Kassaza

Taremwa

et al. 2022

Malar J

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Background The evolution of malaria infection has necessitated the development of highly sensitive diagnostic assays, as well as the use of dried blood spots (DBS) as a potential source of deoxyribonucleic acid (DNA) yield for polymerase chain reaction (PCR) assays. This study identified the different Plasmodium species in malaria-positive patients, and the anti-malarial drug resistance profile for Plasmodium falciparum using DBS samples collected from patients attending Kisoro Hospital in Kisoro district, Southwestern Uganda. Methods The blood samples were prospectively collected from patients diagnosed with malaria to make DBS, which were then used to extract DNA for real-time PCR and high-resolution melting (HRM) analysis. Plasmodium species were identified by comparing the control and test samples using HRM-PCR derivative curves. Plasmodium falciparum chloroquine (CQ) resistance transporter (pfcrt) and kelch13 to screen the samples for anti-malarial resistance markers. The HRM-PCR derivative curve was used to present a summary distribution of the different Plasmodium species as well as the anti-malarial drug profile. Results Of the 152 participants sampled, 98 (64.5%) were females. The average age of the participants was 34.9 years (range: 2 months–81 years). There were 134 samples that showed PCR amplification, confirming the species as Plasmodium. Plasmodium falciparum (N = 122), Plasmodium malariae (N = 6), Plasmodium ovale (N = 4), and Plasmodium vivax (N = 2) were the various Plasmodium species and their proportions. The results showed that 87 (71.3%) of the samples were sensitive strains/wild type (CVMNK), 4 (3.3%) were resistant haplotypes (SVMNT), and 31 (25.4%) were resistant haplotypes (CVIET). Kelch13 C580Y mutation was not detected. Conclusion The community served by Kisoro hospital has a high Plasmodium species burden, according to this study. Plasmodium falciparum was the dominant species, and it has shown that resistance to chloroquine is decreasing in the region. Based on this, molecular identification of Plasmodium species is critical for better clinical management. Besides, DBS is an appropriate medium for DNA preservation and storage for future epidemiological studies.

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“…Currently, treatment using antimalarial drugs is the main control available for clinical malaria infections ( Orwa et al., 2019a ). Moreover, artemisinin-based combination therapy (ACT) is the standard of care for uncomplicated P. falciparum malaria worldwide ( Arya, Foko, Chaudhry, & Singh, 2020 ) . Drug resistance against 4-aminoquinolines and sulpha compounds has remained one of the greatest challenge to malaria chemotherapy development ( Visser, van Vugt, & Grobusch, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Optimal control analysis of hepatocytic-erythrocytic dynamics of Plasmodium falciparum malaria

Orwa

Mbogo

Luboobi

2022

Infectious Disease Modelling

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This paper presents an in-host malaria model subject to anti-malarial drug treatment and malaria vaccine antigens combinations. Pontryagin's Maximum Principle is applied to establish optimal control strategies against infected erythrocytes, infected hepatocytes and malaria parasites. Results from numerical simulation reveal that a combination of pre-erythrocytic vaccine antigen, blood schizontocide and gametocytocide drugs would offer the best strategy to eradicate clinical P. falciparum malaria. Sensitivity analysis, further reveal that the efficacy of blood schizontocides and blood stage vaccines are crucial in the control of clinical malaria infection. Futhermore, we found that an effective blood schizontocide should be used alongside efficacious blood stage vaccine for rapid eradication of infective malaria parasites. The authors hope that the results of this study will help accelerate malaria elimination efforts by combining malaria vaccines and anti-malarial drugs against the deadly P. falciparum malaria.

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Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: A systematic review of clinical studies from two malaria endemic regions – India and sub-Saharan Africa

Cited by 57 publications

References 123 publications

Artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers

Artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers

Molecular identification and anti-malarial drug resistance profile of Plasmodium falciparum from patients attending Kisoro Hospital, southwestern Uganda

Optimal control analysis of hepatocytic-erythrocytic dynamics of Plasmodium falciparum malaria

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