Table 2 A summary of the papers which were analysed in this systematic literature review, detailing which molecular markers were detected following treatment, and any changes in the frequency of molecular markers investigated
Molecular marker associated with DHA-PPQ resistance | Associated trial(s) | Intervention | Publication | Impact of intervention on molecular marker |
|---|---|---|---|---|
Pfpm2 copy number | Samples from multiple trials and epidemiological studies conducted between 1st Jan 2007 and 31st December 2018Â were analysed by Imwong et al. (2020). Therapeutic efficacy studies of artesunate [50] and DHA-PPQ in Yunnan Province of China, from 2009 to 2012 | Multiple trials and epidemiological studies, including MDA with DHA-PPQ in Kayin State, Myanmar | Imwong et al. (2020) [51] Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study | This study found that between Jan 1 2007 and Dec 31 2018, pfpm2 amplification was more frequent in the eastern Grater Mekong subregion than in Myanmar. Regarding mass drug administration, there was no evidence of selection for increased pfpm2 copy number following MDA with DHA-PPQ in Myanmar and Cambodia |
NCT02914145 Mass Drug Administration of Monthly DHA-PQP to Accelerate Towards Malaria Elimination in Magude District, Southern Mozambique | Mass Drug Administration with DHA-PPQ. Two monthly rounds of MDA with DHA-PPQ for two consecutive years in Magude, Southern Mozambique | Gupta et al. (2020) [52] Effect of mass dihydroartemisinin–piperaquine administration in southern Mozambique on the carriage of molecular markers of antimalarial resistance | There was no statistically significant difference in the proportion of isolates with multicopy pfpm2 when comparing samples collected pre and post MDA | |
NCT02282293 Reducing the Burden of Malaria in HIV-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE Birth Cohort 2) | Randomized controlled trial among 300 pregnant women in Uganda. Participants were randomized to receive either: (i) SP (500 mg Sulphadoxine and 25 mg pyrimethamine) every 8 weeks (ii) DHA-PPQ (40 mg dihydroartemisinin and 320 mg PQ) every 8 weeks or (iii) DHA-PPQ every 4 weeks | Conrad et al. (2017) [53] Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance–Mediating Polymorphisms in Uganda | This study found a modest increase in pfpm2 copy number in 1 of 18 samples from patients receiving DHA-PPQ IPTp | |
NCT01872702 Targeted Chemo-elimination (TCE) to Eradicate Malaria in Areas of Suspected or Proven Artemisinin Resistance in Southeast Asia and South Asia | Active comparator: Three monthly rounds of DHA-PPQ and low dose primaquine Placebo comparator: No intervention used Two villages randomly allocated to intervention at each of 4 sites, and two villages randomly allocated to control (no intervention). 500 people per village | von Seidlein et al., (2019) [54] The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomized trial | This study analysed blood specimens from before MDA initiation. They found that 4% of the individuals sampled (10 of 269) had pfkelch13 C580Y and multiple copies of pfpm2/3. This study did not measure the difference in prevalence of markers pre and post MDA | |
Landier et al. (2017) [55] Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: a pilot trial in four villages of Eastern Myanmar | This study found no amplification of pfpm2 copy number in the 69 samples that they analysed, which were 53 collected before the MDA and 16 collected afterwards | |||
NCT02083380 Randomizedd Phase IIb Study of Efficacy, Safety, Tolerability & Pharmacokinetics of a Single Dose Regimen of Artefenomel (OZ439) in Loose Combination With Piperaquine in Adults and Children With Uncomplicated Plasmodium falciparum Malaria | Experimental: A) Artefenomel 800 mg and Piperaquine Phosphate 640 mg Experimental: B) Artefenomel 800 mg and Piperaquine Phosphate 960 mg Experimental: C) Artefenomel 800 mg and Piperaquine Phosphate 1440 mg | Leroy et al. (2019) [56] African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker | This study analysed pfpm2 copy number in samples collected from patients before treatment. They found a higher proportion of multicopy parasites in African samples compared to Asian samples. Parasites with multicopy pfpm2 and single copy pfmdr1 (hypothesized to favour PPQ resistance) were found at similar prevalence in Asian and African samples | |
Samples from multiple trials and epidemiological studies were analysed by Imwong et al. (2017). Those that were trials that included PPQ or DHA-PPQ were NCT02453308 | Longitudinal observational study between 1st January 2008 and 31st December 2015 | Imwong et al. (2017) [57] The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study | This study found pfpm2 amplification in isolates collected between 1st January and 31st December 2008, in western Cambodia and north-eastern Thailand. Pfpm2 amplification was only observed in parasites with the C580Y ‘long haplotype’ | |
Pfexo E415G mutation | NCT02282293 Reducing the Burden of Malaria in HIV-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE Birth Cohort 2) | Randomizedcontrolled trial among 300 pregnant women in Uganda. Participants were randomizedd to receive either: (i) SP (500 mg Sulphadoxine and 25 mg pyrimethamine) every 8 weeks, (ii) DHA-PPQ (40 mg dihydroartemisinin and 320 mg PQ) every 8 weeks, or (iii) DHA-PPQ every 4 weeks | Conrad et al. (2017) [53] Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance–Mediating Polymorphisms in Uganda | Conrad et al.sequenced a 395 bp amplicon surrounding the E415G locus but did not find the E415G mutation in the samples that they analysed. They detected a different non-synonymous mutation in pfexo, R346T, in 1 of 19 samples collected from patients receiving DHA-PPQ treatment |
NCT02788864 A Randomized, Placebo-controlled, Double-blind Trial Using Dihydroartemisinin and Piperaquine (DHA-PPQ) to Protect Forest Workers From Malaria in Bu Gia Map National Park | Active comparator: DHA-PPQ for 3Â days prior to forest visit Placebo comparator: Placebo for 3Â days prior to forest visit 150 participants | Son et al. (2017) [58] The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study | This study found that before MDA, 11 out of 30 samples had the E415G mutation. Following MDA and returning from working in the forest, two study participants were infected with P. falciparum. One in the DHA-PPQ arm and one in the placebo arm. The participant in the placebo arm was infected with wild-type P. falciparum when they entered the forest, but the E415G mutation when they returned | |
Pfcrt mutations | NCT02793622 Prevention of Malaria in HIV-uninfected Pregnant Women and Infants | IPTp during pregnancy: Active comparator arm: Monthly SP during pregnancy Active comparator arm: Monthly DHA-PPQ during pregnancy 782 participants | Nayebare et al. (2020) [59] Associations between Malaria-Preventive Regimens and Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Ugandan Pregnant Women | This study found that pfcrt K76T was more prevalent in parasites collected while women received IPTp with DHA-PPQ, than in parasites collected before the start of IPTp, or while women received IPTp with SP |
Samples from multiple trials and epidemiological studies conducted between 1st Jan 2007 and 31st December 2018Â were analysed by Imwong et al. (2020). Therapeutic efficacy studies of artesunate [50] and DHA-PPQ in Yunnan Province of China, from 2009 to 2012 | Multiple trials and epidemiological studies, including MDA with DHA-PPQ in Kayin State, Myanmar | Imwong et al. (2020) [51] Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study | This study found no evidence for selection of pfcrt mutations associated with piperaquine resistance following MDA with DHA-PPQ in Kayin State, Myanmar, or in Cambodia | |
NCT02914145 Mass Drug Administration of Monthly DHA-PQP to Accelerate Towards Malaria Elimination in Magude District, Southern Mozambique | Mass Drug Administration with DHA-PPQ. Two monthly rounds of MDA with DHA-PPQ for two consecutive years in Magude, Southern Mozambique | Gupta et al. (2020) [52] Effect of mass dihydroartemisinin–piperaquine administration in southern Mozambique on the carriage of molecular markers of antimalarial resistance | This study found no statistically significant difference between the frequency of pfcrt polymorphisms when comparing samples collected before and after MDA | |
NCT02282293 Reducing the Burden of Malaria in HIV-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE Birth Cohort 2) | Randomized controlled trial among 300 pregnant women in Uganda. Participants were randomizedto receive either: (i) SP (500Â mg Sulphadoxine and 25Â mg pyrimethamine) every 8Â weeks, (ii) DHA-PPQ (40Â mg dihydroartemisinin and 320Â mg PQ) every 8Â weeks, or (iii) DHA-PPQ every 4Â weeks | Wallender et al. (2019) [60] Modelling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda | This study used non-linear mixed effects modelling to describe the relationship between PPQ concentration and the probability of finding the mutation N86Y in pfmdr1 and K76T in pfcrt. The models predicted that higher median PPQ concentrations would be required to prevent infections with mutant haplotypes compared to wild-type haplotypes | |
Conrad et al. (2017) [53] Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance–Mediating Polymorphisms in Uganda | Treatment with DHA-PPQ was associated with increased prevalence of pfcrt K76T compared with samples collected before treatment, or treatment with SP. Selection increased with increasing PPQ exposure. Receipt of DHA-PPQ selected for the pfcrt 76T-mdr1 N86-184F-1246D haplotype | |||
NCT00527800 Interactions Between HIV and Malaria in African Children 5 year longitudinal trial from 2007 to 2012 in Tororo, Uganda | Experimental arm 1: Treatment for episodes of uncomplicated malaria with DHA-PPQ, once daily for 3 days Comparator arm 2: Treatment for uncomplicated malaria with artemether-lumefantrine, twice daily for 3 days Experimental A: Prevention of malaria in HIV uninfected, exposed children, with trimethoprim-sulfamethoxazole No intervention B: Prevention of malaria in HIV uninfected, exposed children | Conrad et al. (2014) [42] Comparative Impacts Over 5 Years of Artemisinin-Based Combination Therapies on Plasmodium falciparum Polymorphisms That Modulate Drug Sensitivity in Ugandan Children | Treatment over time with DHA-PPQ or AL was associated with higher prevalences of wildtype K76. The extent of selection was lower than that with recent treatment with AL | |
NCT00941785 Randomized Trial of the Efficacy, Safety, Tolerability and Pharmacokinetics of Dihydroartemisinin-piperaquine for Seasonal IPT to Prevent Malaria in Children Under 5 Years | Experimental: Three monthly rounds of DHA-PPQ in August, September and October Active comparator: Three monthly rounds of Sulphadoxine-Pyrimethamine plus Amodiaquine 1500 particpants | Zongo et al. (2015) [61] Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulphadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso | This study found no significant difference in prevalence of the pfcrt mutation K76T following SMC with DHA-PPQ | |
Somé et al. (2014) [62] Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso | This study measured the prevalence of mutations in parasites collected before the initiation of the intervention, a month after the completion of three-monthly treatments, and from a control group of children not subject to the intervention. They found no significant selection of pfcrt K76T following treatment with DHA-PPQ | |||
NCT00948896 and NCT00978068 | Experimental arm 1: TS; TMP/SMX given daily Experimental arm 2: SP given monthly as a single dose Experimental arm 3: DHA-PPQ given monthly, once a day for 3 consecutive days Arm 4, no intervention | Tumwebaze et al. (2015) [63] Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from Ugandan children | This study found minor differences in the prevalence of SNPs associated with drug resistance between different trial arms. Monthly DHA-PPQ treatment was not associated with polymorphisms in pfcrt | |
Pfmdr1 polymorphisms | NCT02793622 Prevention of Malaria in HIV-uninfected Pregnant Women and Infants | IPTp during pregnancy: Active comparator arm: Monthly SP during pregnancy Active comparator arm: Monthly DHA-PPQ during pregnancy 782 participants | Nayebare et al. (2020) [59] Associations between Malaria-Preventive Regimens and Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Ugandan Pregnant Women | This study found that pfmdr1 N86Y and Y184F were more prevalent in parasites collected while women received IPTp with DHA-PPQ, than in parasites collected before the start of IPTp, or while women received IPTp with SP. The prevalence of D1246Y was similar in parasites collected before and after IPTp |
NCT02914145 Mass Drug Administration of Monthly DHA-PQP to Accelerate Towards Malaria Elimination in Magude District, Southern Mozambique | Mass Drug Administration with DHA-PPQ. Two monthly rounds of MDA with DHA-PPQ for two consecutive years in Magude, Southern Mozambique | Gupta et al. (2020) [52] Effect of mass dihydroartemisinin–piperaquine administration in southern Mozambique on the carriage of molecular markers of antimalarial resistance | This study found no evidence of statistically significant differences in pfmdr1 polymorphisms, including pfmdr1 copy number, when comparing samples collected before and after MDA | |
Samples from multiple trials and epidemiological studies conducted between 1st Jan 2007 and 31st December 2018Â were analysed by Imwong et al. (2020). Therapeutic efficacy studies of artesunate [50] and DHA-PPQ in Yunnan Province of China, from 2009 to 2012 | Multiple trials and epidemiological studies, including MDA with DHA-PPQ in Kayin State, Myanmar | Imwong et al. (2020) [51] Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study | This study found that pfmdr1 amplification is at low prevalence across the Greater Mekong subregion | |
NCT02083380 Randomized Phase IIb Study of Efficacy, Safety, Tolerability & Pharmacokinetics of a Single Dose Regimen of Artefenomel (OZ439) in Loose Combination With Piperaquine in Adults and Children With Uncomplicated Plasmodium falciparum Malaria | Experimental: A) Artefenomel 800Â mg and Piperaquine Phosphate 640Â mg Experimental: B) Artefenomel 800Â mg and Piperaquine Phosphate 960Â mg Experimental: C) Artefenomel 800Â mg and Piperaquine Phosphate 1440Â mg | Leroy et al. (2019) [56] African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker | This study analysed pfmdr1 copy number in samples collected from patients before treatment. They found a threefold higher prevalence of multicopy pfmdr1 in Africa than in Asia. Parasites with multicopy pfpm2 and single copy pfmdr1 (which is hypothesized to favour PPQ resistance) were found at similar prevalence in Asian and African samples | |
NCT02282293 Reducing the Burden of Malaria in HIV-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE Birth Cohort 2) | Randomized controlled trial among 300 pregnant women in Uganda. Participants were randomized to receive either: (i) SP (500Â mg Sulphadoxine and 25Â mg pyrimethamine) every 8Â weeks, (ii) DHA-PPQ (40Â mg dihydroartemisinin and 320Â mg PQ) every 8Â weeks, or (iii) DHA-PPQ every 4Â weeks | Wallender et al. (2019) [60] Modelling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda | This study used non-linear mixed effects modelling to describe the relationship between PPQ concentration and the probability of finding the mutation N86Y in pfmdr1 and K76T in pfcrt. The models predicted that higher median PPQ concentrations would be required to prevent infections with mutant haplotypes compared to wild-type haplotypes | |
Conrad et al. (2017) [53] Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance–Mediating Polymorphisms in Uganda | Treatment with DHA-PPQ was associated with increased prevalence of pfmdr1 N86Y and Y184F mutations compared with before treatment, or treatment with SP. Increased frequency of DHA-PPQ exposure was associated with increased prevalence of pfmdr1 N86Y. Treatment with DHA-PPQ was associated with decreased prevalence of D1246Y compared with samples collected before treatment, or treatment with SP. DHA-PPQ treatment selected for the pfmdr1 86Y-184F, 86Y-D1246, N86-184F-1246D and the pfcrt 76T-mdr1 N86-184F-1246D haplotypes. Consistent with this, a generalized linear model of PPQ exposure demonstrated that increasing PPQ concentration was associated with increasing prevalence of N86Y. There was no evidence of increased pfmdr1 copy number associated with DHA-PPQ treatment | |||
NCT02788864 A Randomized, Placebo-controlled, Double-blind Trial Using Dihydroartemisinin and Piperaquine (DHA-PPQ) to Protect Forest Workers From Malaria in Bu Gia Map National Park | Active comparator: DHA-PPQ for 3Â days prior to forest visit Placebo comparator: Placebo for 3Â days prior to forest visit 150 participants | Son et al. (2017) [58] The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study | This study found that before MDA, no P. falciparum isolates that were genotyped had multiple copies of pfmdr1. Following MDA and returning from working in the forest, two study participants were infected with P. falciparum. Neither had multicopy pfmdr1 | |
NCT00941785 Randomized Trial of the Efficacy, Safety, Tolerability and Pharmacokinetics of Dihydroartemisinin-piperaquine for Seasonal IPT to Prevent Malaria in Children Under 5 Years | Experimental: Three monthly rounds of DHA-PPQ in August, September and October Active comparator: Three monthly rounds of Sulphadoxine-Pyrimethamine plus Amodiaquine 1500 participants | Zongo et al. (2015) [61] Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulphadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso | This study found no significant difference in the prevalence of pfmdr1 mutations N86Y, F184Y or D1246Y following SMC with DHA-PPQ | |
Somé et al. (2014) [62] Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso | Measured the prevalence of mutations in parasites collected from children before the initiation of the intervention, from children a month after the completion of three-monthly treatments, and from a control group of children not subject to the intervention. They found borderline significant selection for pfmdr1 D1246Y following treatment with DHA-PPQ | |||
NCT00527800 Interactions Between HIV and Malaria in African Children 5Â year longitudinal trial from 2007 to 2012 in Tororo, Uganda | Experimental arm 1: Treatment for episodes of uncomplicated malaria with DHA-PPQ, once daily for 3Â days Comparator arm 2: Treatment for uncomplicated malaria with artemether-lumefantrine, twice daily for 3Â days Experimental A: Prevention of malaria in HIV uninfected, exposed children, with trimethoprim-sulfamethoxazole No intervention B: Prevention of malaria in HIV uninfected, exposed children | Taylor et al. (2016) [64] Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine Exert Inverse Selective Pressure on Plasmodium falciparum Drug Sensitivity-Associated Haplotypes in Uganda | This study fit a haplotype frequency estimation model to study pfmdr1 N86Y, Y184F and D1246Y alleles. They found that DHA-PPQ selected for 86Y, but only when this was combined with Y184 and 1246Y, selecting for the haplotype YYY, and against haplotypes NFD and NYY | |
Conrad et al. (2014) [42] Comparative Impacts Over 5 Years of Artemisinin-Based Combination Therapies on Plasmodium falciparum Polymorphisms That Modulate Drug Sensitivity in Ugandan Children | The prevalences of N86, 184F and D1246 increased over the time of the study. When comparing the ALÂ and DHA-PPQ treatment arms, the prevalences of these alleles was greater in the AL treatment arm. Recent treatment with DHA-PPQ was associated with increased prevalence of pfmdr1 N86Y, D1246Y and a lower prevalence of Y184F. The extent of selection was lower than that with recent treatment with AL. There was no association between treatment arm and pfmdr1 copy number | |||
NCT00948896 A Randomized Controlled Trial of Monthly Dihydroartemisinin-piperaquine Versus Monthly Sulfadoxine-pyrimethamine Versus Daily Trimethoprim-sulfamethoxazole Versus No Therapy for the Prevention of Malaria | Experimental arm 1: TS; TMP/SMX given daily Experimental arm 2: SP given monthly as a single dose Experimental arm 3: DHA-PPQ given monthly, once a day for 3 consecutive days Arm 4, no intervention | Tumwebaze et al. (2015) [63] Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from Ugandan children | This study found minor differences in the prevalence of SNPs associated with drug resistance between different trial arms. Monthly DHA-PPQ treatment was not associated with polymorphisms in pfmdr1. However, when samples from the DHA-PPQ treatment arm were sorted based on circulating PPQ levels, parasites with higher PPQ exposure showed evidence for selection for pfmdr1 86Y and 1246Y mutations | |
Ochong et al. (2013) [65] Fitness Consequences of Plasmodium falciparum pfmdr1Polymorphisms Inferred from Ex Vivo Culture of Ugandan Parasites | This study did not measure changes in molecular markers of resistance in trial participants; this study cultured parasites from participants to evaluate fitness advantages of certain pfmdr1 polymorphisms. Their results suggest fitness advantages for parasites with the pfmdr1 N86Y mutation and wild-type D1246Y | |||
Artemisinin-resistance associated mutations | NCT02914145 Mass Drug Administration of Monthly DHA-PQP to Accelerate Towards Malaria Elimination in Magude District, Southern Mozambique | Mass Drug Administration with DHA-PPQ. Two monthly rounds of MDA with DHA-PPQ for two consecutive years in Magude, Southern Mozambique | Gupta et al. (2020) [52] Effect of mass dihydroartemisinin–piperaquine administration in southern Mozambique on the carriage of molecular markers of antimalarial resistance | There was no statistically significant difference between the frequency of polymorphisms when comparing samples collected pre and post MDA. No pfkelch13 polymorphisms associated with partial-resistance to artemisinin were found in the isolates analyzed |
Samples from multiple trials and epidemiological studies conducted between 1st Jan 2007 and 31st December 2018Â were analysed by Imwong et al. (2020). Therapeutic efficacy studies of artesunate[50] and DHA-PPQ in Yunnan Province of China, from 2009 to 2012 | Multiple trials and epidemiological studies, including MDA with DHA-PPQ in Kayin State, Myanmar | Imwong et al. (2020) [51] Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study | The longitudinal study found that two genotypes of pfkelch have come to dominate: the Cys580Tyr mutation in the eastern Greater Mekong subregion, and the Phe446Ile mutation in Myanmar. They found no evidence for further selection of pfkelch mutations following mass treatment with DHA-PPQ | |
NCT01872702 Targeted Chemo-elimination (TCE) to Eradicate Malaria in Areas of Suspected or Proven Artemisinin Resistance in Southeast Asia and South Asia | Active comparator: Three monthly rounds of DHA-PPQ and low dose primaquine Placebo comparator: No intervention used Two villages randomly allocated to intervention at each of 4 sites, and two villages randomly allocated to control (no intervention). 500 people per village | von Seidlein et al. (2019) [54] The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomized trial | This study analysed blood specimens from before MDA initiation. They found that 4% of the individuals sampled (10 of 269) had pfkelch13 C580Y and multiple copies of pfpm2/3. This study did not measure the difference in prevalence of markers pre and post MDA. 9/10 of the participants with the C580Y genotyped parasites cleared their parasitaemia after receiving the MDA | |
Tripura et al. (2018) [66] A Controlled Trial of Mass Drug Administration to Interrupt Transmission of Multidrug-Resistant Falciparum Malaria in Cambodian Villages | This study found that all genotyped Plasmodium infections carried the pfkelch13 C580Y mutation. Of isolates genotyped up to April 2016, 34 had the C580Y mutation and 1 had the F446I mutation | |||
Landier et al. (2017) [55] Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar | This study measured the prevalence of pfkelch13 mutations before and after MDA. They found that the prevalence was 85.6% before and 56.7% afterwards. The most frequent mutations were C580Y and G358V | |||
NCT number not available Large-scale Artemisinin-Piperaquine Mass Drug Administration with or Without Primaquine, Anjouan Island, Union of Comoros | Artemisinin-piperaquine (AP), with or without primaquine, was given in 3 monthly rounds as MDA | Deng et al. (2018) [67] Large-scale Artemisinin–Piperaquine Mass Drug Administration With or Without Primaquine Dramatically Reduces Malaria in a Highly Endemic Region of Africa | This study found no evidence for the selection of pfkelch mutations in the analysis of 52 malaria samples collected following MDA with artemisinin-piperaquine (with or without PMQ) | |
NCT02282293 Reducing the Burden of Malaria in HIV-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE Birth Cohort 2) | Randomized controlled trial among 300 pregnant women in Uganda. Participants were randomized to receive either (i) SP (500 mg Sulphadoxine and 25 mg pyrimethamine) every 8 weeks (ii) DHA-PPQ (40 mg dihydroartemisinin and 320 mg PQ) every 8 weeks or (iii) DHA-PPQ every 4 weeks | Conrad et al. (2017) [53] Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Uganda | This study found no evidence for the selection of pfkelch13 mutations between treatment groups | |
NCT02083380 Randomized Phase IIb Study of Efficacy, Safety, Tolerability & Pharmacokinetics of a Single Dose Regimen of Artefenomel (OZ439) in Loose Combination With Piperaquine in Adults and Children With Uncomplicated Plasmodium falciparum Malaria | Experimental: A) Artefenomel 800Â mg and Piperaquine Phosphate 640Â mg Experimental: B) Artefenomel 800Â mg and Piperaquine Phosphate 960Â mg Experimental: C) Artefenomel 800Â mg and Piperaquine Phosphate 1440Â mg | Leroy et al. (2019) [56] African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker | This study analysed samples collected from patients before treatment. They found that 67.6% of isolates genotyped from Vietnam had pfkelch13 resistance mutations. In contrast, none of the 332 isolates successfully genotyped from African patients carried validated or candidate pfkelch13 mutations | |
Macintyre et al. (2017) [68] A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria | This study analysed pfkelch13 mutations and found a high mutation frequency in Vietnam of 70.1%. Five mutations were detected, including C580Y, I543T, P553L and V568G, all associated with artemisinin partial resistance, and C469P, which is not associated with artemisinin partial resistance. The presence of these mutations was associated with parasite clearance half-life. The most common pfkelch13 genotypes were C580Y and P553L | |||
Samples from multiple trials and epidemiological studies were analysed by Imwong et al. (2017). Those that were trials that included PPQ or DHA-PPQ were NCT02453308 | Longitudinal observational study between 1st January 2008 and 31st December 2015 | Imwong et al. (2017) [57] The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study | This study found that over a large area of the Greater Mekong subregion, a single long haplotype pfkelch C580Y mutant lineage has come to dominate | |
NCT02788864 A Randomized, Placebo-controlled, Double-blind Trial Using Dihydroartemisinin and Piperaquine (DHA-PPQ) to Protect Forest Workers From Malaria in Bu Gia Map National Park | Active comparator: DHA-PPQ for 3Â days prior to forest visit Placebo comparator: Placebo for 3Â days prior to forest visit 150 participants | Son et al. (2017) [58] The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study | This study found that before MDA, 11 out of 30 P. falciparum had the C580Y kelch13 mutation. Following MDA and returning from working in the forest, two study participants were infected with P. falciparum. One in the DHA-PPQ arm and one in the placebo arm. The participant in the placebo arm was infected with wild-type P. falciparum when they entered the forest, but the C580Y mutation when they returned |