Dataset Information

Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017-2018.

ABSTRACT:

Background

The World Health Organization recommends regularly assessing the efficacy of artemisinin-based combination therapy (ACT), which is a critical tool in the fight against malaria. This study evaluated the efficacy of two artemisinin-based combinations recommended to treat uncomplicated Plasmodium falciparum malaria in Burkina Faso in three sites: Niangoloko, Nanoro, and Gourcy.

Methods

This was a two-arm randomized control trial of the efficacy of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months old were monitored for 42 days. The primary outcomes of the study were uncorrected and PCR-corrected efficacies to day 28 for AL and 42 for DP. Molecular markers of resistance to artemisinin derivatives and partner drugs were also analysed.

Results

Of 720 children enrolled, 672 reached study endpoints at day 28, 333 in the AL arm and 339 in the DP arm. PCR-corrected 28-day per protocol efficacy in the AL arm was 74% (64-83%) in Nanoro, 76% (66-83%) in Gourcy, and 92% (84-96%) in Niangoloko. The PCR-corrected 42-day per protocol efficacy in the DP arm was 84% (75-89%) in Gourcy, 89% (81-94%) in Nanoro, and 97% (92-99%) in Niangoloko. No Pfk13 mutation previously associated with artemisinin-resistance was observed. No statistically significant association was found between treatment outcome and presence of the 86Y mutation in the Pfmdr1 gene. There was also no association observed between treatment outcome and Pfpm2 or Pfmdr1 copy number variation.

Conclusion

The results of this study indicate evidence of inadequate efficacy of AL at day 28 and DP at day 42 in the same two sites. A change of first-line ACT may be warranted in Burkina Faso. Trial Registry Pan African Clinical Trial Registry Identifier: PACTR201708002499311. Date of registration: 8/3/2017 https://pactr.samrc.ac.za/Search.aspx.

SUBMITTER: Gansane A

PROVIDER: S-EPMC7816451 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017-2018.

Gansané Adama A Moriarty Leah F LF Ménard Didier D Yerbanga Isidore I Ouedraogo Esperance E Sondo Paul P Kinda Rene R Tarama Casimir C Soulama Edwige E Tapsoba Madou M Kangoye David D Compaore Cheick Said CS Badolo Ousmane O Dao Blami B Tchwenko Samuel S Tinto Halidou H Valea Innocent I

Malaria journal 20210119 1

<h4>Background</h4>The World Health Organization recommends regularly assessing the efficacy of artemisinin-based combination therapy (ACT), which is a critical tool in the fight against malaria. This study evaluated the efficacy of two artemisinin-based combinations recommended to treat uncomplicated Plasmodium falciparum malaria in Burkina Faso in three sites: Niangoloko, Nanoro, and Gourcy.<h4>Methods</h4>This was a two-arm randomized control trial of the efficacy of artemether-lumefantrine ( ...[more]

PMID: 33468147

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Project description:BackgroundArtemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Togo. This study assessed the efficacy of these combinations, the proportion of Day3-positive patients (D3 +), the proportion of molecular markers associated with P. falciparum resistance to anti-malarial drugs, and the variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).MethodsA single arm prospective study evaluating the efficacy of AL and DP was conducted at two sites (Kouvé and Anié) from September 2021 to January 2022. Eligible children were enrolled, randomly assigned to treatment at each site and followed up for 42 days after treatment initiation. The primary endpoint was polymerase chain reaction (PCR) adjusted adequate clinical and parasitological response (ACPR). At day 0, samples were analysed for mutations in the Pfkelch13, Pfcrt, Pfmdr-1, dhfr, dhps, and deletions in the hrp2/hrp3 genes.ResultsA total of 179 and 178 children were included in the AL and DP groups, respectively. After PCR correction, cure rates of patients treated with AL were 97.5% (91.4-99.7) at day 28 in Kouvé and 98.6% (92.4-100) in Anié, whereas 96.4% (CI 95%: 89.1-98.8) and 97.3% (CI 95%: 89.5-99.3) were observed at day 42 in Kouvé and Anié, respectively. The cure rates of patients treated with DP at day 42 were 98.9% (CI 95%: 92.1-99.8) in Kouvé and 100% in Anié. The proportion of patients with parasites on day 3 (D3 +) was 8.5% in AL and 2.6% in DP groups in Anié and 4.3% in AL and 2.1% DP groups in Kouvé. Of the 357 day 0 samples, 99.2% carried the Pfkelch13 wild-type allele. Two isolates carried nonsynonymous mutations not known to be associated with artemisinin partial resistance (ART-R) (A578S and A557S). Most samples carried the Pfcrt wild-type allele (97.2%). The most common Pfmdr-1 allele was the single mutant 184F (75.6%). Among dhfr/dhps mutations, the quintuple mutant haplotype N51I/C59R/S108N + 437G/540E, which is responsible for SP treatment failure in adults and children, was not detected. Single deletions in hrp2 and hrp3 genes were detected in 1/357 (0.3%) and 1/357 (0.3%), respectively. Dual hrp2/hrp3 deletions, which could affect the performances of HRP2-based RDTs, were not observed.ConclusionThe results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention.Trial registrationACTRN12623000344695.

Project description:ObjectivesTo compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda.DesignRandomized single-blinded clinical trial.SettingApac, Uganda, an area of very high malaria transmission intensity.ParticipantsChildren aged 6 mo to 10 y with uncomplicated falciparum malaria.InterventionTreatment of malaria with AL or DP, each following standard 3-d dosing regimens.Outcome measuresRisks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.ResultsOf 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%-26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%-19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%-12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%-16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs.ConclusionDP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity.

Project description:BackgroundIn 2009, the Papua New Guinea (PNG) Department of Health adopted artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy.MethodsBetween June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined.ResultsA total of 274 P. falciparum and 70 P. vivax cases were enrolled. The day-42 PCR-corrected ACPR for P. falciparum was 98.1% (104/106) for AL and 100% (135/135) for DHA-PPQ. The day-42 PCR-corrected ACPR for P. vivax was 79.0% (15/19) for AL and 92.3% (36/39) for DHA-PPQ. Day 3 parasite clearance of P. falciparum was 99.2% with AL and 100% with DHA-PPQ. In vitro testing of 96 samples revealed low susceptibility to chloroquine (34% of samples above IC50 threshold) but not to lumefantrine (0%). Molecular markers assessed in a sub-set of the study population indicated high rates of chloroquine resistance in P. falciparum (pfcrt SVMNT: 94.2%, n = 104) and in P. vivax (pvmdr1 Y976F: 64.8%, n = 54).ConclusionsAL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG.

Project description:Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ?75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine Cmax by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC0-?) by 12% (1 to 26%), and the half-life (t1/2) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC0-last). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.).

Project description:BACKGROUND:Malaria endemic countries need to assess efficacy of anti-malarial treatments on a regular basis. Moreover, resistance to artemisinin that is established across mainland South-East Asia represents today a major threat to global health. Monitoring the efficacy of artemisinin-based combination therapies is of paramount importance to detect as early as possible the emergence of resistance in African countries that toll the highest burden of malaria morbidity and mortality. METHODS:A WHO standard protocol was used to assess efficacy of the combinations artesunate-amodiaquine (AS-AQ Winthrop®), dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) and artemether-lumefantrine (AM-LM, Coartem®) taken under supervision and respecting pharmaceutical recommendations. The study enrolled for each treatment arm 212 children aged 6-59 months living in Maradi (Niger) and suffering with uncomplicated falciparum malaria. The Kaplan-Meier 42-day PCR-adjusted cure rate was the primary outcome. A standardized parasite clearance estimator was used to assess delayed parasite clearance as surrogate maker of suspected artemisinin resistance. RESULTS:No early treatment failures were found in any of the study treatment arms. The day-42 PCR-adjusted cure rate estimates were 99.5, 98.4 and 99.0% in the AS-AQ, DHA-PPQ and AM-LM arms, respectively. The reinfection rate (expressed also as Kaplan-Meier estimates) was higher in the AM-LM arm (32.4%) than in the AS-AQ (13.8%) and the DHA-PPQ arm (24.9%). The parasite clearance rate constant was 0.27, 0.26 and 0.25 per hour for AS-AQ, DHA-PPQ and AM-LM, respectively. CONCLUSIONS:All the three treatments evaluated largely meet WHO criteria (at least 95% efficacy). AS-AQ and AL-LM may continue to be used and DHA-PPQ may be also recommended as first-line treatment for uncomplicated falciparum malaria in Maradi. The parasite clearance rate were consistent with reference values indicating no suspected artemisinin resistance. Nevertheless, the monitoring of anti-malarial drug efficacy should continue. Trial registration details Registry number at ClinicalTrial.gov: NCT01755559.

Project description:BACKGROUND:Artemether-lumefantrine (AL) is the recommended first-line artemisinin-based combination therapy (ACT) for the treatment of uncomplicated falciparum malaria in most of the malaria-endemic countries, including Tanzania. Recently, dihydroartemisinin-piperaquine (DP) has been recommended as the alternative anti-malarial to ensure effective case management in Tanzania. This study assessed the parasite clearance rate and efficacy of AL and DP among patients aged 6 months to 10 years with uncomplicated falciparum malaria in two sites with different malaria transmission intensity. METHODS:This was an open-label, randomized trial that was conducted at two sites of Muheza Designated District Hospital and Ujiji Health Centre in Tanga and Kigoma regions, respectively. Patients meeting inclusion criteria were enrolled, treated with either AL or DP and followed up for 28 (extended to 42) and 42 (63) days for AL and DP, respectively. Parasite clearance time was monitored in the first 72 h post treatment and the clearance rate constant and half-life were calculated using an established parasite clearance estimator. The primary outcome was parasitological cure on days 28 and 42 for AL and DP, respectively, while secondary outcome was extended parasitological cure on days 42 and 63 for AL and DP, respectively. RESULTS:Of the 509 children enrolled (192 at Muheza and 317 at Ujiji), there was no early treatment failure and PCR uncorrected cure rates on day 28 in the AL group were 77.2 and 71.2% at Muheza and Ujiji, respectively. In the DP arm, the PCR uncorrected cure rate on day 42 was 73.6% at Muheza and 72.5% at Ujiji. With extended follow-up (to day 42 for AL and 63 for DP) cure rates were lower at Ujiji compared to Muheza (AL: 60.2 and 46.1%, p?=?0.063; DP: 57.6 and 40.3% in Muheza and Ujiji, respectively, p?=?0.021). The PCR corrected cure rate ranged from 94.6 to 100% for all the treatment groups at both sites. Parasite clearance rate constant was similar in the two groups and at both sites (<?0.28/h); the slope half-life was <?3.0 h and all but only one patient cleared parasites by 72 h. CONCLUSION:These findings confirm high efficacy of the first- and the newly recommended alternative ACT for treatments for uncomplicated falciparum malaria in Tanzania. The high parasite clearance rate suggests absence of suspected artemisinin resistance, defined as delayed parasite clearance. Trial registration This trial is registered at ClinicalTrials.gov under registration number NCT02590627.

Dataset Information

Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017-2018.

Background

Methods

Results

Conclusion

Publications

Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017-2018.

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