Fixed-Dose Artesunate–Amodiaquine Combination vs Chloroquine for Treatment of Uncomplicated Blood Stage P. vivax Infection in the Brazilian Amazon: An Open-Label Randomized, Controlled Trial

Siqueira, André; Alencar, Aline; Melo, Gisely Cardoso de; Magalhaes, Belisa L.; Machado, Kim Vinícius Amaral; Filho, Aristóteles C. Alencar; Kuehn, Andrea; Marques, Marly M.; Manso, Monica Costa; Felger, Ingrid; Vieira, José Luiz Fernandes; Lameyre, Valérie; Daniel-Ribeiro, Cláudio Tadeu; Lacerda, Marcus Vinícius Guimarães

doi:10.1093/cid/ciw706

Cited by 23 publications

(24 citation statements)

References 51 publications

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“…CQ remains the first-line treatment for uncomplicated P. vivax malaria in Brazil (28), but declining efficacy has been repeatedly characterized in the large port city of Manaus, using both in vivo (8)(9)(10) and ex vivo (26,27) assays. However, it remains undetermined whether CQ resistance has spread to other sites across the Amazon Basin and represents a major challenge for current malaria elimination in this country and its neighbors (12,29).…”

Section: Discussionmentioning

confidence: 99%

“…We suggest that at least some of these subpatent parasitemias detected only by PCR on day 28 might have later been detected by standard microscopy in a clinical trial with an extended duration. Indeed, most CQ failures in a recent trial in Manaus, Brazil, were seen between days 29 and 42 after treatment and would have been missed in a 28-day trial (9). Whether monitoring CQ responses requires an extended follow-up is open to debate, and further data on CQ levels beyond day 28 of standard CQ regimens are urgently needed to inform clinicians and policy makers.…”

Section: Discussionmentioning

confidence: 99%

“…Whether CQ resistance significantly contributes to persisting vivax malaria transmission across the Brazilian Amazon remains undetermined. P. vivax resistance to CQ has been documented in the major Amazonian port city of Manaus, in northwestern Brazil, with parasitological failure rates of 6.4% to 10.1% over 28 days of follow-up in patients treated with CQ alone (8,9), compared with 5.2% failures in patients treated according to the current malaria therapy guidelines in Brazil with concomitant CQ and primaquine (PQ) (10). Moreover, P. vivax resistance to CQ has been occasionally described in countries sharing borders with Brazil, such as Bolivia (11), Peru, and Guyana (12).…”

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confidence: 99%

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Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

Ladeia‐Andrade

et al. 2019

Antimicrob Agents Chemother

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Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus but not in the main malaria hot spots across the Amazon Basin of Brazil, where CQ is routinely coadministered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (arm 1) or concomitant (arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in arm 1 subjects, who had PQ administered only at the end of the 28-day follow-up. We found adequate clinical and parasitological responses in all subjects assigned to arm 2. However, 2.2% of arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo. In contrast, ex vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ coadministration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g., CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax-infected populations. (This study has been registered at ClinicalTrials.gov under identifier NCT02691910.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

Ladeia‐Andrade

et al. 2019

Antimicrob Agents Chemother

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“…Approximately 60% of P. vivax patients treated with chloroquine experienced a recurrence within 28 days in studies from Malaysia and Vietnam [ 24 , 52 ]. Yet chloroquine sensitivity was better preserved in studies conducted in Cambodia [ 29 , 44 ], the Brazilian Amazon [ 53 ], Myanmar [ 54 ], India [ 55 ] and Ethiopia [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Measuring ex vivo drug susceptibility in Plasmodium vivax isolates from Cambodia

Chaorattanakawee

Lon

Chann

et al. 2017

Malar J

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BackgroundWhile intensive Plasmodium falciparum multidrug resistance surveillance continues in Cambodia, relatively little is known about Plasmodium vivax drug resistance in Cambodia or elsewhere. To investigate P. vivax anti-malarial susceptibility in Cambodia, 76 fresh P. vivax isolates collected from Oddar Meanchey (northern Cambodia) in 2013–2015 were assessed for ex vivo drug susceptibility using the microscopy-based schizont maturation test (SMT) and a Plasmodium pan-species lactate dehydrogenase (pLDH) ELISA. P. vivax multidrug resistance gene 1 (pvmdr1) mutations, and copy number were analysed in a subset of isolates.ResultsEx vivo testing was interpretable in 80% of isolates using the pLDH-ELISA, but only 25% with the SMT. Plasmodium vivax drug susceptibility by pLDH-ELISA was directly compared with 58 P. falciparum isolates collected from the same locations in 2013–4, tested by histidine-rich protein-2 ELISA. Median pLDH-ELISA IC50 of P. vivax isolates was significantly lower for dihydroartemisinin (3.4 vs 6.3 nM), artesunate (3.2 vs 5.7 nM), and chloroquine (22.1 vs 103.8 nM) than P. falciparum but higher for mefloquine (92 vs 66 nM). There were not significant differences for lumefantrine or doxycycline. Both P. vivax and P. falciparum had comparable median piperaquine IC50 (106.5 vs 123.8 nM), but some P. falciparum isolates were able to grow in much higher concentrations above the normal standard range used, attaining up to 100-fold greater IC50s than P. vivax. A high percentage of P. vivax isolates had pvmdr1 Y976F (78%) and F1076L (83%) mutations but none had pvmdr1 amplification.ConclusionThe findings of high P. vivax IC50 to mefloquine and piperaquine, but not chloroquine, suggest significant drug pressure from drugs used to treat multidrug resistant P. falciparum in Cambodia. Plasmodium vivax isolates are frequently exposed to mefloquine and piperaquine due to mixed infections and the long elimination half-life of these drugs. Difficulty distinguishing infection due to relapsing hypnozoites versus blood-stage recrudescence complicates clinical detection of P. vivax resistance, while well-validated molecular markers of chloroquine resistance remain elusive. The pLDH assay may be a useful adjunctive tool for monitoring for emerging drug resistance, though more thorough validation is needed. Given high grade clinical chloroquine resistance observed recently in neighbouring countries, low chloroquine IC50 values seen here should not be interpreted as susceptibility in the absence of clinical data. Incorporating pLDH monitoring with therapeutic efficacy studies for individuals with P. vivax will help to further validate this field-expedient method.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-2034-2) contains supplementary material, which is available to authorized users.

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“…There have been many reports on CQ-resistance from different regions of the world [ 15 – 19 ] including Brazil [ 20 – 23 ]. The widespread emergence and spread of CQ-resistance in P .…”

Section: Introductionmentioning

confidence: 99%

Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria

et al. 2017

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BackgroundChloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance.MethodsAn untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ ≥100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog.ResultsLinear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p<0.05) of glycerophospholipid metabolism, glycosphingolipid metabolism, aspartate and asparagine metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Glycerophosphocholines levels were significantly lower in the CQ-R group as compared to CQ-S patients and also to independent control samples.ConclusionsThe results show differences in lipid, amino acids, and nucleotide metabolism pathways in the plasma of CQ-R versus CQ-S patients prior to antimalarial treatment. Metabolomics phenotyping of P. vivax samples from patients with well-defined clinical CQ-resistance is promising for the development of new tools to understand the biological process and to identify potential biomarkers of PvCR.

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Fixed-Dose Artesunate–Amodiaquine Combination vs Chloroquine for Treatment of Uncomplicated Blood Stage P. vivax Infection in the Brazilian Amazon: An Open-Label Randomized, Controlled Trial

Cited by 23 publications

References 51 publications

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil

Measuring ex vivo drug susceptibility in Plasmodium vivax isolates from Cambodia

Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria

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