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

Abstract

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.)

Plasmodium vivax transcriptional profiling of low input cryopreserved isolates through the intraerythrocytic development cycle

“…The Institutional Review Boards of the Institute of Biomedical Sciences at the University of São Paulo, Brazil (1169/ CEPSH, 2014) and Harvard T. H. Chan School of Public Health (21410-101) approved the protocols for parasite sample collection. Samples were collected in Mâncio Lima, Acre State, Brazil, from P. vivax patients diagnosed via conventional thick-smear microscopy performed in the context of a randomized, open-label clinical trial [16], and the samples were depleted of leukocytes and cryopreserved as previously described [17].…”

Population genomics reveals the expansion of highly inbred Plasmodium vivax lineages in the main malaria hotspot of Brazil

“…However, we argue that drug-associated selective sweeps are very unlikely to have played a major role in the Juruá Valley hotspot, where resistance to chloroquine, the first-line antimalarial drug used to treat P . vivax infections in the Americas, remains very rare [ 18 , 44 ].…”

“…Single-species P . vivax infection was confirmed by microscopy and quantitative PCR as described [ 18 ]. Template DNA was isolated with QIAamp DNA blood kits (Qiagen, Hilden, Germany).…”

Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population: a case study in the Amazon Basin

“…Next, we assume that, on average, symptomatic infections can be detected by laboratory methods during 4, 8 and 12 days. Symptomatic infections are curtailed by treatment and their average length primarily depends on: (a) the duration of the patent but subclinical period that precedes full-blown disease manifestations, which remains elusive; (b) the mean time from the appearance of symptoms to the introduction of CQ-PQ treatment (2.7 days in our population [28]), and (c) the mean P. vivax clearance time following CQ-PQ treatment (1.9 day in our population; [28]). We thus divided the proportion of individuals within the infected ( I ) compartments by 7 (=28/4), 3.5 (28/8) or 2.3 (28/12) to represent the prevalence of symptomatic blood-stage infections that can be detected by laboratory methods during the subject’s 28-day stay in the I compartments.…”