Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

ABSTRACTChloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure ofPlasmodium vivaxmalaria. Emergence of CQ-resistant (CQR)P. vivaxparasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ forP. vivaxmalaria in northeast Myanmar. We recruited 587 patients withP. vivaxmonoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine ofP. vivaxin northeastern Myanmar may be deteriorating.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01965-18 ◽

2019 ◽

Vol 63 (5) ◽

Cited By ~ 9

Author(s):

Simone Ladeia-Andrade ◽

Maria José Menezes ◽

Taís Nóbrega de Sousa ◽

Ana Carolina R. Silvino ◽

Jaques F. de Carvalho ◽

...

Keyword(s):

Plasmodium Vivax ◽

Vivax Malaria ◽

Amazon Basin ◽

Ex Vivo ◽

Hot Spot ◽

Radical Cure ◽

Content Type ◽

Plasmodium Vivax Malaria

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.)

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PvMSP8 as a Novel Plasmodium vivax Malaria Sero-Marker for the Peruvian Amazon

Pathogens ◽

10.3390/pathogens10030282 ◽

2021 ◽

Vol 10 (3) ◽

pp. 282

Author(s):

Elizabeth Villasis ◽

Katherine Garro ◽

Angel Rosas-Aguirre ◽

Pamela Rodriguez ◽

Jason Rosado ◽

...

Keyword(s):

Plasmodium Vivax ◽

Area Under The Curve ◽

Surface Protein ◽

Merozoite Surface Protein ◽

Population Based ◽

Peruvian Amazon ◽

Cross Sectional Survey ◽

Cross Sectional ◽

Malaria Exposure ◽

Plasmodium Vivax Malaria

The measurement of recent malaria exposure can support malaria control efforts. This study evaluated serological responses to an in-house Plasmodium vivax Merozoite Surface Protein 8 (PvMSP8) expressed in a Baculovirus system as sero-marker of recent exposure to P. vivax (Pv) in the Peruvian Amazon. In a first evaluation, IgGs against PvMSP8 and PvMSP10 proteins were measured by Luminex in a cohort of 422 Amazonian individuals with known history of Pv exposure (monthly data of infection status by qPCR and/or microscopy over five months). Both serological responses were able to discriminate between exposed and non-exposed individuals in a good manner, with slightly higher performance of anti-PvMSP10 IgGs (area under the curve AUC = 0.78 [95% CI = 0.72–0.83]) than anti-PvMSP8 IgGs (AUC = 0.72 [95% CI = 0.67–0.78]) (p = 0.01). In a second evaluation, the analysis by ELISA of 1251 plasma samples, collected during a population-based cross-sectional survey, confirmed the good performance of anti-PvMSP8 IgGs for discriminating between individuals with Pv infection at the time of survey and/or with antecedent of Pv in the past month (AUC = 0.79 [95% CI = 0.74–0.83]). Anti-PvMSP8 IgG antibodies can be considered as a good biomarker of recent Pv exposure in low-moderate transmission settings of the Peruvian Amazon.

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Confirmed Plasmodium vivax Resistance to Chloroquine in Central Vietnam

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00791-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7411-7419 ◽

Cited By ~ 17

Author(s):

Pham Vinh Thanh ◽

Nguyen Van Hong ◽

Nguyen Van Van ◽

Melva Louisa ◽

Kevin Baird ◽

...

Keyword(s):

Plasmodium Vivax ◽

Cumulative Risk ◽

Artemisinin Resistance ◽

Blood Levels ◽

Radical Cure ◽

Blood Concentrations ◽

Content Type ◽

Central Vietnam ◽

Almost All ◽

First Time

ABSTRACTPlasmodium vivaxresistance to chloroquine (CQ) is currently reported in almost all countries whereP. vivaxis endemic. In Vietnam, despite a first report onP. vivaxresistance to chloroquine published in the early 2000s,P. vivaxwas still considered sensitive to CQ. Between May 2009 and December 2011, a 2-year cohort study was conducted in central Vietnam to assess the recommended radical cure regimen based on a 10-day course of primaquine (0.5 mg/kg/day) together with 3 days of CQ (25 mg/kg). Here we report the results of the first 28-day follow-up estimating the cumulative risk ofP. vivaxrecurrences together with the corresponding CQ blood concentrations, among other endpoints. Out of 260 recruitedP. vivaxpatients, 240 completed treatment and were followed up to day 28 according to the WHO guidelines. Eight patients (3.45%) had a recurrentP. vivaxinfection, at day 14 (n= 2), day 21 (n= 1), and day 28 (n= 5). Chloroquine blood concentrations, available for 3/8 recurrent infections (days 14, 21, and 28), were above the MIC (>100 ng/ml whole blood) in all of these cases. Fever and parasitemia (both sexual and asexual stages) were cleared by day 3. Anemia was common at day 0 (35.8%), especially in children under 10 years (50%), and hemoglobin (Hb) recovery at day 28 was substantial among anemic patients (median change from day 0 to 28, +1.7 g/dl; interquartile range [IQR], +0.7 to +3.2). This report, based on CQ blood levels measured at the time of recurrences, confirms for the first timeP. vivaxCQ resistance in central Vietnam and calls for further studies using standardized protocols for accurately monitoring the extent and evolution ofP. vivaxresistance to chloroquine in Vietnam. These results, together with the mounting evidence of artemisinin resistance in central Vietnam, further highlight the increasing threat of antimalarial drug resistance to malaria elimination in Vietnam.

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The Plasmodium vivax Merozoite Surface Protein 1 Paralog Is a Novel Erythrocyte-Binding Ligand of P. vivax

Infection and Immunity ◽

10.1128/iai.01117-12 ◽

2013 ◽

Vol 81 (5) ◽

pp. 1585-1595 ◽

Cited By ~ 33

Author(s):

Yang Cheng ◽

Yue Wang ◽

Daisuke Ito ◽

Deok-Hoon Kong ◽

Kwon-Soo Ha ◽

...

Keyword(s):

Plasmodium Vivax ◽

Vaccine Candidate ◽

Structural Characteristics ◽

Surface Protein ◽

Merozoite Surface Protein ◽

Open Reading Frames ◽

Content Type ◽

Merozoite Surface Protein 1 ◽

Human Sera

ABSTRACTMerozoite surface protein 1 ofPlasmodium vivax(PvMSP1), a glycosylphosphatidylinositol-anchored protein (GPI-AP), is a malaria vaccine candidate forP. vivax. The paralog of PvMSP1, namedP. vivaxmerozoite surface protein 1 paralog (PvMSP1P; PlasmoDB PVX_099975), was recently identified and predicted as a GPI-AP. The similarities in genetic structural characteristics between PvMSP1 and PvMSP1P (e.g., size of open reading frames, two epidermal growth factor-like domains, and GPI anchor motif in the C terminus) led us to study this protein. In the present study, different regions of the PvMSP1P protein, demarcated based on the processed forms of PvMSP1, were expressed successfully as recombinant proteins [i.e., 83 (A, B, and C), 30, 38, 42, 33, and 19 fragments]. We studied the naturally acquired immune response against each fragment of recombinant PvMSP1P and the potential ability of each fragment to bind erythrocytes. The N-terminal fragment (83A) and two C-terminal fragments (33 and 19) reacted strongly with sera fromP. vivax-infected patients, with 50 to 68% sensitivity and 95 to 96% specificity, respectively. Due to colocalization of PvMSP1P with PvMSP1, we supposed that PvMSP1P plays a similar role as PvMSP1 during erythrocyte invasion. Anin vitrocytoadherence assay showed that PvMSP1P, especially the 19-kDa C-terminal region, could bind to erythrocytes. We also found that human sera from populations naturally exposed to vivax malaria and antisera obtained by immunization using the recombinant molecule PvMSP1P-19 inhibitedin vitrobinding of human erythrocytes to PvMSP1P-19. These results provide further evidence that the PvMSP1P might be an essential parasite adhesion molecule in theP. vivaxmerozoite and is a potential vaccine candidate againstP. vivax.

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The use of ultrasensitive quantitative-PCR to assess the impact of primaquine on asymptomatic relapse of Plasmodium vivax infections: a randomized, controlled trial in Lao PDR

Malaria Journal ◽

10.1186/s12936-019-3091-5 ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 3

Author(s):

Koukeo Phommasone ◽

Frank van Leth ◽

Mallika Imwong ◽

Gisela Henriques ◽

Tiengkham Pongvongsa ◽

...

Keyword(s):

Plasmodium Vivax ◽

Quantitative Pcr ◽

Cumulative Incidence ◽

Controlled Trial ◽

Lao Pdr ◽

Radical Cure ◽

Directly Observed Therapy ◽

Exact Test ◽

The Impact

Abstract Background Trials to assess the efficacy of the radical cure of Plasmodium vivax malaria with 8-aminoquinolines require that most post-treatment relapses are identified, but there is no consensus on the optimal duration of follow-up in either symptomatic or asymptomatic vivax malaria. The efficacy of a 14-day course of primaquine on the cumulative incidence of recurrent asymptomatic P. vivax infections detected by ultrasensitive quantitative PCR (uPCR) as a primary endpoint was assessed. Methods A randomized, placebo-controlled, single-blind trial was conducted in four villages of the Lao PDR during 2016–2018 nested in a larger project evaluating mass drug administrations (MDA) with dihydroartemisinin-piperaquine (DP) and a single low-dose primaquine to clear Plasmodium falciparum infections. In the nested sub-study, eligible participants with mono- or mixed P. vivax infections detected by uPCR were randomized to receive either 14 days of primaquine (0.5 mg/kg/day) or placebo during the last round of MDA (round 3) through directly observed therapy. Participants were checked monthly for 12 months for parasitaemia using uPCR. The primary outcome was cumulative incidence of participants with at least one recurrent episode of P. vivax infection. Results 20 G6PD-normal participants were randomized in each arm. 5 (29%) of 20 participants in the placebo arm experienced asymptomatic, recurrent P. vivax infections, resulting in a cumulative incidence at month 12 of 29%. None of the 20 participants in the intervention arm had recurrent infections (p = 0.047 Fisher’s exact test). Participants with recurrent P. vivax infections were found to be parasitaemic for between one and five sequential monthly tests. The median time to recurrence of P. vivax parasitaemia was 178 days (range 62–243 days). Conclusions A 14-day course of primaquine in addition to a DP-MDA was safe, well-tolerated, and prevented recurrent asymptomatic P. vivax infections. Long follow-up for up to 12 months is required to capture all recurrences following the treatment of asymptomatic vivax infection. To eliminate all malarias in settings where P. vivax is endemic, a full-course of an 8-aminoquinolines should be added to MDA to eliminate all malarias. Trial registration This study was registered with ClinicalTrials.gov under NCT02802813 on 16th June 2016. https://clinicaltrials.gov/ct2/show/NCT02802813

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