Research Article: Plasmodium vivax morbidity after radical cure: A cohort study in Central Vietnam

Date Published: May 17, 2019

Publisher: Public Library of Science

Author(s): Thanh Vinh Pham, Hong Van Nguyen, Angel Rosas Aguirre, Van Van Nguyen, Mario A. Cleves, Xa Xuan Nguyen, Thao Thanh Nguyen, Duong Thanh Tran, Hung Xuan Le, Niel Hens, Anna Rosanas-Urgell, Umberto D’Alessandro, Niko Speybroeck, Annette Erhart, Elizabeth A Ashley

Abstract: BackgroundIn Vietnam, the importance of vivax malaria relative to falciparum during the past decade has steadily increased to 50%. This, together with the spread of multidrug-resistant Plasmodium falciparum, is a major challenge for malaria elimination. A 2-year prospective cohort study to assess P. vivax morbidity after radical cure treatment and related risk factors was conducted in Central Vietnam.Methods and findingsThe study was implemented between April 2009 and December 2011 in four neighboring villages in a remote forested area of Quang Nam province. P. vivax-infected patients were treated radically with chloroquine (CQ; 25 mg/kg over 3 days) and primaquine (PQ; 0.5 mg/kg/day for 10 days) and visited monthly (malaria symptoms and blood sampling) for up to 2 years. Time to first vivax recurrence was estimated by Kaplan–Meier survival analysis, and risk factors for first and recurrent infections were identified by Cox regression models. Among the 260 P. vivax patients (61% males [159/260]; age range 3–60) recruited, 240 completed the 10-day treatment, 223 entered the second month of follow-up, and 219 were followed for at least 12 months. Most individuals (76.78%, 171/223) had recurrent vivax infections identified by molecular methods (polymerase chain reaction [PCR]); in about half of them (55.61%, 124/223), infection was detected by microscopy, and 84 individuals (37.67%) had symptomatic recurrences. Median time to first recurrence by PCR was 118 days (IQR 59–208). The estimated probability of remaining free of recurrence by month 24 was 20.40% (95% CI [14.42; 27.13]) by PCR, 42.52% (95% CI [35.41; 49.44]) by microscopy, and 60.69% (95% CI [53.51; 67.11]) for symptomatic recurrences. The main risk factor for recurrence (first or recurrent) was prior P. falciparum infection. The main limitations of this study are the age of the results and the absence of a comparator arm, which does not allow estimating the proportion of vivax relapses among recurrent infections.ConclusionA substantial number of P. vivax recurrences, mainly submicroscopic (SM) and asymptomatic, were observed after high-dose PQ treatment (5.0 mg/kg). Prior P. falciparum infection was an important risk factor for all types of vivax recurrences. Malaria elimination efforts need to address this largely undetected P. vivax transmission by simultaneously tackling the reservoir of P. falciparum and P. vivax infections.

Partial Text: Radical cure of P. vivax malaria, the most prevalent species outside sub-Saharan Africa [1], remains a challenge because preventing subsequent relapses and onward transmission requires treatment of both circulating blood (schizonticidal drugs) and the dormant liver (hypnozoiticidal drug) stages [2]. Chloroquine (CQ) and primaquine (PQ) have been combined for this purpose since the late 1950s, and PQ—an 8-aminoquinoline licensed in 1952—remained the only antirelapse therapy available until July 2018 [3]. Its use implies several challenges, including the risk of acute hemolysis in Glucose-6-Phosphate-dehydrogrenase–deficient (G6PDd) patients and poor adherence to the 14-day treatment schedule [2]. Moreover, the rapid spread of P. vivax CQ resistance will require alternative blood schizonticides and thus new combinations for radical cure to be tested [4]. Over the past 60 years, various PQ regimens have been used [5], and currently the World Health Organization (WHO) guidelines recommend PQ at 0.25 mg/kg/day for 14 days, together with CQ or an artemisinin-based combination therapy (ACT) [6]. In Southeast Asia and Oceania, where the vivax Chesson strain is prevalent, a higher PQ daily dose (0.5 mg/kg/day; 7.0 mg/kg total dose) is recommended.

Data were collected following a prospective study protocol that did not include a detailed prospective statistical analysis plan (S1 Text).

Post-treatment vivax recurrences were extremely frequent, especially SM infections, which tended to occur earlier than patent or symptomatic infections. Prior falciparum infection was the main risk factor for all types of vivax recurrence (first and all recurrences; PCR-detected, patent, and symptomatic recurrences) together with prior CQ treatment for the risk of repeated recurrences. The drop-out rate was low given the length of follow-up, and most withdrawals occurred during the 10-day PQ treatment.



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