Effectiveness of combined chloroquine and primaquine treatment in 14 days versus intermittent single dose regimen, in an open, non-randomized, clinical trial, to eliminate Plasmodium vivax in southern Mexico

Abstract

Background: In Mexico, combined chloroquine (CQ) and primaquine (PQ) treatment has been used since the late 1950s to treat Plasmodium vivax infections. Although malaria transmission has declined, current treatment strategies must be evaluated to advance towards malaria elimination.

Methods: The clinical and parasitological outcome of treating symptomatic P. vivax with the 14-day (T14) treatment or intermittent single dose (ISD) regimen was evaluated in southern Mexico between February 2008 and September 2010. Patients over 12 months old with P. vivax mono-infection and asexual parasitaemia ≥500 parasites/µl were treated under supervision. After diagnosis (day 0), treatment began immediately. T14 patients received CQ for 3 days (10, 10 and 5 mg/kg) and PQ daily for 14 days (0.25 mg/kg), while ISD patients received a single dose of CQ (10 mg/kg) and PQ (0.75 mg/kg) on days 0, 30, 60, 180, 210, and 240. Follow-up was done by observing clinical and laboratory (by microscopy, serology and PCR) outcome, considering two endpoints: primary blood infection clearance and clinical response at ~28 days, and the incidence of recurrent blood infection during 12 months. Parasite genotypes of primary/recurrent blood infections were analysed.

Results: During the first 28 days, no differences in parasite clearance or clinical outcome were observed between T14 (86 patients) and ISD (67 patients). On day 3, 95 % of patients in both groups showed no blood parasites, and no recurrences were detected on days 7-28. Contrarily, the therapeutic effectiveness (absence of recurrent parasitaemia) was distinct for T14 versus ISD at 12 months: 83.7 versus 50 %, respectively (p = 0.000). Symptomatic and asymptomatic infections were recorded on days 31-352. Some parasite recurrences were detected by PCR and/or serological testing.

Conclusions: T14 was effective for opportune elimination of the primary blood infection and preventing relapse episodes. The first single dose of CQ-PQ eliminated primary blood infection as efficiently as the initial three-dose scheme of T14, but the ISD regimen should be abandoned. A single combined dose administered to symptomatic patients in remote areas while awaiting parasitological diagnosis may contribute to halting P. vivax transmission. Alternatives for meeting the challenge of T14 supervision are discussed.

Trial registration: NIH-USA, ClinicalTrial.gov Identifier: NCT02394197.

Figures

Fig. 1

Flow chart of Plasmodium vivax patient detection and recruitment for T14 and ISD treatment regimens, in southern Mexico. D day

Fig. 2

Cumulative incidence of Plasmodium vivax recurrences during the 12-month follow-up in groups of patients treated under supervision with combined CQ–PQ for 14 days (T14) and intermittent single doses (ISD). The CI at 95 % is shown

Fig. 3

IgG antibodies against the Plasmodium vivax blood stage in blood samples. a 37 patients treated with T14 and b 49 patients under ISD, during the 3–12 month follow-up. Most patients had positive ELISA OD values on day 7 after the initial treatment. Following treatment, OD values decreased or were negative, except in patients with recurrent blood infections. Squares with (+) indicate symptomatic P. vivax blood infections. Square with (×) indicate asymptomatic P. vivax that were microscopy and/or PCR-positive. The ELISA OD cut-off value is indicated with a hidden red line