Vivax Malaria Relapses Predominantly Delayed by Chloroquine, Prevented by Primaquine

Vivax malaria relapses are predominantly delayed by chloroquine (CQ) but prevented by primaquine (PMQ), according to a study published in Clinical Infectious Diseases.

Plasmodium vivax exerts considerable morbidity by causing repeat relapses. For nearly 70 years, CQ has been the standard P vivax treatment, although resistance is increasing. CQ is eliminated slowly, resulting in the suppression of recurrences for more than a month following treatment, but it is uncertain whether the first observed relapse after treatment derives from a delay or clearance of this infection and emergence of the second relapse. Artemisinin combination therapies are more potent but rapidly eliminated and therefore do not provide post-treatment suppression of recurrent infections. Furthermore, radical-cure PMQ regimens prevent relapse, but carry a risk for hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals.

Therefore, the benefits of using slowly eliminated CQ vs rapidly eliminated (arsenuate [AS]) anti-malarials were assessed in a 3-way randomized comparison trial conducted on the Thailand-Myanmar border (ClinicalTrails.gov Identifier: NCT01074905).

A total of 644 participants were randomly assigned to either: (1) AS 2 mg/kg/day for 5 days (Medopharm, India and/or Guilin Pharmaceuticals, China; 50-mg tablets); (2) CQ 25 mg base/kg divided over 3 days (10 mg/kg, 10 mg/kg, 5 mg/kg) (Maneesh Pharmaceuticals, Ltd., India and Medopharm, India; 250-mg tablets); or (3) CQ given concomitantly with PMQ 0.5 mg base/kg/day (given within 15 minutes after food) for 14 days (Maneesh Pharmaceuticals, Ltd., India and Government Pharmaceutical Organization, Thailand; 15-mg tablets).

Participants with G6PD deficiency were randomly assigned to arms 1 or 2 only. The total follow-up duration was 1 year from enrollment. The primary end point was P vivax malaria recurrence within 28 days. Secondary end points were interval to first recurrence, P vivax malaria recurrences for 1 year, relationships with CQ levels, and adverse events within 28 days.

Overall, P vivax parasitemia recurrences (n=1349) occurred in 59% of patients. Day 28 recurrence rates and median intervals to first recurrence were 50% and 28 days with AS, 8% and 49 days with CQ, and 0.5% and 195 days with PMQ (P <.001 for both).

Adding PMQ to CQ reduced the P vivax first recurrence rate over 1 year by 85.6%. The percentage of patients who had a second P vivax recurrence was similar in the AS (79%) and CQ (78%) groups, but was substantially lower in the CQ+PMQ group (14%; P <.001).

Over the 1-year follow-up, there were more recurrences per person-year in the AS group (4.51) than the CQ group (3.45; P =.002), and substantially fewer in the CQ+PMQ group (0.26; P <.001). This suggests that CQ delays rather than prevents relapse.

Age and gender did not affect either the risk for or number of P vivax malaria recurrences. A history of previous malaria was more common in patients with recurrences (61%) than patients without recurrences (39%; P <.001). Adverse events were similar in all treatment groups. However, using PMQ caused substantially greater hematocrit reductions in G6PD-heterozygous females.

Overall, the study investigators concluded that, “The benefits of slowly eliminated antimalarials in delaying early relapse are small in comparison with high-dose PMQ radical cure, which prevents nearly all relapses.”

Reference

Chu CS, Phyo AP, Lwin KM, et al. Comparison of the cumulative efficacy and safety of chloroquine, artesunate, and chloroquine-primaquine in Plasmodium vivax malaria [published online June 8, 2018]. Clin Infec Dis. doi:10.1093.cid.ciy319