Dihydroartemisinin-piperaquine versus chloroquine in the treatment of Plasmodium vivax malaria in Thailand: a randomized controlled trial

Abstract

Background: Chloroquine (CQ) remains the treatment of choice for Plasmodium vivax malaria. Initially confined to parts of Indonesia and Papua, resistance of P. vivax to CQ seems to be spreading, and alternative treatments are required.

Methods: We conducted a randomized controlled study to compare the efficacy and the tolerability of CQ and dihydroartemisinin-piperaquine (DP) in 500 adults and children with acute vivax malaria on the Northwestern border of Thailand.

Results: Both drugs were well tolerated. Fever and parasite clearance times were slower in the CQ than in the DP group (P < .001). By day 28, recurrent infections had emerged in 18 of 207 CQ recipients compared with 5 of 230 treated with DP (relative risk, 4.0; 95% confidence interval [CI], 1.51-10.58; P = .0046). The cumulative risk of recurrence with P. vivax at 9 weeks was 79.1% (95% CI, 73.5%-84.8%) in patients treated with CQ compared with 54.9% (95% CI, 48.2%-61.6%) in those receiving DP (hazard ratio [HR], 2.27; 95% CI, 1.8-2.9; P < .001). Children <5 years old were at greater risk of recurrent P. vivax infection (74.4%; 95% CI, 63.2%-85.6%) than older patients (55.3% [95% CI, 50.2%-60.4%]; HR, 1.58 [95% CI, 1.1-2.2]; P = .005). In vitro susceptibility testing showed that 13% of the tested isolates had a CQ median inhibitory concentration >100 nmol/L, suggesting reduced susceptibility.

Conclusions: The efficacy of CQ in the treatment of P. vivax infections is declining on the Thai-Myanmar border. DP is an effective alternative treatment.

Figure 1.

Study profile.

Figure 2.

A, Cumulative risk of treatment failure in patients with Plasmodium vivax parasitemia (P. vivax alone or mixed infections). Diamonds represent chloroquine (CQ); circles, dihydroartemisinin-piperaquine (DP). The overall difference between treatment groups at day 63 was significant (P < .001). B, Cumulative risk of treatment failure in patients with Plasmodium falciparum parasitemia (P. falciparum infection alone or mixed infections). The overall difference between treatment groups was significant at day 28 (P = .015) but not by day 63 (P = .176).

Figure 3.

Adverse events on day 1 or 2 in patients without symptoms at admission.

Figure 4.

Ex vivo drug susceptibility to chloroquine and piperaquine. IC₅₀, median inhibitory concentration.