Whole blood chloroquine concentrations with Plasmodium vivax infection in Irian Jaya, Indonesia.

Whole blood concentrations of self-administered chloroquine (CQ) and its metabolite desethylchloroquine (DCQ) were measured in 168 patients with microscopically confirmed infection by Plasmodium vivax in northeastern Irian Jaya, Indonesia. The study consisted of both survey and passive case detection in four separate villages between 1992 and 1994. The subjects were Javanese people 4-51 years old who had lived in the Arso region for up to two years. The sum of CQ and DCQ ranged from 0 to 8,342 ng/ml of whole blood, and 122 subjects (73%) had > or = 100 ng/ml of CQ plus DCQ, the estimated minimally effective concentration (MEC) in whole blood against chloroquine-sensitive P. vivax. Among 56 subjects reporting to a clinic with symptoms of malaria, 53 (95%) had ordinarily effective levels of chloroquine in blood. Among 109 largely asymptomatic malaria patients found by survey case detection, 69 (63%) had chloroquine blood levels greater than the MEC. Virtually all clinical and most subclinical vivax malaria in this region occurs despite ordinarily effective levels of chloroquine in blood.

Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels.

To develop criteria for the diagnosis of resistance to chloroquine using an in vivo test, we examined published records of early clinical trials of quinine and chloroquine against Plasmodium vivax. These data established the timing of relapse by tropical P. vivax relative to therapy by these drugs. The first relapse occurred 17 days after initiating and three days after terminating quinine therapy. The median day of relapse was day 23, and 59% of the patients had relapsed by day 30 (n = 333). In contrast, no relapse occurred until day 36 following chloroquine treatment (n = 256). Data from our laboratory may help explain this difference; among 91 Indonesian patients with malaria, the mean whole blood levels of chloroquine (CQ) and desethylchloroquine (DCQ) were 141 ng/ml (95% confidence interval = 115-167) on day 28 after initiating standard therapy (25 mg base/kg in three doses over a 48-hr period). This exceeds the estimated minimal effective concentration of chloroquine (100 ng/ml of whole blood). Thus, chloroquine lingering in the blood for at least 28 days after starting standard therapy was sufficient to eliminate or at least suppress chloroquine-sensitive tropical P. vivax. We conclude that a parasitemia by P. vivax recurring in the 28 days after full compliance to standard chloroquine therapy demonstrates resistance. If the recurrence appears before day 16, it is almost certainly a recrudescence and between days 17 and 28 it may be either a recrudescence or a relapse by chloroquine-resistant parasites. Recurrences beyond day 28 could be relapse by chloroquine-sensitive P. vivax.

In vivo resistance to chloroquine by Plasmodium vivax and Plasmodium falciparum at Nabire, Irian Jaya, Indonesia.

A survey of resistance to chloroquine by Plasmodium vivax and P. falciparum was conducted during May 1995 at three mesoendemic villages 30 km southeast of Nabire, near the central northern coast of Irian Jaya, Indonesia. The prevalence of malaria at Urusumu (n = 157), Margajaya (n = 573), and Topo (n = 199) was 18%. 9%, and 9%, respectively, with spleen rates among children of 79%, 10%, and 27%. Infected patients among those screened formed a study population of 64 subjects eligible for a 28-day in vivo test of resistance to chloroquine. Sixty-three patients successfully completed the test; 45 males and 18 females 1-60 years of age, of whom 29 were Javanese transmigrants of five years residence in Irian Jaya and 34 were native to Irian Jaya. The seven-day day cumulative incidence of therapeutic failure for P. vivax and P. falciparum was 15% (n = 34) and 30% (n = 37). The 14- and 28-day estimates of cumulative incidence were 45% and 64% for P. vivax and 58% and 89% for P. falciparum. Almost all recurrences appeared in the face of ordinarily effective levels of chloroquine and its major metabolite, desethylchloroquine, in whole blood (> or = 100 ng/ml). Four infections by P. malariae in subjects enrolled in this study cleared by day 2 and none reappeared within 28 days. Chloroquine no longer provides effective therapy for falciparum or vivax malaria along the northern coast of Irian Jaya, Indonesia.