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.