Development of halofantrine resistance and determination of cross-resistance patterns in Plasmodium falciparum

Abstract

Intermittent exposure to halofantrine (HF) of both chloroquine-susceptible (T9.96) and chloroquine-resistant (K1) isolates of Plasmodium falciparum in vitro resulted in a rapid reduction in susceptibility to HF. After 6 months, the 50% inhibitory concentration (IC50) of HF, determined with [G-3H]hypoxanthine incorporation as a marker, increased ninefold for the chloroquine-resistant (K1) isolate and threefold for the cloned chloroquine-susceptible (T9.96) isolate, the derived isolates being termed the K1HF3 and T9.96HF4 isolates, respectively. By microscopic examination of cultured erythrocytes, we determined that there was a fivefold increase in the IC50 for isolate T9.96HF4. The responses of the parental isolates and the HF-resistant isolates to chloroquine, mefloquine, quinine, amodiaquine, qinghaosu, and pyrimethamine were determined. In comparison with the parental K1 isolate, HF-resistant isolate K1HF3 was significantly more susceptible to the action of chloroquine and exhibited a significantly reduced susceptibility to quinine and mefloquine. The other HF-resistant isolate, T9.96HF4, showed no alteration in susceptibility to amodiaquine or chloroquine but a significantly decreased susceptibility to mefloquine. Resistance was stable in the two isolates, both in the absence of drug pressure or when kept frozen in liquid nitrogen. In contrast, continuous exposure to HF had no effect on the susceptibility of the parasites to this drug above HF concentrations of 3.2 x 10(-9) M.