7

Among cohorts in Thailand and Indonesia, the incidence density of first relapse in the 2 months after a primary attack was about 5/person-year. 8, 9 and 10 Such attack rates approximate those of Plasmodium falciparum in the highest risk zones of sub-Saharan Africa. 11 Failure to prevent relapse in vivax malaria results in very high risk of debilitating illness of deepening seriousness and opportunities for onward transmission to others. Nonetheless, most patients diagnosed with vivax malaria do not receive therapy against relapse as a consequence of the rational fear of causing serious harm with primaquine among unscreened patients with G6PD deficiency. 5 Among the many drugs KU-60019 available to treat the acute attack of vivax malaria, none affect the latent hypnozoites.12 The only drug registered as safe and effective in preventing relapses is primaquine, and it has been in continuous use since 1952. At therapeutic dosing against relapse, primaquine causes a mild to severe acute STI571 hemolytic anemia in patients having an inborn deficiency of G6PD.13 and 14 This extraordinarily diverse and complex X-linked trait occurs most frequently where there is endemic malaria transmission, as it may confer some protection against the onset of severe and threatening malaria.15 About 400 million people are affected, with an average prevalence of G6PD deficiency in

malaria endemic nations of about 8%.16 The blind administration of primaquine to patients diagnosed with vivax malaria is often rationally considered unacceptably hazardous or reckless by providers of malaria treatment services. In impoverished rural settings, patients very often are not provided primaquine therapy as a direct consequence of a lack of access to G6PD screening. G6PD deficiency as the basis of hemolytic sensitivity to primaquine was described in 1956,17 and a variety of diagnostic tests for the disorder appeared

within a decade. One of the most widely recommended and used has been the fluorescent spot test (FST) described in 1966 by hematologist and pioneering G6PD scientist Ernest Beutler.18 It has seen several decades of practical and safe triclocarban use in the developed world, but finds almost no routine application where most patients with malaria live. The reasons include cost, specialized equipment, laboratory skills, temperature sensitivity, and a cold chain for the reagents. Any one of those pitfalls may suffice to prohibit routine use in impoverished tropical settings. The combination of them explains more than 50 years without access to G6PD screening, which in turn accounts for the lack of access to primaquine therapy against vivax malaria for almost all those patients. We consider this deceptively simple problem the likely basis of most clinical attacks of vivax malaria and attendant burdens of morbidity and mortality.