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(presumptive anti-relapse therapy (PART)) - has been used, or at least
recommended, globally since the 1950s. Evidence of resistance to chlo-
roquine appeared during the late 1980s from the island of New Guinea
( Whitby et al., 1989 ), has spread across the Indonesian archipelago, and
now reaches into the Mekong region where it threatens the Indian sub-
continent ( Baird, 2009 ; Price et al., 2009 ). Newer blood schizontocides
developed for falciparum malaria have shown very good activity against
the acute attack of vivax malaria ( Pukrittayakamee et al., 2000 ; Price
and Douglas, 2010 ), but simply substituting any one of those for chloro-
quine as a new partner with primaquine in radical cure risks safety and
efficacy of the treatment ( Baird, 2011 ). A substantial body of evidence
(reviewed here) shows that the activity of primaquine against relapse var-
ies substantially with blood schizontocidal companion drug. New blood
schizontocide(s) against the acute attack of vivax malaria also requires
evidence of primaquine safety and efficacy against relapse for any given
drug partnership for radical cure.
Chapter 2 explains the biology behind relapse, highlighting the technical
and ethical challenges of measuring the efficacy of hypnozoitocidal thera-
pies. Relapse rates vary dramatically across regions and parasitemia originat-
ing from them cannot be distinguished from those caused by recrudescence
or re-infection. This problem renders clinical trials of hypnozoitocides in
endemic zones subject to serious confounding. Indeed, chloroquine and
primaquine were developed in clinical trials employing prisoner volun-
teers in the United States, effectively ruling out confounding by reinfection.
Alternative approaches to gauging anti-relapse therapy in endemic settings
needs to be explored and validated.
The greatest challenge for vivax chemotherapeutics is the safe delivery
of primaquine. This risk of primaquine-induced haemolysis in patients
with G6PDd is detailed in Chapter 4 of Volume B of this series and
explains the impracticability of prolonged dosing of standard therapy -
daily for 14 days - that leads to serious adherence problems. Finally, pri-
maquine is contraindicated in pregnancy, a target population who would
benefit most from radical cure, due to risk of haemolysis in a foetus with
unknown G6PD status. The emerging threat of chloroquine-resistant
P. vivax demands newer blood schizontocidal agents which, in turn, impose
the necessity of demonstrating the safety and efficacy of primaquine with
each new partner therapy in radical cure. Ultimately, the effectiveness of
primaquine in endemic zones will require the development of safer and
more practical dosing regimens. As currently prescribed, primaquine is
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