Biology Reference
In-Depth Information
required resistance in both asexual and sexual blood stages. The intrinsically
chloroquine-tolerant gametocytes of falciparum malaria, on the other hand,
would have greatly accelerated propagation of the drug-resistant genotype/
phenotype.
A crucial determinant of
de novo
selection is the degree of selective
drug pressure exerted on a parasite population (
White, 1999
). This is, at
least in theory, significantly lower in
P. vivax
infections, a consequence of
higher rates of asymptomatic parasitaemia and lower parasite biomass. In
P. falciparum
infections, gametocytogenesis occurs after the appearance of
symptoms and is refractory to schizontocidal drugs. Carriage of
P. falciparum
gametocytes increases greatly with delayed patient clearance favouring the
transmission of resistant genotypes (
Price et al., 1999
). In contrast,
P. vivax
gametocytes appear earlier, usually before presentation to the clinic, and
are susceptible to schizontocidal agents ensuring transmission occurs before
drug selection.
In any event, resistance to chloroquine did emerge, probably on the
island of New Guinea at the eastern edge of the Indonesian archipelago.
The treatment has been abandoned in Indonesia, the Solomon Islands, and
Vanuatu. The same decision is under review in Cambodia, Thailand, and
Vietnam. The problem has been documented at relatively low frequencies
in Burma and India, and those nations account for the majority of vivax
malaria cases globally. The loss of chloroquine to resistance unhinges vivax
malaria therapeutics as a whole, that is, it incites loss of the only practical
and proven means of radical cure - its pairing with primaquine. The real-
ity of this problem and its serious consequences are already mobilizing the
scientific community, as it did in the wake of the onset of World War II
and the loss of quinine, to commit to the daunting challenge of develop-
ing and licensing new radical cures for vivax malaria. The three therapeutic
principles for 8-aminoquinolines against relapse laid down by Alving et al.
should guide renewed efforts in this arena.
The epicentre of
P. vivax
chloroquine resistance is the island of New
Guinea. In both Indonesian Papua and Papua New Guinea, clinical trials of
P. vivax
have documented high rates of early clinical deterioration requir-
ing hospitalization, delayed parasite clearance and recurrent parasitaemia
within 28 days in over 65% of patients (
Rieckmann et al., 1989
;
Baird et al.,
1991
;
Sumawinata et al., 2003
;
Ratcliff et al., 2007b
). These extremely poor
clinical responses are markedly different from those apparent from the same
locations in the 1990s, suggesting an evolving trait of increasingly drug-
tolerant parasites.
