Biology Reference
In-Depth Information
studies of hypnozoitocidal drugs since recurrence may appear from either
(1) recrudescence despite therapy with blood schizontocide(s) (genetic
match); (2) reinfection (genetic mismatch) or (3) relapse despite hypnozo-
itocidal therapy (genetic match or mismatch).
Considerable geographical differences exist between strains of
P. vivax
with regard to the absolute risk of relapse and the timing at which these
occur. These range from 50% to 80% relapse within 3-6 weeks of an initial
infection with Chesson strain to <5-20% risk occurring at 12 months in
temperate strains (
White, 2011
). These relapse rates are clearly observed in
the early clinical trials in which a curative but short-acting quinine regi-
men was used as a positive control for therapeutic activity of primaquine
(
Wiselogle, 1946
). The clinical response with a long-acting antimalarial
drug such as chloroquine is very different. A standard dose of chloroquine
(total dose of 25 mg/kg) should eliminate all of the initial parasite biomass
in blood, and its sustained effective blood concentrations prevent early rein-
fection or relapse. Clinical studies demonstrate that following a standard
dose against sensitive parasites, the first recurrences are not observed until
approximately 35 days following treatment; at this time, the mean whole
blood concentrations of chloroquine have fallen to ∼100 ng/ml (
Baird
et al., 1997
). This figure concurs with previous studies to determine the
MIC of CQS parasite which estimated a whole blood value between 90
and 120 ng/ml (
Berliner et al., 1948a
;
Rombo et al., 1985
).
The current 28-day
in vivo
test of chloroquine works on the basic prin-
ciple that if the treatment regimen was well absorbed, no parasite recur-
rence should be observed within the duration of follow-up, regardless of its
origin. Pharmacokinetic analysis, for instance, a measurement at day 7, can
help to confirm adequate drug absorption (
White et al., 2008
) and estab-
lish whether recurrent infections occur in the face of blood concentrations
known to exceed the MIC of the parasite (
Baird et al., 1997
). In practice,
pharmacokinetic analyses are often omitted because of logistical constraints
or cost. Anti-relapse therapy with primaquine is often administered con-
comitantly with a blood schizontocidal study drug. Since primaquine has
both hypnozoitocidal and blood schizontocidal activity, its early administra-
tion can augment initial asexual parasite clearance and thus mask early indi-
cators of declining blood schizontocidal drug efficacy. Primaquine should
therefore be delayed until after the 28-day follow-up.
Although such
in vivo
tests have a useful positive predictive value
in identifying populations where declining drug efficacy is evolving, it
has some notable shortcomings. Early clinical resistance to long-acting
