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difficulty of demonstrating resistance. However, efficacy cannot be estimated
in such populations unless they come in relatively large numbers from the
same locality, thereby providing a means to estimate the natural relapse rate
among them. In individual patients coming from scattered locations, risk
of relapse linked to each patient may be unknowable. Thus, demonstrating
resistance to primaquine in them becomes a task of proving that a recurrent
parasitaemia occurred despite fully compliant and naturally metabolized
standard primaquine therapy, i.e. knowing the patient was infected by a pri-
maquine-resistant strain of P. vivax . Investigators should resist the temptation
to put denominators under these treatment failures. The absence of relapse
following primaquine therapy in such patients may be a consequence of
primaquine-sensitive hypnozoites, or simply the absence of hypnozoites.
Treatment efficacy in the absence of certainty regarding natural risk of
relapse is unknowable even if individual cases of primaquine-resistance are
demonstrable.
Patients free of risk of reinfection and experiencing a recurrent para-
sitaemia within 2 weeks-3 years of starting standard primaquine therapy
for a primary attack may be considered possibly infected by a primaquine-
resistant strain of P. vivax . Standard therapy should be a total dose of 3 or
6 mg/kg (Korea, India, Americas vs tropical Asia or Oceania) delivered in
daily doses over 2 weeks. Some means of assuring adherence should be
implemented. Plasma or blood levels of primaquine are not helpful in dem-
onstrating resistance beyond simply confirming adherence: blood levels of
8-aminoquinolines do not correlate with therapeutic effect. There may be
human genetic mutations to CYP genes that profoundly impact metabolism
of primaquine, and as these become better characterized and understood,
they should certainly be considered as a possible basis of therapeutic failure.
8.3.2. Ex vivo
Methods to assess therapeutic responses of P. vivax isolates in in vitro hepatic
cell lines have been described ( Chattopadhyay et al., 2010 ; Sattabongkot
et al., 2006 ; Millet et al., 1989 ; Mazier et al., 1983 ). No procedure or hepa-
tocyte line has yet been standardized or wholly validated. The requirement
for viable sporozoites of P. vivax poses a daunting challenge to such systems.
Not only must these be obtained from patients (or chimpanzees) via anoph-
eline mosquitoes fed on their blood but also each such isolation will bring
a distinct strain of parasite to bear (except in chimpanzees challenged with
a known strain). This makes standardizing therapeutic responses observed
in hepatocyte lines very difficult. A possible and partial solution would be
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