Relapse in experimental and naturally acquired vivax malaria
In the experimental malaria studies, non-immune volunteers were infected
either by blood taken from a malaria patient or by infected mosquito
bites. The volunteers were then observed daily, usually for at least one
year (many were prison volunteers). Building on the extensive
experiences of malariatherapy of neurosyphilis during the early to
mid-20th century, which had refined and standardized
the methods of infection and clinical management, at least five and
usually ten infected (i.e. sporozoite positive) laboratory reared
anopheline mosquitoes were used to initiate the infection. This ensured
a substantial sporozoite inoculum was delivered to the recipient. With
the Chesson strain of P. vivax the consequent early relapse rate
was 100% (7).
This high relapse rate in experimental malaria should be contrasted with
natural infections in which a single mosquito, with an infection of
variable age (and thus transmission potential), infects an individual
who may already have significant natural immunity dampening illness (8).
This distinction is important because it has a substantial bearing on
the binary outcome therapeutic response to 8-aminoquinolines i.e.
relapse or no relapse. Very high relapse rates usually result from
multiple inoculations (e.g. in soldiers fighting in the Pacific theatre
of World War 2) (9). Overall, the relapse prevention (i.e. radical
curative) efficacy of 8-aminoquinolines was substantially better in
clinical practice compared with the stern test applied in the volunteer
infections. For example, the combination of quinine and plasmoquine at
doses > 30mg base/day was considered highly
effective in preventing relapse in clinical studies in endemic areas,
but doses below 90mg base/day were relatively ineffective in the
experimental challenge model (2, 3, 10, 11). Thus, to compare radical
curative efficacies it is necessary to consider both drug dosage, and
thus exposure, and also the likely hypnozoite burden (12).