Plasmodium Vivax Malaria Without Complication Clinical Trial
Official title:
Artemether-lumefantrine vs Chloroquine in Patients With Acute Non-severe P. Vivax Malaria in Sabah, Malaysia
Both artemether-lumefantrine and chloroquine are currently used and recommended by Malaysian
Ministry of Health as blood stage treatments for non-severe P. vivax and P. knowlesi
malaria. Microscopic misdiagnosis between Plasmodium species remains a large issue in Sabah,
Malaysia and elsewhere. In order to facilitate potential policy change to a unified ACT
guideline for all malaria species in Sabah artemether-lumefantrine needs to be evaluated for
P. vivax malaria.
Preliminary data in a recently completed RCT evaluating artesunate-mefloquine vs chloroquine
for P. vivax showed up to 36% P. vivax recurrence with chloroquine monotherapy by day 28
post treatment without primaquine. Based on these data blood stage chloroquine treatment
failure rates should also be evaluated in the context of standard concurrent (rather than
delayed) liver stage primaquine dosing, due to both its potential blood stage synergistic
effect in addition to known decreased recurrence rates. As artemether-lumefantrine is one of
the current first line Ministry of Health ACTs used in Sabah with a lower adverse event
profile compared to artesunate-mefloquine, this was recommended as the more appropriate ACT
to evaluate against chloroquine.
Malaria due to infection with P. vivax is currently estimated at up to 390 million episodes
per year worldwide, with substantial morbidity caused by the recurrent nature of its
infection, associated anaemia and adverse effects on pregnancy, and ability to cause severe
disease and death. The majority of malaria cases from all Plasmodium species in Malaysia are
from the Eastern state of Sabah, where despite around a 36-fold reduction in incidence since
the implementation of malaria eradication programs in 1961, minimum estimates based on
unpublished microscopy data from Sabah State public health records still detailed 8685
malaria cases in 2009-2011. While P. vivax accounts for between 30-50% of these figures
currently, studies have demonstrated as overall transmission rates in countries previously
endemic for malaria decline the proportion of cases attributable to P. vivax increases.
Mixed P. falciparum / P. vivax infections are also likely to be underestimated in areas of
co-endemicity, with high rates of recurrence of P. vivax shown in studies following
treatment for apparent P. falciparum mono-infection or mixed Plasmodium spp. infections.
Malaysian Ministry of Health guidelines currently recommends chloroquine and primaquine as
first line treatment for the erythrocytic and hypnozoite life stages of uncomplicated P.
vivax malaria respectively. While resistance to chloroquine has previously been documented
in Sabah and also Peninsular Malaysia, the unstable transmission dynamics and recent
reduction in P. vivax incidence due to public health measures mean the current risk of
chloroquine-resistant P.vivax transmission is likely to be low. Despite this, due to
documented increasing resistance in surrounding countries including Indonesia, Thailand,
Vietnam, and PNG, transient populations of migrant workers, and recent concerns of the
failing efficacy of hypnozoite eradication by primaquine, the need for ongoing therapeutic
efficacy monitoring is recommended.
There is also growing support for artemisinin-based combination therapy (ACT) as a unified
first line treatment choice in areas co-endemic for P. falciparum and P. vivax, as adopted
by a small number of countries including PNG, Solomon Islands, Vanuatu and Papua, Indonesia,
due to the regional increase of chloroquine-resistant P. vivax, and ongoing concerns over
the microscopic misdiagnosis of Plasmodium species. This is also particularly relevant for
P. knowlesi malaria, as it is frequently misidentified on microscopy as P. falciparum and P.
malariae due to morphological similarities in the early trophozoite, and late trophozoite
and schizont life stages respectively, with studies showing up to 80% of P. malariae and
7-12% of P. falciparum in this region are actually P. knowlesi when definitively evaluated
with PCR. Misdiagnosis has concerning treatment implications, as although P. knowlesi has
been shown to respond well to ACT and chloroquine, unlike P. malariae, knowlesi malaria has
a rapid 24-hour replication rate and can cause hyperparasitaemia, severe complications and
fatal outcomes, while the inadvertent use of chloroquine for widely chloroquine-resistant P.
falciparum may also have fatal consequences.
Previous reluctance to use ACTs in presumed chloroquine-sensitive P.vivax areas were
centered on concerns over efficacy and cost. The advent of generically produced ACTs is
improving cost-related issues, while a recent Cochrane review of clinical trials looking at
the use of ACT versus chloroquine for uncomplicated vivax malaria showed that ACTs are
equivalent to chloroquine in preventing recurrent parasitaemia in the first 28 days (RR 1,
95% CI 0.30 to 3.39), and those with long half lives such as mefloquine or piperaquine are
superior over a 6-8 week follow up, with fewer recurrent episodes after day 28 (RR 0.47, 95%
CI 0.29 to 0.76). This post treatment prophylaxis benefit of longer acting agents extends to
the reduction in gametocyte carriage, delay in relapse or re-infection and decreased risk of
anaemia development, all of which contribute to decreased transmissibility and health care
cost.
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