Artesunate-mefloquine vs Chloroquine in Patients With Acute Uncomplicated P. Knowlesi and P. Vivax Malaria: a Randomized Open Label Trial in Sabah, Malaysia

1.1 Background

Naturally acquired infections with Plasmodium knowlesi, the fifth human malaria, are growing [1]. Since 2004 increasing numbers of cases have been reported from residents and returned travelers predominantly from Malaysia and other countries in South-East Asia including Thailand, Vietnam, Myanmar, Singapore, Indonesia and the Philippines [2-8]. Cases coincide with the geographic distribution of its natural simian hosts (long-tailed and pig-tailed macaques) and Anopheles leucosphyrus group mosquito vector [9, 10], with potential human-to-human transmission unknown. Eastern Malaysia appears to be the epicentre, with around 1400 PCR-confirmed P. knowlesi human mono-infections reported in 2009, comprising 41% of 2,189 total malaria cases in Sarawak [11] and 343 cases from selected samples sent to Sabah's State Reference Laboratory [12]. P. knowlesi is also now the most common cause of malaria in different contrasting regions, including 70% of malaria admissions in the heavily forested area of Kapit in Sarawak [1, 13], 63% of samples from the interior division of Sabah [14], and in 87% of malaria admissions in the deforested coastal area of Kudat in Sabah, where it is also the major cause of malaria in children [15].

Despite the increase in reported incidence, difficulties with microscopic diagnosis and a lack of PCR based epidemiological surveillance studies throughout South-East Asia mean the true disease burden is underestimated. P. knowlesi is microscopically misidentified 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 [16-19] and 7-12% of P. falciparum [1, 16] in this region are actually P. knowlesi when definitively evaluated with PCR. Current rapid diagnostic tests (RDT) for malaria can distinguish falciparum Current rapid diagnostic tests (RDT) for malaria can distinguish falciparum from other Plasmodium species with a sensitivity of up to 99% at parasite counts > 1,000/ μL [20], but a knowlesi specific antigen has not been developed and current antibody panels are unable to differentiate between P. knowlesi and other mixed Plasmodium spp. infections [21]. Misdiagnosis has concerning treatment implications, as unlike P. malariae, knowlesi malaria has a rapid 24-hour replication rate and can cause hyperparasitaemia, severe complications and fatal outcomes [13, 17, 18], while the inadvertent use of chloroquine for widely chloroquine-resistant P. falciparum may also have fatal consequences.

1.2 Treatment

Initial observational and retrospective studies have suggested both chloroquine and artemisinin combination therapy (ACT) are effective therapy for uncomplicated P. knowlesi infection [15, 16, 22, 23]. Justification for treatment selection for this trial is based on this literature review. Case reports predominantly from returned travelers to South-East Asia also document uncomplicated knowlesi malaria responding well to conventional anti-malarials such as chloroquine, mefloquine, atovaquone with proguanil, doxycycline and quinine [4, 24- 31], supporting its zoonotic and drug naïve origin. However to date there have been no prospective randomised trials to compare chloroquine and ACT as the anti-malarials currently used for uncomplicated P. knowlesi infection in Malaysia, and there are no current recommendations on how to treat P. knowlesi infection in the WHO 2010 malaria treatment guidelines. As ACTs are already being used for treating P. falciparum and are recommended for the increasingly chloroquine-resistant P. vivax found in the surrounding countries in South East Asia [32], the potential benefit of a unified treatment policy to facilitate prompt and effective treatment of all Plasmodium species needs evidence of ACT as the optimal treatment for P. knowlesi infection also.