Tafenoquine in the prophylaxis and treatment of malaria in Australian Defence Force personnel

The Australian Defence Force has a long history of exposure to malaria and frequently deploys into the immediate area of the Pacific Rim where drug resistance has been noted to be problematic. In the late 1990s failures of established malaria prophylaxis regimens were beginning to become more prevalent within the ADF and a search was commenced to identify alternative or promising emerging prophylaxis and treatment regimens. In this context the work presented within this thesis was undertaken with a new 8-aminoquinolone antimalarial, initially formulated by the United States Army's Walter Reed Army Institute of Research (WRAIR) and identified as investigative compound WR 238605. The thesis investigates its utility as both prophylaxis and treatment for malaria infection. The compound was subsequently identified in a joint development arrangement between the US Army and GlaxoSmithKline as etaquine, before a final naming of the compound as tafenoquine. The thesis presents three distinct challenges in the development of this promising antimalarial drug and describes the early human use of tafenoquine in the following settings: • Prophylaxis against malaria infection during deployment to a malarious area; • Post exposure prophylaxis of malaria on return from a malarious area; and • Treatment of recurrences of malaria infection. Methods: The thesis is developed through the description of three distinct human clinical trials. Each of these will be developed as individual chapters within the thesis although the reality is that there was some overlap between the activities with developments observed in early activity being used to define both later stages of long term trials and inform the development of the newer activities, some of which are now ongoing in other countries and research institutions. The first double blind comparative study investigates the use of tafenoquine and mefloquine for the longer term (6 months) prophylaxis of malaria in Australian Defence personnel on deployment to Timor Leste. The second, an open label comparative study of the use of tafenoquine and primaquine in the post exposure prophylaxis of vivax malaria in a defence population in Bougainville, Papua New Guinea and in Timor Leste, and the third looks at the treatment of recurring vivax malaria with tafenoquine in an open label study in a non randomised population of defence personnel. Results: Prophylaxis against malaria infection during deployment to a malarious area: Tafenoquine at a weekly dose of 200mg and mefloquine at a dose of 250mg were well tolerated amongst subjects in a military deployment. No malaria occurred in either the tafenoquine and mefloquine arms during the prophylactic phase of this Phase III study. During the relapse follow-up phase, <1% of subjects in either treatment group developed Plasmodium vivax malaria. The incidence and nature of adverse events was similar between the two treatment groups. The most common adverse events were gastroenteritis and unrelated injury. Tafenoquine was associated with the development of vortex keratopathy (secondary to phospholipidosis) in 69/74 (93.2%) subjects tested (compared to no mefloquine subjects). This effect was benign and reversible, with resolution in >90% subjects at 6 months and complete resolution in all subjects by 1 year post-treatment. No significant changes were seen in most laboratory indices during the study. Increases in methaemoglobin in the tafenoquine group were small. Renal follow-up confirmed a lack of long-term renal effects of tafenoquine. Post exposure prophylaxis of malaria on return from a malarious area: A 3-day dosing regimen of tafenoquine (400 mg od, 200 mg bd or 200 mg od) was effective as a post-exposure prophylaxis agent in this study, demonstrating similar efficacy to 14-day primaquine. Tafenoquine, with a shorter dosing regimen (3 days compared to 14 days primaquine), could be used as a more convenient, yet effective, post-exposure prophylaxis agent. Tafenoquine was well tolerated, with no subjects being withdrawn due to adverse events. The most common adverse events were gastrointestinal events. Treatment of recurrences of malaria infection: This small scale study showed that tafenoquine is safe and effective (following chloroquine treatment) in prevention of relapse of multi-relapsing vivax malaria. The management of relapsing vivax malaria with chloroquine/tafenoquine may be more effective and convenient in preventing further relapses than the standard chloroquine/primaquine treatment regimen. Larger studies are required to address the effectiveness and tolerability of chloroquine/tafenoquine for the treatment of vivax malaria. There is also a requirement to more extensively address tafenoquine used on its own for the treatment of recurring vivax malaria. There remains a need to investigate this regimen in other ethnic populations, including special risk groups such as children and pregnant women. Conclusions: Tafenoquine displays the properties required of a promising antimalarial compound. It has, in two phase III clinical trials, established prophylaxis properties; a demonstrated advantage over the classical 14 days of primaquine treatment for post exposure prophylaxis against P. vivax in its reduced treatment time of 3 days; and has a suggested role in the management of recurrences of vivax malaria, although further research will be required to firmly establish this role. It has an acceptable adverse event profile in the limited treatments undertaken to date, when compared to other available antimalarial compounds. Additionally, it has the advantage of once weekly dosing and shorter post exposure prophylaxis regimens when compared to other available treatments