Single-dose radical cure for Plasmodium vivax

Plasmodium vivax is the most geographically diverse cause of malaria and results in an estimated 70–390 million infections each year.1,2 Relapse infections are a major barrier to vivax management and are responsible for the majority of clinical episodes of vivax infection. Radical cure for P. vivax refers to treatments that target both the blood stage and the dormant liver stages of infection (i.e. hypnozoites) responsible for relapses. Radical cure is also essential to current malaria control and elimination efforts, especially since relapse infections can result in outbreaks in regions where malaria has previously been eliminated. For over one-half of a century, radical cure strategies for vivax malaria have relied on a single agent, primaquine (PQ), as the only drug active on the hypnozoite stage of infection. However, PQ has several limitations, most notably a 14-day treatment regimen that has poor adherence. If three or more primaquine doses are missed during this 2-week regimen, then the treatment efficacy falls by ≥ 3-fold.3 In this issue of the JTM,2 Professor Kevin Baird reviews the pharmacology, safety, tolerability and pivotal clinical studies leading to the licensure of a new synthetic PQ derivative, tafenoquine (TQ), as a single-dose agent for relapsing malaria (P. vivax and Plasmodium ovale). TQ represents a major advance in our efforts to effectively treat vivax infections in endemic areas and in travellers as well as to control and eliminate vivax infections globally.4–6 In multi-site randomized clinical trials, chloroquine + TQ (as a single 300 mg dose) was shown to be superior to chloroquine alone and comparable to chloroquine + PQ × 14 days (with adherence confirmed) in preventing vivax recurrences within 6 months.2,7 In addition to the advantages of adherence to TQ versus the 14-day courses of PQ in treating acute vivax infections, another clear benefit to travellers and migrants will be the use of TQ as single-dose presumptive anti-relapse therapy (PART) following exposure in regions of high endemicity for P. vivax and P. ovale. PART is often recommended for travellers when leaving regions after prolonged exposure (>6 months) to relapsing malaria or for even short exposures in regions with intense transmission of P. vivax, such as Papua New Guinea, Papua and other regions of Indonesia. However, PART was infrequently used by travellers who return from the endemic areas, at least in part, due to the poor compliance with 14 days of PQ. Now single-dose TQ becomes the preferred option for PART delivered as a single 300 mg dose (with food) when the travellers leave the endemic area while still taking their chemoprophylaxis (i.e. the last week of atovaquone–proguanil or during the last 2 weeks of chloroquine, doxycycline or mefloquine, as appropriate). PART is not required if the individual has used PQ or TQ as chemoprophylaxis. Of note, the weekly chemoprophylactic dose of TQ is 200 mg versus the 300 mg dose used for PART. Despite the clear advantages TQ offers as a single-dose radical cure for vivax and ovale infection, there remain knowledge gaps and limitations regarding its use. TQ, like PQ, can induce severe intravascular haemolysis in individuals who are glucose-6-phosphate dehydrogenase (G6PD) deficient. TQ has a longer T1/2 life than PQ and patients should not receive TQ without evidence that they have >70% of G6PD levels. In non-pregnant non-lactating patients over 16 years old with G6PD levels > 70% and without a history of neuropsychiatric illness, TQ is well tolerated and safe. The global use of TQ especially in malaria elimination and control programmes will be enhanced with the development of quantitative rapid point-of-care G6PD tests. It appears that TQ metabolism and efficacy may be less impacted by cytochrome P-450 CYP2D6 alleles compared to PQ, but more data are needed. Finally as discussed in detail by Dr Baird, TQ efficacy in pre-clinical models is enhanced ~10-fold when used concurrently with chloroquine-, mefloquine- or artemisinin-based therapies. There are currently no data on doxycycline, atovaquone/proguanil but are presumed to enhance TQ efficacy as well.2,8 TQ treatment efficacy in the absence of any blood stage of an agent is currently unclear and warrants further study. Conflict of interest: None declared.

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