Tafenoquine for the radical cure versus prophylaxis of Plasmodium vivax malaria: the importance of using the appropriate data set

Sir,

We read with interest the December 2021 article by Sharma et al1, discussing the efficacy and safety of tafenoquine (TQ) in Plasmodium vivax malaria. This is an important topic as P. vivax is the most common malarial parasite globally2,3. However, the article by Sharma et al1 contains numerous inaccuracies and inconsistencies, for which comments and corrections are required. Principally, the article failed to distinguish appropriately between different indications (radical cure of P. vivax malaria vs. malaria prophylaxis) and dosing regimens4. TQ at a single dose (SD) of 300 mg in combination with chloroquine (CQ) is approved for the radical cure of P. vivax malaria (i.e. eradication of both the blood schizont and dormant hepatic hypnozoite stages)3,5; however, for malaria prophylaxis, the dosing regimen is TQ 200 mg daily for three days preceding exposure, 200 mg weekly during the time of exposure and 200 mg in the week following return from an endemic area4,6. If the intention of the article by Sharma et al1 is indeed to explore the efficacy and safety of TQ plus CQ for the radical cure, only data for this indication should have been included. In addition, as illustrated below, the article inaccurately outlines the efficacy data from safety studies (i.e. studies primarily designed to highlight TQ safety in the registration dossier for the compound), confuses TQ dosages, inappropriately includes certain studies, misinterprets study results and overstates safety concerns.

Importantly, in describing the efficacy of TQ observed in various studies, Sharma et al1 improperly highlighted the efficacy findings from two studies, in which the safety of multiple-dose, rather than SD, TQ was in focus7,8; moreover, in these two studies and three other trials, the principal consideration was malaria prophylaxis rather than radical cure with TQ7-11.

When discussing the phase 3 Global Assessment of Tafenoquine Hemolytic Risk (GATHER) study12 of SD TQ 300 mg in combination with CQ, Sharma et al1 did not clarify that the six month recurrence-free rates of 67 per cent [95% confidence interval (CI): 61, 72.3] for TQ and 72.8 per cent (95% CI: 65.6, 78.8) for primaquine (PQ) were from a patient-level meta-analysis of the pooled per-protocol population (n=510) in the GATHER and Dose and Efficacy Trial Evaluating Chloroquine and Tafenoquine in Vivax Elimination (DETECTIVE) studies12,13. The non-inferiority conclusion by Sharma et al1 also warrants clarification in reference to the conclusion in the report of the efficacy meta-analysis, which states that ‘… non-inferiority of TQ to PQ could not be shown’12.

Discussion of the ‘similar results’ from Fukuda et al14 is inappropriate, as this study evaluated a TQ dosage of 400 mg daily for three days, which is considerably higher than the licensed SD of 300 mg co-administered with CQ. Given this dosage discrepancy, it is inaccurate for Sharma et al1 to subsequently emphasize, based on Fukuda et al’s14 paper, ‘… the likely resistance to TQ (TQ) monotherapy’ or to compare the rates of thrombocytopenia, methemoglobinemia and keratopathy for TQ vs. PQ. Moreover, in the discussion of the pivotal phase 3 DETECTIVE study,13 Sharma et al1 did not acknowledge that the study was designed to primarily compare the six month relapse free efficacy rates for TQ in combination with CQ (62.4%, 95% CI: 54.9, 69) vs. CQ alone (27.7%, 95% CI: 19.6, 36.6; hazard ratio for risk of recurrence 0.3; P<0.001) and instead stated that ‘single-dose TQ was slightly less efficacious than PQ in intention-to-treat and per-protocol population’. The study made no conclusions with regard to TQ vs. PQ since this was neither the primary objective nor was it statistically powered to evaluate this13.

Regarding potential safety concerns, Sharma et al1 mentioned that ‘a higher dose of TQ is associated with the development of eye-related disorders such as keratopathy and retinal disorders’. The ‘higher dose’ is not stipulated; however, it should be emphasized that it seems to refer to TQ use in the prophylaxis setting rather than the use of SD TQ 300 mg in the licensed indication of radical cure. Furthermore, Sharma et al1 failed to include any discussion of a dedicated study to evaluate the ophthalmic safety of SD TQ 300 mg in healthy volunteers, which concluded that there was no evidence of any pharmacodynamic effect of SD TQ 300 mg on the retina or any short-term clinically relevant effects on ophthalmic safety15. Indeed, it is misleading to discuss several studies that refer to TQ use in the prophylaxis setting7-11. In addressing the phase 2b component of the DETECTIVE study16, Sharma et al1 considered that it ‘does not seem to be meaningful’ in ‘enroling (a) CQ alone group (n=54)’; however, the study protocol was submitted to several regulatory bodies and ethics committees in the relevant jurisdictions, including in India, who all approved the study design. The protocol also included a requirement to provide rescue treatment for any patient experiencing a relapse. Sharma et al1 also compared the incidence of diarrhoea for TQ vs. PQ (16 vs. 8%), but at the higher, non-approved TQ dose of 600 mg. In addition, Sharma et al1 highlighted a single case of QT prolongation that occurred with TQ 300 mg; however, this is unbalanced, as the integrated safety summary (in the New Drug Application to the U.S. Food and Drug Administration), which clearly reports that TQ had no clinically meaningful effect on QT interval in healthy volunteers, was not cited17.

Based on the phase 3 component of the DETECTIVE study13, Sharma et al1 stated that ‘… no statistical analysis was carried out for safety parameters’; however, this contradicts the conclusion of the paper reporting pooled GATHER and DETECTIVE data: ‘among patients with normal G6PD (glucose-6-phosphate dehydrogenase) enzyme activity, the decline in the haemoglobin level with TQ did not differ significantly from that with PQ’12. Sharma et al1 also used emotive and unqualified terms such as ‘safety issues of TQ, which are alarming’, ‘some serious safety concerns’ and ‘potential safety concerns’. It must be emphasized that the safety profile of SD TQ 300 mg is similar to that of PQ 15 mg for 14 days12.

In their ‘implications for India’ section, Sharma et al1 caused confusion by failing to acknowledge that studies 2012/03/002511 (Clinical Trials Registry-India)18 and NCT01376167 (ClinicalTrials.gov)19 are the same study; moreover, they do not recognize that these two reports18,19 only describe data from the four Indian sites involved in the phase 2b component of the DETECTIVE study, which involved seven sites across Brazil, India, Peru and Thailand16. Sharma et al1 also incorrectly listed the dosages evaluated in the DETECTIVE study16, and erroneously asserted that ‘… recruitment has been stopped and results are awaited’1; the study has been completed, and results have been published16.

Although Sharma et al1 mentioned that ‘TQ carries a significant risk of inadvertent use in G6PD-deficient subjects, they do not discuss, as clearly stated in the TQ Prescribing Information5, that due to the risk of haemolytic anaemia in patients with G6PD deficiency or unknown G6PD status:

• (i) G6PD testing must be performed before prescribing TQ

• (ii) Withhold TQ from patients with G6PD enzyme levels <70 per cent of normal

• (iii) Monitor patients for clinical signs or symptoms of haemolytic anaemia

• (iv) Advise patients to seek medical attention if signs of haemolytic anaemia occur.

In summary, the article by Sharma et al1 contains many errors and baseless assertions that mislead the reader. Overall, it would have been prudent for Sharma et al1 to have accentuated that the approach to 8-aminoquinoline (e.g. TQ) use in the radical cure of P. vivax malaria requires a delicate balance between anti-hypnozoite activity plus relapse prevention and the potential for erythrocyte damage and clinical haemolysis20.