High-dose primaquine regimens against relapse of Plasmodium vivax malaria

21 Jul 2008

Maria Victoria Valero

Source: American Journal Tropical Medicine and Hygiene (see original article)

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Citation: Krudsood S, Tangpukdee N, Wilairatana P, Phophak N, Baird JK, Brittenham GM, Looareesuwan S (2008). High-dose primaquine regimens against relapse of Plasmodium vivax malaria. Am J Trop Med Hyg;78(5):736-40

Plasmodium vivax infects 130-435 million of the 2.6 billion people living in endemic areas; i.e. Asia, Central and South America, the most affected regions. Recent studies suggest that vivax malaria can lead to substantial morbidity and can result in fatal outcomes in a similar manner to malaria caused by Plasmodium falciparum (1,2). Vivax malaria has a relapse potential, resulting in the re-appearance of parasitaemia, owing to the persistence of latent pre-erythrocytic parasites (hypnozoites) in the liver. First-line therapies have remained unchanged for 50 years. The standard adult treatment regimen for P. vivax malaria is chloroquine (1500 mg over three days) plus primaquine (15 or 30 mg daily for 14 days) (3,4).

Primaquine treatment is the only therapeutic option against relapse but patient compliance tends to be poor, given the lengthy course required for effective clearance (1-3). Some studies have observed poor efficacy of the standard regimen (1,2). This has been attributed to an intrinsic tolerance of primaquine by parasites in some regions (3). It is, for example, well documented for the Chesson strain of P. vivax from New Guinea (4,5).

The study by Krudsood et al., conducted in Thailand with 399 patients was a randomized, controlled trial to determine the efficacy, safety and tolerability of artesunate with selected regimens of primaquine, and the parasite and fever clearance times. All patients received artesunate, 600 mg over five days and were randomly assigned into one of six groups:

Groups 1-5: received 30 mg /primaquine/daily /14 day
Group 6: received 30 mg/ twice a day (60 mg/day) /7 days.

Patients having recurrent parasitaemia on or before 14 days were considered to be artesunate treatment failures, whereas recurrent parasitaemia between days 15 and 28 was considered primaquine treatment failure.

Abbreviated high-dose regimens of primaquine after artesunate therapy proved efficacious, safe, and well-tolerated therapy against relapses of P. vivax malaria. The regimen of two daily doses of 30 mg for seven days was efficacious against early relapses in 94% of cases. It is explained because primaquine can eliminate the asexual erythrocytic stage of P.v. The findings corroborate similar results of good tolerability in other placebo-controlled double-blinded trials. Patients are also more likely to complete the course (3-5).

Most endemic countries have adopted a primaquine dose of 15mg/day/5 days. However, the evidence suggests that this scheme is ineffective, as mentioned above. In addition, further studies and considerations of safety are required in endemic areas where there are patients with of glucose-6-phosphate-dehydrogenase (G6DP) deficiency. G6DP is a crucial enzyme for erythrocytes survival and deficient patients are susceptible to haemolytic anaemia. This deficiency, in the presence of oxidative agents such as primaquine, exacerbates the anaemia. This pathology is hereditary and linked to the X chromosome. Previous screening tests to establish the frequency of G6DP deficiency are required before primaquine treatment is introduced on a wide scale . Some countries do not approve primaquine for prevention or treatment and its use requires a specific temporary authorization.

Given the complex life cycle of P.v, additional efforts are needed to develop a vaccine or new drugs, as well as guidelines for the clinical management of vivax malaria in different endemic areas. This was a small trial; only 66 patients in one country received the seven-day treatment. Therefore additional research is required so that further evidence may be accumulated.

References

1. Silachamroon U, Krudsood S, Treeprasertsuk S, Wilairatana P, Chalearmrult K, Mint HY, Maneekan P, White NJ, Gourdeuk VR, Brittenham GM, Looareesuwan S (2003). Clinical trial of oral artesunate with or without high-dose primaquine for the treatment of vivax malaria in Thailand. Am J Trop Med Hyg; 69(1):14-18. Available From: http://www.ajtmh.org/cgi/content/abstract/69/1/14

2. Looareesuwan S, Buchachart K, Wilairatana P, Chalermrut K, Rattanapong Y, Amradee S, Siripiphat S, Chullawichit S, Thimasan K, Ittiverakul M, Triampon A, Walsh DS (1997). Primaquine-tolerant vivax malaria in Thailand. Ann Trop Med Parasitol; 91(8):939-44. Available from: http://dx.doi.org/10.1080/00034989760338

3. Baird JK (2007). Neglect of Plasmodium vivax malaria. Trends Parasitol; 23(11):533-9. Available from: http://dx.doi.org/10.1016/j.pt.2007.08.011

4. Baird JK, Hoffman SL (2004). Primaquine therapy for malaria. Clin Infect Dis; 39(9):1336-45. Available from: http://dx.doi.org/10.1016/j.pt.2007.08.011

5. Baird JK, Schwartz E, Hoffman SL (2007). Prevention and treatment of vivax malaria. Curr Infect Dis Rep; 9(1):39-46. Available from: http://dx.doi.org/10.1007/s11908-007-0021-4

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2008 The American Society of Tropical Medicine and Hygiene