I was concerned to read in Hugh Reyburn’s recent editorial[1]
(regarding the new WHO malaria treatment guidelines[2]) that a single dose
of primaquine is now recommended at the end of artemisinin-based
combination treatment, in areas where reduction in transmission of malaria
is a priority. This recommendation is “based on its historical use of
primaquine and a single trial that showed excellent clearance of
gametocytes”. The WHO guidelines actually note that studies on the impact
of this strategy are very limited and, in the one referenced study,
primaquine actually caused a transient fall in haemoglobin[3]. Yet the
guidelines still state that where a single does of primaquine has been
used, it is well tolerated, and prior testing for glucose-6-phosphate
dehydrogenase (G6PD) deficiency was not required[2].
This was not my own experience of primaquine use in Vanuatu. A single
dose of primaquine was introduced into malaria treatment protocol in
Vanuatu in the late 80s. In 1989 and 1990 I saw a number of patients with
severe haemolysis following malaria treatment[4]. All were subsequently
found to have G6PD deficiency. Prevalence studies showed G6PD deficiency
was fairly common in Vanuatu; 61 one of 784 individuals tested (7.8%) were
G6PD deficient[4]. Because of the number of cases of haemolysis and the
prevalence of G6PD deficiency, the use of primaquine as a gametocytocidal
agent in Vanuatu was discontinued[5].
The risk of haemolysis may not be confined to individuals with G6PD
deficiency. In a recent Tanzanian study, in which a single dose of
primaquine was given as part of a mass drug intervention to children aged
1 to 12 years, there was a significant fall in haemoglobin with
primaquine[6]. This reduction was most pronounced in G6PD-deficient
individuals, but was also observed in heterozygotes and individuals with
the wild-type genotype. The authors concluded that primaquine may cause
moderate anemia when co-administered with artemisinins, and that excluding
individuals based on G6PD status alone may not be sufficient to prevent
primaquine-induced haemolysis.
Given the risk to individuals of a drug that is of no benefit to
them, I believe it is unethical to use primaquine as a malarial control
measure. The lack of quality evidence for any benefit also means that any
recommendation for primaquine lacks scientific credibility.
References
1. Reyburn H, New WHO Guidelines for the treatment of malaria, BMJ
2010;340:c2637.
3. Shekalaghe S, Drakeley C, Gosling R, Ndaro A, van Meegeran M,
Enevold A et al. Primaquine clears sub-microscopic Plasmodium falcipairun
gametocytes that persist after treatment with sulphrdoxine-pyrimethanine
and artesunate. PLoS One 2007;2:e1023.
4. Reeve PA, Toaliu H, Kaneko A, Hall JJ, Ganczakowski M. Acute
intravascular haemolysis in Vanuatu following a single dose of primaquine
in individuals with glucose-6-phosphate dehydrogenase deficiency. J Trop
Med Hyg 1992 Oct;95(5):349-51.
5. Reeve PA. Malaria treatment in Vanuatu: new national treatment
guidelines. P N G Med J 1994 Sep;37(3):181-8.
6. Shekalaghe S, ter Braak R, Daou M, Kavishe R, van den Bijllaardt
W, van den Bosch S, et al. In Tanzania, haemolysis after a single dose of
primaquine co-administered with an artemisinin is not restricted to
glucose-6-phosphate dehydrogenase-deficient individuals. Antimicrobial
Agents and Chemotherapy 2010;54:1762-1768.
Sir,
I was concerned to read in Hugh Reyburn’s recent editorial[1]
(regarding the new WHO malaria treatment guidelines[2]) that a single dose
of primaquine is now recommended at the end of artemisinin-based
combination treatment, in areas where reduction in transmission of malaria
is a priority. This recommendation is “based on its historical use of
primaquine and a single trial that showed excellent clearance of
gametocytes”. The WHO guidelines actually note that studies on the impact
of this strategy are very limited and, in the one referenced study,
primaquine actually caused a transient fall in haemoglobin[3]. Yet the
guidelines still state that where a single does of primaquine has been
used, it is well tolerated, and prior testing for glucose-6-phosphate
dehydrogenase (G6PD) deficiency was not required[2].
This was not my own experience of primaquine use in Vanuatu. A single
dose of primaquine was introduced into malaria treatment protocol in
Vanuatu in the late 80s. In 1989 and 1990 I saw a number of patients with
severe haemolysis following malaria treatment[4]. All were subsequently
found to have G6PD deficiency. Prevalence studies showed G6PD deficiency
was fairly common in Vanuatu; 61 one of 784 individuals tested (7.8%) were
G6PD deficient[4]. Because of the number of cases of haemolysis and the
prevalence of G6PD deficiency, the use of primaquine as a gametocytocidal
agent in Vanuatu was discontinued[5].
The risk of haemolysis may not be confined to individuals with G6PD
deficiency. In a recent Tanzanian study, in which a single dose of
primaquine was given as part of a mass drug intervention to children aged
1 to 12 years, there was a significant fall in haemoglobin with
primaquine[6]. This reduction was most pronounced in G6PD-deficient
individuals, but was also observed in heterozygotes and individuals with
the wild-type genotype. The authors concluded that primaquine may cause
moderate anemia when co-administered with artemisinins, and that excluding
individuals based on G6PD status alone may not be sufficient to prevent
primaquine-induced haemolysis.
Given the risk to individuals of a drug that is of no benefit to
them, I believe it is unethical to use primaquine as a malarial control
measure. The lack of quality evidence for any benefit also means that any
recommendation for primaquine lacks scientific credibility.
References
1. Reyburn H, New WHO Guidelines for the treatment of malaria, BMJ
2010;340:c2637.
2. WHO. Guidelines for the treatment of Malaria, Second Edition 2010,
www.who.int/malaria/publications/atoz/9789241547925/en/imdex.html.
3. Shekalaghe S, Drakeley C, Gosling R, Ndaro A, van Meegeran M,
Enevold A et al. Primaquine clears sub-microscopic Plasmodium falcipairun
gametocytes that persist after treatment with sulphrdoxine-pyrimethanine
and artesunate. PLoS One 2007;2:e1023.
4. Reeve PA, Toaliu H, Kaneko A, Hall JJ, Ganczakowski M. Acute
intravascular haemolysis in Vanuatu following a single dose of primaquine
in individuals with glucose-6-phosphate dehydrogenase deficiency. J Trop
Med Hyg 1992 Oct;95(5):349-51.
5. Reeve PA. Malaria treatment in Vanuatu: new national treatment
guidelines. P N G Med J 1994 Sep;37(3):181-8.
6. Shekalaghe S, ter Braak R, Daou M, Kavishe R, van den Bijllaardt
W, van den Bosch S, et al. In Tanzania, haemolysis after a single dose of
primaquine co-administered with an artemisinin is not restricted to
glucose-6-phosphate dehydrogenase-deficient individuals. Antimicrobial
Agents and Chemotherapy 2010;54:1762-1768.
Yours sincerely,
Paul A Reeve
Specialist Physician
Waikato Hospital, P Bag
Hamilton,
New Zealand
Competing interests:
None declared
Competing interests: No competing interests