Mini Primaquine?

Controversy and
Uncertainty Surround WHO Guidelines for
the Antimalarial Primaquine
By Lorenz von Seidlein
Posted: October 11, 2012
This year has seen a considerable increase in interest in primaquine, an antimalarial that has
been around for more than 60 years. The answer to why the spotlight has recently intensified
on this old drug lies in three key questions in malaria research and control: How do we
contain the spread of artemisinin resistance; how do we minimise the transmission of
P.falciparum in regions of sub-Saharan Africa which have reached low malaria endemicity;
and what is the optimal treatment to achieve radical cure of P. vivax? The answers to all three
questions lead to primaquine, which is the only drug that can prevent both the transmission of
falciparum malaria, by killing mature sexual stage parasites (gametocytes), and relapse of
vivax malaria by eliminating dormant liver stage parasites (hypnozoites). Alternative drugs,
such as methylene blue and tafenoquine, are in development but for the time being there is no
alternative to primaquine.
While primaquine is set to play a key role in global efforts to control malaria, it is not a
panacea and has considerable drawbacks. In particular, primaquine can cause the potentially
severe side effect of haemolysis in individuals with glucose-6-phosphate dehydrogenase
(G6PD) deficiency, a congenital anomaly which is not uncommon. The last few months in
particular have led to much debate about what the optimal dose of primaquine should be
given efforts to control malaria and concerns over primaquines safety:
First, in September a Cochrane analysis concluded, In light of these doubts about safety, and
lack of evidence of any benefit in reducing transmission, countries should question whether
to continue to use [primaquine] routinely in primary treatment of malaria.
Secondly, a group of experts was asked to review the WHO guidelines which currently
recommend a single 0.75mg/kg dose of primaquine to kill gametocytes and thus prevent the
transmission of falciparum malaria. The experts, some of whom had drafted the current and
previous WHO malaria treatment guidelines came to the conclusion that countries should
continue to use single dose primaquine but reduce the dose by two thirds from 0.75 to 0.25
mg/kg.
Third, the recommendation of the experts was submitted to the WHO Global Malaria
Programmes malaria policy advisory committee where it triggered controversy. The final
decision if and how to accept the recommendations is expected shortly.
What has happened? The Cochrane analysis is based on stringent and hence exclusive
criteria. Only 1776 individuals enrolled in 11 randomised controlled trials were included in
the Cochrane analysis. None of the trials assessed effects on malaria transmission hence no
evidence for an impact on malaria transmission was demonstrated.

The WHO experts took a very different approach and looked for evidence that primaquine
reduces gametocytaemia or more importantly prevents the infection of mosquitoes in feeding
experiments i.e. it is assumed that a reduction in infectivity translates into lower transmission
rates at least in low transmission areas. Secondly the WHO experts felt no constraint to look
exclusively at evidence from randomised controlled trials and reviewed the extensive
historical experience with primaquine. Single dose primaquine has been used as an addition
to falciparum therapy and in mass drug administrations most recently in Tanzania. This last
trial, which started in 2008 couldnt detect any evidence in a reduction of transmission
because there were no malaria cases in the intervention or in the control group. But the
investigators detected high levels of haemolysis in study participants especially in study
participants who had an underlying congenital deficiency of G6PD. The surprise was that a
single dose of 0.75mg/kg primaquine could trigger acute haemolytic anaemia. But then again
haemoglobin levels had not been routinely measured after single dose primaquine
administrations and none of the study participants had clinical signs associated with acute
haemolytic anaemia. This experience in Tanzania put an end to the belief that the
administration of a single dose of 0.75mg/kg primaquine is safe in individuals with G6PD
deficiency.
Equally or even more important than the reported trials is the unreported experience with
single dose primaquine. Trainloads of primaquine have been used in mass drug
administrations in China, Russia and North Korea during the second half of the last century.
These mass drug administration coincided with a nadir in individual rights when the benefit
of the community had a higher priority than individual health risks. A safety assessment of
these huge campaigns is difficult and the completeness of adverse events data is hard to
assess. The WHO experts commissioned a safety review of all documents related to
primaquine use archived by the League of Nations and its successor the WHO. The review
found 13 deaths associated with primaquine administrations and estimated the risk of death
around 1:700,000 with considerable uncertainty surrounding the denominator (Recht J,
Ashley E, White NJ. unpublished). It is expected that the review will be made available with
the revised WHO guidelines. Malaria has been eliminated from the former Soviet republics,
and has reached very low levels in China, suggesting but not proving an effect of single dose
primaquine on malaria transmission.
Evidence for the efficacy of small primaquine doses comes from the review of the historical
literature. More recent, unpublished laboratory work in Jiangsu province, China suggests that
a single primaquine dose of 0.125mg/kg or even less can reliably kill oocytes and
gametocytes. Whether the large amounts of primaquine administered in the last century have
resulted elsewhere in primaquine resistant P.falciparum strains has yet to be explored.
When asked why the experts felt an urgent need to change the treatment guidelines for single
dose primaquine the emergence of artemisinin resistant P.falciparum strains and their spread
in South East Asia was mentioned. This threat has triggered series of high level meetings yet
no viable containment plan has so far emerged. Adding a single dose of primaquine to the
treatment of falciparum malaria is recommended in many countries but in practice this is
rarely done. Furthermore a substantial proportion of gametocyte carriers are subclinically
infected and very low gametocyte densities cant be detected by microscopy or PCR of dried
blood spots. Eliminating this gametocyte reservoir will require mass drug administrations
which will probably need to include primaquine. However, uncertain about the safety of
primaquine, practitioners are reluctant to prescribe it and policy makers, well aware of the
consequences of adverse events caused by public health measures, shy away from
recommending the administration of primaquine.
Members of the WHO expert group believe that a reduced single dose primaquine will find
wider acceptance than the previously recommended dose and will thus help to contain the
spread of artemisinin resistance. They also feel that the spread of artemisinin resistance
represents a sufficiently big threat not to wait for more current data. To retain credibility the
WHO would be well advised to make without delay the data available on which the proposed
changes in treatment guidelines are based. How the WHO identifies and selects their experts
is not transparent and several emails to explore this selection process didnt result in a
satisfactory answer. Changes in guidelines may reach wider acceptance if they are the result
of a transparent process. Time will tell whether a recommendation to reduce the dose of
primaquine by two thirds has any impact on the spread of artemisinin resistance. A much
more courageous strategy may be needed to prevent a health disaster.