Mini Primaquine? Controversy and Uncertainty Surround WHO Guidelines for the Antimalarial Primaquine

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 primaquine’s 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 Programme’s 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 couldn’t 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 can’t 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 didn’t 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.

Lorenz von Seidlein works for the Menzies School of Health Research, Australia and coordinates the vivax working group of the Asian Pacific Malaria Elimination Network (APMEN). He is a co-investigator in several primaquine trials and a member of the PLOS Medicine editorial board.