Tuesday, 13 May 2014

Primaquine for P.vivax malaria - 5 days or 14?: A short summary

Post by Liaquat Roopesh Johnson, currently employed as a member of the faculty in a private medical college in South India. Roopesh has a post-graduate degree in Community Medicine from the Christian Medical College, Vellore. 

The Anopheles mosquito.
Root word is Anofelis, in Greek,
which means good-for-nothing!  
When it comes to P.vivax malaria, many of us continue to follow the 5-day primaquine regimen. A recent update of  a Cochrane Systematic Review compares the 5 day primaquine regimen with the 14 day primaquine regimen recommended by the WHO. The following is a short summary of the review. (Click here to go to the detailed summary)

Malaria is one of the leading causes of morbidity and mortality in the world, especially in sub-Saharan Africa, Latin America, Asia and South-East Asia. According to WHO estimates, there were between 135-287 million cases of malaria in 2012. Of the estimated 473,000-789,000 deaths due to malaria in the same year, 77% were children less than 5 years of age.

While P. falciparum is the main malarial parasite in Africa, P. vivax and P. falciparum are present in equal proportions in Latin America, Asia and South-East Asia. The highest burden of P. vivax malaria is in four countries- Ethiopia, India, Indonesia and Pakistan. Together, they account for more than 80% of all P. vivax cases in the world.

Traditional radical cure for P. vivax malaria involved the administration of chloroquine for 3 days, followed by 5 days of primaquine. This regimen was thought to prevent the occurrence of relapse. However, various studies (including the 2007 version of this review) demonstrated that a 14 day primaquine was better suited for the prevention of relapse of P. vivax malaria.

After weighing the available evidence, the WHO recommended that P. vivax be treated with 3 days of chloroquine followed by 14 days of primaquine.

While countries like India and Sri Lanka promptly changed their National Malaria Control Policies to reflect the new recommendations, many other countries persisted with the traditional radical cure regimen.

Concerns were raised about the safety  and effectiveness of a 14 day primaquine regimen for radical cure of P. vivax malaria. Principal among these was the risk of haemolysis in individuals with G6PD deficiency. It was also noticed that many patients failed to adhere to the 14 day regimen as they felt much better after 3 days of chloroquine.

The 2013 update of the 2007 review was focused on comparing the recommended 14 day primaquine regimen with alternative regimens in preventing relapses in people with P. vivax malaria that had been treated with chloroquine. They also compared primaquine containing regimens with regimens having only chloroquine or placebo.

The reviewers excluded studies involving P. falciparum and P. vivax co-infection (mixed infection).
In all, 15 RCTs were included in the review. One of these was a Cluster RCT.

The first objective was to compare 14 day primaquine with primaquine regimens of shorter duration. The reviewers found that 14 day primaquine was probably better than primaquine regimens of shorter duration (5 days, 7 days, etc.) in preventing relapses of P. vivax malaria. The quality of evidence is the reason for uncertainty in the findings. If the studies were of high quality, there would have been no ambiguity. However, the included trials were at best of moderate quality. This implies that further research may possibly change the estimates and findings. In general, increasing the dose of primaquine beyond 15mg/day did not seem to confer additional benefit in terms of lower relapse rates.

Another objective was to compare regimens without primaquine and those with primaquine in preventing relapse in P. vivax malaria. Here, the reviewers found clear, high quality evidence that supported the use of primaquine for radical cure of P. vivax malaria. Trials consistently showed much fewer relapse rates when regimens included primaquine, than when they did not. This unequivocally establishes the superiority of chloroquine  plus primaquine regimens to chloroquine only regimens. Since the evidence is of high quality, further research is unlikely to alter the findings.

 Although many have expressed concern about the potential for serious adverse events due to primaquine, none of the included trials reported any serious or non-serious adverse events. Part of the reason could be that individuals with G6PD deficiency were excluded from the trials. Therefore, the lack of reported serious adverse events cannot be taken as indicative of no serious adverse events. The review did not directly seek out such adverse events. Therefore, this limitation will have to be considered when interpreting the findings of the review.

A common concern about the 14 day primaquine regimen has been that of adherence to treatment. This review did not seek to obtain answers to that problem. It is not known whether treatment adherence rates are similar to or much worse than the traditional 5 day primaquine regimen.

Since mixed infections were outside the purview of this review, we do not know if the 14 day primaquine regimen performs as well in that situation.

The above limitations aside, since the review included trials involving both adults and children, the findings can be generalized to these populations.

Sceptics may not be convinced about the effectiveness of the 14 day primaquine regimen for preventing relapse in P. vivax malaria, due to the quality of evidence involved. However, considering that about 77% of deaths due to P. vivax malaria are among children less than 5 years, should one wait for better quality evidence, or change to what probably does work?

Read the Cochrane Review