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.
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. (Click here to go to a shorter summary)
Background
The World Health Organization (WHO) estimates that there were between 135-287 million cases, and
between 473,000 – 789,000 deaths due to malaria in 2012. 90% of these deaths occurred in sub-Saharan Africa, with under-five children accounting for 77% of the deaths.
Malaria is a major public health problem in Africa and Asia, where the disease is usually caused by either plasmodium falciparum or plasmodium vivax. About 9% of estimated cases globally are due to plasmodium vivax. However, outside the African continent, the proportion is 50%. Four countries account for more than 80% of estimated P. vivax cases- Ethiopia, India, Indonesia and Pakistan.
Current evidence suggests that P.vivax responds more slowly to control measures. Therefore, the WHO recommends that National Malaria Control Programs, especially outside sub-Saharan Africa, should give greater attention to the control of P.vivax.
The WHO recommends that P.vivax be treated with a 3-day course of chloroquine followed by 14 days of primaquine (15 mg/day).
Although chloroquine is well tolerated by most patients, primaquine treatment may cause some serious side effects. The most serious of these are haemolysis among those with G6PD deficiency, and methaemoglobinaemia.
Primaquine treatment failure or relapse is defined as the presence of P. vivax parasites more than 28-30 days after a full course of primaquine in people living in a non-endemic area.
Why this review?
Till the publication of the 2007 version of this review, P. vivax malaria was treated with a 5 day primaquine regimen. Subsequently policies in only a few countries were modified to accommodate the new 14-day primaquine regimen for radical cure of P. vivax malaria. Many countries in South Asia, South-East Asia and
Latin America continue to follow the 5 day primaquine regimen.
The main concerns about the 14-day primaquine regimen are:
1. Poor adherence, as many become rapidly asymptomatic after treatment with chloroquine. Such individuals are poorly motivated to complete primaquine treatment.
2. The risk (perceived and real) of adverse events.
3. Despite adherence to the regimen, due to primaquine resistance in some areas, there is less than optimal prevention of relapse.
4. Cheap, rapid and practical tests for G6PD deficiency are unavailable.
Due to the above, practitioners are struggling to successfully implement the 14-day primaquine regimen.
The alternatives suggested to the five day and 14 day primaquine regimens include:
1. Using higher doses of primaquine (after chloroquine) for shorter periods to overcome problems with adherence.
2. Using higher doses of primaquine (after chloroquine) for 14 days or longer to overcome primaquine resistance.
3. Ensuring an adequate total dose of primaquine.
4. Concurrent (instead of sequential) administration of chloroquine and primaquine.
5. Chloroquine monotherapy.
Effective treatment of P. vivax is important due to the disease burden and cost of treating relapses. With many treatment regimens in current use, it is important to determine the comparative effects of the different regimens.
Main objective
To compare the recommended 14-day primaquine regimen with alternative regimens for preventing relapses (radical cure) in people with P. vivax malaria treated with chloroquine.
Methodology (in brief)
The reviewers searched for and included RCTs and quasi-RCTs that involved adults and children with microscopically confirmed asexual P. vivax malaria. Trials recruiting people co-infected with both P. vivax and P. falciparum were excluded.
The following types of interventions were studied:
Efficacy of alternative regimens
Intervention: Primaquine (any dose or duration other than that used in control group) plus chloroquine*
Control: Primaquine (15 mg/day for 14 days) plus chloroquine*
Efficacy of regimens compared to either placebo or no treatment
Intervention: Primaquine (any dose or duration) pluls chloroquine*
Control: Placebo or no intervention plus chloroquine*
*same dose in each group
The primary outcomes were
1. P. vivax parasitaemia detected more than 30 days after starting primaquine.
2. Serious adverse events (fatal, life threatening, or requiring hospitalization).
Results
15 RCTs were included, of which one was a cluster RCT.
Alternative regimens versus 14 days primaquine
Shorter daily regimens (five trials)
a. Primaquine 5 days versus 14 days: Those receiving primaquine for 5 days experienced more relapses as compared to those receiving a 14 day primaquine regimen (RR 10.05, 95% CI 2.8-35.8). However, the evidence was only of moderate quality, indicating that further research may change the estimate.
b. Primaquine 3 days versus 14 days: Those receiving primaquine for 3 days experienced more relapses as compared to those receiving primaquine for 14 days (RR 3.18, 95% CI 2.1-4.8). Here, too, the evidence is only of moderate quality.
c. Primaquine 7 days versus 14 days: Low quality evidence from a single study indicates that those receiving a 7 day primaquine regimen are more likely to experience relapse than those receiving 14 days of primaquine (RR 2.24, 95% CI 1.2-4.0). Since the evidence is of low quality, caution must be exercised in interpreting the result of the study.
Weekly primaquine (one trial)
a. Primaquine (weekly for 8 weeks) compared to daily primaquine for 14 days: A single study reported that those receiving weekly primaquine are more likely to experience relapses as compared to those receiving 14 days of daily primaquine (RR 2.97, 95% CI 0.3-25.8). The evidence is of very low quality, hence must be interpreted with caution.
Any primaquine regimens compared to no intervention or placebo
Five days primaquine (four trials)
a. Chloroquine only versus chloroquine plus 5 days primaquine: Compared to those receiving no primaquine, those receiving 5 days of primaquine in addition to chloroquine were less likely to experience relapses (RR 0.98, 95% CI 0.73-1.3). The evidence is of high quality, and unlikely to change with further research.
Fourteen days primaquine (ten trials)
a. Chloroquine only versus chloroquine plus 14 days primaquine: Compared to those receiving no primaquine, those receiving 14 days of primaquine in addition to chloroquine were considerably less likely to experience relapses (RR 0.60, 95% CI 0.48-0.75). Since the evidence is of high quality, it is unlikely to change with further research.
Discussion
This review demonstrates that the WHO treatment guidelines for radical cure of P. vivax malaria are based on current best evidence.
14 day primaquine is probably more effective than shorter regimens containing primaquine in reducing relapse. Although the effect estimates are impressive on occasion, they are susceptible to revision in the future as they are derived from moderate quality studies.
However, there is a clear and unambiguous benefit to using chloroquine plus primaquine, as opposed to chloroquine alone for the radical treatment of P. vivax malaria. The evidence is of high quality, and unlikely to change with further research. Therefore, all practitioners should be encouraged to prescribe chloroquine plus primaquine regimens for P. vivax malaria.
No adverse events were reported in the trials included, suggesting that primaquine may be safe for use in radical cure of P. vivax malaria. However, most trials excluded people with G6PD deficiency. Moreover, since at least a few trials had an unacceptable risk of bias, the safety of primaquine may not be assured (at least in some sub-populations).
The review did not directly evaluate the safety of different primaquine regimens in those with and without G6PD deficiency. Therefore, it is not possible to comment on the safety of primaquine per se. In order to do so comprehensively, drug safety trials may have to be included.
Although a single trial demonstrated the usefulness of a weekly regimen, further research is needed to establish that it is as good as a daily primaquine regimen.
It is important to note that the review excluded trials involving mixed (P. vivax plus P. falciparum) infections. Therefore, the findings of the review may not be applicable to that situation.
In terms of generalizability, the review included trials involving both adults and children; and trials conducted in Africa, Latin America and Asia. Therefore, the findings are applicable to a large geographical area. Since much of the burden of P. vivax malaria is outside sub-Saharan Africa, the inclusion of trials from these areas lends strength to the recommendations of the WHO.
Bottom line
Despite limitations of the quality of evidence, the review demonstrates that 14 day primaquine is probably more effective at preventing relapse in P. vivax malaria, as compared to shorter regimens.
There is clear, high quality evidence to indicate that chloroquine plus primaquine is more beneficial than chloroquine alone in the prevention of relapse in P. vivax malaria.
Concluding thoughts
Since there is a definite benefit with chloroquine plus primaquine regimens as opposed to chloroquine alone, in the prevention of P. vivax malaria, I expect practitioners to switch to the former regimen.
Since the present review establishes in some measure that 14 day primaquine is preferable to shorter regimens, one may expect some countries to alter their policies regarding the treatment of P. vivax malaria.
In any case, it seems prudent to reduce the overall cost of treatment of P. vivax malaria by opting for a 14 day primaquine regimen and decreasing the relapse (and therefore, re-treatment) rate. However, given the moderate quality of evidence, some may hesitate to effect the change. Considering that P. vivax affects a large number of under-5 children, I would rather choose a regimen that is even marginally better at preventing relapse, than one of uncertain/ unknown efficacy. One could possibly wait for high quality evidence to settle the matter, but the larger question is- is it really worth it?
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. (Click here to go to a shorter summary)
Background
The World Health Organization (WHO) estimates that there were between 135-287 million cases, and
 |
| An Anopheles stephensi mosquito, a known malarial vector (photo source: CDC) http://en.wikipedia.org/wiki/File:Anopheles_stephensi.jpeg |
Malaria is a major public health problem in Africa and Asia, where the disease is usually caused by either plasmodium falciparum or plasmodium vivax. About 9% of estimated cases globally are due to plasmodium vivax. However, outside the African continent, the proportion is 50%. Four countries account for more than 80% of estimated P. vivax cases- Ethiopia, India, Indonesia and Pakistan.
Current evidence suggests that P.vivax responds more slowly to control measures. Therefore, the WHO recommends that National Malaria Control Programs, especially outside sub-Saharan Africa, should give greater attention to the control of P.vivax.
The WHO recommends that P.vivax be treated with a 3-day course of chloroquine followed by 14 days of primaquine (15 mg/day).
Although chloroquine is well tolerated by most patients, primaquine treatment may cause some serious side effects. The most serious of these are haemolysis among those with G6PD deficiency, and methaemoglobinaemia.
Primaquine treatment failure or relapse is defined as the presence of P. vivax parasites more than 28-30 days after a full course of primaquine in people living in a non-endemic area.
Why this review?
Till the publication of the 2007 version of this review, P. vivax malaria was treated with a 5 day primaquine regimen. Subsequently policies in only a few countries were modified to accommodate the new 14-day primaquine regimen for radical cure of P. vivax malaria. Many countries in South Asia, South-East Asia and
Latin America continue to follow the 5 day primaquine regimen.
The main concerns about the 14-day primaquine regimen are:
1. Poor adherence, as many become rapidly asymptomatic after treatment with chloroquine. Such individuals are poorly motivated to complete primaquine treatment.
2. The risk (perceived and real) of adverse events.
3. Despite adherence to the regimen, due to primaquine resistance in some areas, there is less than optimal prevention of relapse.
4. Cheap, rapid and practical tests for G6PD deficiency are unavailable.
Due to the above, practitioners are struggling to successfully implement the 14-day primaquine regimen.
The alternatives suggested to the five day and 14 day primaquine regimens include:
1. Using higher doses of primaquine (after chloroquine) for shorter periods to overcome problems with adherence.
2. Using higher doses of primaquine (after chloroquine) for 14 days or longer to overcome primaquine resistance.
3. Ensuring an adequate total dose of primaquine.
4. Concurrent (instead of sequential) administration of chloroquine and primaquine.
5. Chloroquine monotherapy.
Effective treatment of P. vivax is important due to the disease burden and cost of treating relapses. With many treatment regimens in current use, it is important to determine the comparative effects of the different regimens.
Main objective
To compare the recommended 14-day primaquine regimen with alternative regimens for preventing relapses (radical cure) in people with P. vivax malaria treated with chloroquine.
Methodology (in brief)
The reviewers searched for and included RCTs and quasi-RCTs that involved adults and children with microscopically confirmed asexual P. vivax malaria. Trials recruiting people co-infected with both P. vivax and P. falciparum were excluded.
The following types of interventions were studied:
Efficacy of alternative regimens
Intervention: Primaquine (any dose or duration other than that used in control group) plus chloroquine*
Control: Primaquine (15 mg/day for 14 days) plus chloroquine*
Efficacy of regimens compared to either placebo or no treatment
Intervention: Primaquine (any dose or duration) pluls chloroquine*
Control: Placebo or no intervention plus chloroquine*
*same dose in each group
The primary outcomes were
1. P. vivax parasitaemia detected more than 30 days after starting primaquine.
2. Serious adverse events (fatal, life threatening, or requiring hospitalization).
Results
15 RCTs were included, of which one was a cluster RCT.
Alternative regimens versus 14 days primaquine
Shorter daily regimens (five trials)
a. Primaquine 5 days versus 14 days: Those receiving primaquine for 5 days experienced more relapses as compared to those receiving a 14 day primaquine regimen (RR 10.05, 95% CI 2.8-35.8). However, the evidence was only of moderate quality, indicating that further research may change the estimate.
b. Primaquine 3 days versus 14 days: Those receiving primaquine for 3 days experienced more relapses as compared to those receiving primaquine for 14 days (RR 3.18, 95% CI 2.1-4.8). Here, too, the evidence is only of moderate quality.
c. Primaquine 7 days versus 14 days: Low quality evidence from a single study indicates that those receiving a 7 day primaquine regimen are more likely to experience relapse than those receiving 14 days of primaquine (RR 2.24, 95% CI 1.2-4.0). Since the evidence is of low quality, caution must be exercised in interpreting the result of the study.
Weekly primaquine (one trial)
a. Primaquine (weekly for 8 weeks) compared to daily primaquine for 14 days: A single study reported that those receiving weekly primaquine are more likely to experience relapses as compared to those receiving 14 days of daily primaquine (RR 2.97, 95% CI 0.3-25.8). The evidence is of very low quality, hence must be interpreted with caution.
Any primaquine regimens compared to no intervention or placebo
Five days primaquine (four trials)
a. Chloroquine only versus chloroquine plus 5 days primaquine: Compared to those receiving no primaquine, those receiving 5 days of primaquine in addition to chloroquine were less likely to experience relapses (RR 0.98, 95% CI 0.73-1.3). The evidence is of high quality, and unlikely to change with further research.
Fourteen days primaquine (ten trials)
a. Chloroquine only versus chloroquine plus 14 days primaquine: Compared to those receiving no primaquine, those receiving 14 days of primaquine in addition to chloroquine were considerably less likely to experience relapses (RR 0.60, 95% CI 0.48-0.75). Since the evidence is of high quality, it is unlikely to change with further research.
Discussion
This review demonstrates that the WHO treatment guidelines for radical cure of P. vivax malaria are based on current best evidence.
14 day primaquine is probably more effective than shorter regimens containing primaquine in reducing relapse. Although the effect estimates are impressive on occasion, they are susceptible to revision in the future as they are derived from moderate quality studies.
However, there is a clear and unambiguous benefit to using chloroquine plus primaquine, as opposed to chloroquine alone for the radical treatment of P. vivax malaria. The evidence is of high quality, and unlikely to change with further research. Therefore, all practitioners should be encouraged to prescribe chloroquine plus primaquine regimens for P. vivax malaria.
No adverse events were reported in the trials included, suggesting that primaquine may be safe for use in radical cure of P. vivax malaria. However, most trials excluded people with G6PD deficiency. Moreover, since at least a few trials had an unacceptable risk of bias, the safety of primaquine may not be assured (at least in some sub-populations).
The review did not directly evaluate the safety of different primaquine regimens in those with and without G6PD deficiency. Therefore, it is not possible to comment on the safety of primaquine per se. In order to do so comprehensively, drug safety trials may have to be included.
Although a single trial demonstrated the usefulness of a weekly regimen, further research is needed to establish that it is as good as a daily primaquine regimen.
It is important to note that the review excluded trials involving mixed (P. vivax plus P. falciparum) infections. Therefore, the findings of the review may not be applicable to that situation.
In terms of generalizability, the review included trials involving both adults and children; and trials conducted in Africa, Latin America and Asia. Therefore, the findings are applicable to a large geographical area. Since much of the burden of P. vivax malaria is outside sub-Saharan Africa, the inclusion of trials from these areas lends strength to the recommendations of the WHO.
Bottom line
Despite limitations of the quality of evidence, the review demonstrates that 14 day primaquine is probably more effective at preventing relapse in P. vivax malaria, as compared to shorter regimens.
There is clear, high quality evidence to indicate that chloroquine plus primaquine is more beneficial than chloroquine alone in the prevention of relapse in P. vivax malaria.
Concluding thoughts
Since there is a definite benefit with chloroquine plus primaquine regimens as opposed to chloroquine alone, in the prevention of P. vivax malaria, I expect practitioners to switch to the former regimen.
Since the present review establishes in some measure that 14 day primaquine is preferable to shorter regimens, one may expect some countries to alter their policies regarding the treatment of P. vivax malaria.
In any case, it seems prudent to reduce the overall cost of treatment of P. vivax malaria by opting for a 14 day primaquine regimen and decreasing the relapse (and therefore, re-treatment) rate. However, given the moderate quality of evidence, some may hesitate to effect the change. Considering that P. vivax affects a large number of under-5 children, I would rather choose a regimen that is even marginally better at preventing relapse, than one of uncertain/ unknown efficacy. One could possibly wait for high quality evidence to settle the matter, but the larger question is- is it really worth it?
