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Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial.

Awab GR, Pukrittayakamee S, Imwong M, Dondorp AM, Woodrow CJ, Lee SJ, Day NP, Singhasivanon P, White NJ, Kaker F - Malar. J. (2010)

Bottom Line: The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003).Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence.Both regimens were well tolerated and no serious adverse events were reported.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

ABSTRACT

Background: Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail.

Methods: Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Delta = 5% difference in proportion of failures).

Results: Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported.

Conclusions: Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment.

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Analysis of primary outcome (cumulative failure rate at day 56). Non-inferiority analysis refers to the pre-specified survival analysis.
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Figure 3: Analysis of primary outcome (cumulative failure rate at day 56). Non-inferiority analysis refers to the pre-specified survival analysis.

Mentions: By the end of the 56-day follow-up period, there were 23 recurrences (parasitological failures) in the chloroquine group and 7 in the dihydroartemisinin-piperaquine group, giving a day 56 failure rate of 8.9% (95% CI 6.0 - 13.1%) in the chloroquine group and 2.8% (1.4 - 5.8%) in the dihydroartemisinin-piperaquine group (Figure 2). The difference in day 56 parasitological failure rates between chloroquine and dihydroartemisinin-piperaquine was 6.1% (2-sided 90% CI +2.6 to +9.7%). The lower bound of this confidence interval was not only higher than the prespecified non-inferiority margin (i.e. -5%), but also did not include zero, indicating that dihydroartemisinin-piperaquine was superior to chloroquine in terms of outcome (Figure 3) [26]. The superiority of dihydroartemisinin-piperaquine was confirmed by the log rank test (p = 0.003).


Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial.

Awab GR, Pukrittayakamee S, Imwong M, Dondorp AM, Woodrow CJ, Lee SJ, Day NP, Singhasivanon P, White NJ, Kaker F - Malar. J. (2010)

Analysis of primary outcome (cumulative failure rate at day 56). Non-inferiority analysis refers to the pre-specified survival analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864284&req=5

Figure 3: Analysis of primary outcome (cumulative failure rate at day 56). Non-inferiority analysis refers to the pre-specified survival analysis.
Mentions: By the end of the 56-day follow-up period, there were 23 recurrences (parasitological failures) in the chloroquine group and 7 in the dihydroartemisinin-piperaquine group, giving a day 56 failure rate of 8.9% (95% CI 6.0 - 13.1%) in the chloroquine group and 2.8% (1.4 - 5.8%) in the dihydroartemisinin-piperaquine group (Figure 2). The difference in day 56 parasitological failure rates between chloroquine and dihydroartemisinin-piperaquine was 6.1% (2-sided 90% CI +2.6 to +9.7%). The lower bound of this confidence interval was not only higher than the prespecified non-inferiority margin (i.e. -5%), but also did not include zero, indicating that dihydroartemisinin-piperaquine was superior to chloroquine in terms of outcome (Figure 3) [26]. The superiority of dihydroartemisinin-piperaquine was confirmed by the log rank test (p = 0.003).

Bottom Line: The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003).Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence.Both regimens were well tolerated and no serious adverse events were reported.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

ABSTRACT

Background: Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail.

Methods: Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Delta = 5% difference in proportion of failures).

Results: Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported.

Conclusions: Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment.

Show MeSH
Related in: MedlinePlus