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Correction to paper by Artesunate-Amodiaquine / Artemether Lumefantrine (AS-AQ/AL) Molecular Marker Study Group

Authors:
Venkatesan M et al.

It has come to WWARN's attention that one of our paper's published in 2014 requires revision. The paper was published by the AS-AQ/AL Study Group and was entitled Venkatesan M, et al. Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors that Affect Treatment Outcomes for P. falciparum Malaria after Artemether-Lumefantrine and Artesunate-Amodiaquine. Am J Trop Med Hyg. 2014 Oct;91(4):833-43. doi: 10.4269/ajtmh.14-0031

The updated paper is available to read in full, with highlighted changes, summarised below:

1) 69 out of more than 800 patients treated with AL4 were erroneously included in the original analysis of the association of increased pfmdr1 copy number on the risk of clinical failure after AL treatment;  

2)  There was an error in the code for running the Cox regression model for increased copy number of pfmdr1.   

As a result, the presence of more than one copy of pfmdr1 was no longer a significant risk factor for recrudescence after AL treatment and did not become a significant risk factor when the effect of region was added to the model. Once adjusted by study site, AL efficacy in patients infected with parasites carrying multiple copies of pfmdr1 was not significantly different from efficacy in patients whose parasites had a single copy of pfmdr1 with multi-copy infections (see table in the corrected paper p=0.47; Figure 2B).  

This change affected only the subgroup analysis of the risk of increased copy number of pfmdr1 on clinical treatment efficacy. The association of the prevalence of parasites carrying the N86 allele of pfmdr1 and increased risk of clinical failure after AL remains the same.

The following revisions have been made to the original paper. Changes described below are highlighted in the corrected version.

  • The statement that increased copy number of pfmdr1 is significantly associated with increased risk of treatment failure has been deleted.
  • The results of the model that concern the increased copy number in Table 4 have been modified.
  • Figure 2B has been recalculated with the correct sample numbers and the difference in treatment failure between the two genotypes is no longer significant. The corrected figure is now in the linked corrected version.
  • The change in the total population of patient isolates analyzed required minor adjustments in the number of isolates assessed. The smaller sample size has been used to recalculate the risks of clinical failure associated with specific SNPs and haplotypes of pfmdr1 as well as post-treatment selection of mutations in pfcrt and pfmdr1; these remain significant as originally reported in the results on p. 836 of the print version, 2 paragraphs beginning with “The presence of more than one copy of pfmdr1…..”  have been replaced with the following paragraph:

The presence of more than one copy of pfmdr1 was not a significant risk factor for recrudescence after AL treatment and did not become a significant risk factor when the effect of region was added to the model. Once adjusted by study site, AL efficacy in patients with infections with a single copy of pfmdr1 was not significantly different from efficacy in patients with multi-copy infections (p=0.47; Figure 2B).   

  • In the discussion, beginning on p. 839 of the print version with the paragraph that begins In Southeast Asia, parasites with increased copy number of pfmdr1 are common….”   And the next paragraph This study supported the conclusion…..”   have been replaced with the three paragraphs below.

In Southeast Asia, parasites with multi-copy pfmdr1 are common in areas where mefloquine has been intensively deployed,36 and increased pfmdr1 copy number is strongly associated with artesunate-mefloquine treatment failures. Almost half of the samples in our data set from Southeast Asia region had at least two copies of the gene. In contrast, multiple copy number was rarely observed in our large sample of isolates from Africa, where populations have had little exposure to mefloquine.

The results of this study did not indicate that parasites with increased copy number of pfmdr1 are less sensitive to lumefantrine. Our findings contrast with reports of decreased in vitro lumefantrine susceptibility with increased copy number3740, but support the conclusions of in vivo studies38 which indicate that multi-copy pfmdr1 is not a risk factor for AL treatment failure.

In our data set from Southeast Asia, the amplified alleles all carried the N86 allele of pfmdr134,36,62. This association was not found in the few parasites from Africa in our data set that did have an increased copy number31, indicating that either of the N86Y alleles of pfmdr1 can apparently be amplified in this region.

Read the revised paper in full.

For more information, please contact carol [dot] sibley [at] wwarn [dot] org and CC/ copy molecular [at] wwarn [dot] org

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