Analysis of the mdr-1 gene in patients co-infected with Onchocerca volvulus and Loa loa who experienced a post-ivermectin serious adverse event

Abstract

Ivermectin (IVM) is exceptionally safe in humans, and is used for mass treatment of onchocerciasis and lymphatic filariasis. However, cases of encephalopathy, sometimes fatal, have been reported in a small number of individuals who harbored large numbers of Loa loa microfilariae (mf). A loss-of-function mutation in the mdr-1 gene in some dog breeds and in mice leads to accumulation of the drug in the brain, causing coma and death. This hypothesis was tested in four individuals from Cameroon who experienced a post-IVM serious adverse event (SAE) and in nine non-SAE matched controls. No loss-of-function mutation was detected in mdr-1 in any subject. However, haplotypes, associated with altered drug disposition, were present as homozygotes in two of the SAE patients (50%), but absent as homozygotes in the controls (0%). An association of high Loa mf load and a genetic predisposition to altered IVM distribution could be involved in IVM SAEs.

Figure 1.

Location of the single nucleotide polymorphisms (SNPs) in the mdr-1 protein sequence. TM is used for transmembrane domain. Letter O located on the top of the protein sequence represents a silent mutation. Letters V and A are used for valine and alanine, respectively. The letters are located on the top of the protein sequence and they represent amino acid changes in the protein sequence caused by single nucleotide polymorphism at cDNA positions 781 and 3151, respectively.