Anti-Wolbachia Treatment of Lymphatic Filariasis and Genetic Analysis of the Pathology of Lymphedema as a Clinical Manifestation of the Disease

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Lymphatic filariasis (LF) caused by Wuchereria bancrofti is a disease of considerable public health and socio-economic burden in the tropics. The recommended drugs (ivermectin and albendazole) for the control of lymphatic filariasis are only microfilaricidal. The regimen of the standard treatment with doxycycline which has proven macrofilaricidal is 200mg/d for 4 weeks. This is considered a long period and dissuades complaince by patients receiving treatment. Therefore reducing the duration or the dosage from the current 200mg/d to 100mg/d would be a better option and will also increase compliance. In search of a more effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 261 adult worm positive men were recruited for a double blind placebo-controlled study in the Ahanta West District of Ghana. Six groups of patients were treated with the gold standard (4 weeks 200mg/d doxycycline), 5 weeks and 4 weeks 100mg/d doxycycline, 3 and 2 weeks combination of 200mg/d doxycycline and 10mg/kg rifampicin and 5 weeks placebo. The effect of the treatment on Wolbachia depletion was assessed at 4 months after treatment; adult worm vitality assessed at pre-treatment, 12, 18 and 24 months, and microfilarial depletion assessed at pre-treatment, 4, 12, 18 and 24 months follow up time points. In accordance with the national mass drug administration programme, all the study participants were given 150mg/kg ivermectin and 400mg albendazole four months after treatment. The treatment drugs were well tolerated with no serious adverse effects in both the treated and the placebo groups. There was significant Wolbachia depletion at 4 months time point in the standard group (p=0.001), 5 weeks 100mg doxycycline (p=0.019), 4 weeks 100mg doxycycline (p=0.03) and 3 weeks combination treatment (p=0.028). However there was no significant Wolbachia depletion in the 2 weeks combination group as well as the placebo group (p>0.05). Microfilarial assessment at 12, 18 and 24 months follow up time points showed a significant depletion in the standard group, 5 weeks and 4 weeks 100mg doxycycline groups as well as the 3 weeks combination of 200mg plus rifampicin group but not in the 2 weeks and placebo groups (p>0.05). The macrofilaricidal activity was significant at 12, 18 and 24 months in the standard and the 5 weeks groups. In the 4 weeks group, it was significant at 18 and 24 months time point and in the 3 weeks group it was significant at 18 months follow up time point, but no significant difference was observed for the 2 weeks and the placebo groups. On the other hand, there is the need to know the genetic markers associated with LF. Such knowledge will be beneficial in terms of diagnosis and possible therapy of various forms of the pathology. For this reason, a cross-sectional study of unrelated Ghanaian volunteers were designed to genotype single nucleotide polymorphisms (SNPs) in 266 lymphedema patients as cases and 691 infected patients without pathology as well as 346 endemic controls. Out of the 147 chosen SNPs that were genotyped, 11 SNPs in eight genes were found to be associated with lymphedema. The associated SNPs were in the vascular endothelial growth factor receptor 3 (VEGFR3), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (NFKB- inhibition alpha), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1), tissue inhibitor of metallopeptidase 2 (TIMP) genes, interleukin 10 and two SNPs in insulin like growth factor-1 (IGF-1) and matrix metallopeptidase 2 (MMP-2). A SNP in the interleukin 17 gene revealed a trend but there was significant haplotype association. In conclusion 5 weeks, 4 weeks and 3 weeks combination regimens of doxycycline were effective in treating LF infections, and SNPs in the angiogenic pathway were found to be associated with the pathology of lymphatic filariasis.
A thesis submitted to the Department of Clinical Microbiology, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Clinical Microbiology