Investigating the Pharmacogenetic Basis of Nevirapine-Induced Cutaneous Reactions among Selected HIV Patients in Ghana
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Date
JULY, 2017
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Abstract
Nevirapine (NVP) is a potent nonnucleoside reverse transcriptase inhibitor, widely prescribed for the treatment of HIV-1 infections, as part of HAART treatment in developing countries. The use of NVP, however, is linked to some mild to severe adverse drug reactions (ADRs) of which various skin reactions and liver toxicities are notable. Major NVP-related hypersensitivity reactions have been associated with various mutations in cytochrome P450 enzymes and HLA alleles but these associations are yet to make their translations into clinical usefulness. As more pharmacogenetic associations are established, it may soon become necessary that patients be offered genetic testing prior to NVP treatment to reduce their risk of developing these related ADRs — as in the case of Abacavir hypersensitivity. HLA class I and II molecules, by means of their extraordinary high polymorphic nature, have and continue to pose great challenges to high resolution HLA typing using current available methods. In the present study, HLA-A and -B genes from a Ghanaian HIV population were typed by Sanger sequence-based typing (SBT) using locus-specific PCR. Following BLAST analysis in the IPD-IMGT/HLA database, 10% of HLA-A and 28.6% HLA-B samples typed were successfully assigned genotypes at the allele-level, whereas 83.3% HLA-A and 64.3% HLA-B genotypes were successfully assigned to the serotype level. The majority of alleles typed were ambiguous at the allele-level resolution. These results reflect the current state of HLA typing by SBT using locus-specific PCR and further corroborates the need to: a) augment locus-specific PCR with sequence-specific primers (SPPs) and/or sequence-specific oligonucleotide probes (SSOPs), b) incorporate sequences from outside the peptide binding regions for HLA typing, and c) opt for higher DNA sequencing resolving power as provided by next generation sequencing. No significant association was found between alleles observed and NVP-induced rash in this study but allele frequency distribution between the rash and tolerant groups may suggest different alleles are involved in NVP-rash among Ghanaian population — although this requires further testing.
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A thesis submitted to the Department of Biochemistry and Biotechnology, Faculty of
Biosciences, College of Science in partial fulfillment of the requirements for the degree of
Master of Science in Biotechnology