Prevalence and correlates of CYP2B6-G516T polymorphisms in a cohort of HIV-infected women and children in Canada
Background: The G516T polymorphism within the CYP2B6-gene
affects the metabolism of non-nucleoside reverse transcriptase inhibitors
(NNRTIs), with rapid NNRTI metabolism among homozygous GG individuals, and slow
metabolism among those with TT genotype.
The objective of this study was to describe the prevalence of the G516T genotypes
among a cohort of HIV infected women and children in Canada, and associated
clinical correlates.
Methods: HIV infected women and children were
recruited from the Centre Maternel et Infantil sur le SIDA (CMIS) mother-child
cohort between 2013-2014; family members were excluded from the study. DNA was extracted from saliva samples, and
genotyping was performed using CYP2B6-G516T specific amplification and
restriction fragment length polymorphism (PCR-RFLP).
Results: Genotyping was performed on 89 subjects (46
women, 43 children). Self-described ethnic
distribution was African (46.1%), Haitian (31.5%), Caucasian (12.4%), and mixed
origin (10%). Overall, 38.2% were GG
(rapid metabolizers), 49.4% were GT , and 12.4% were TT (slow metabolizers). Among Africans, the GG genotype was most
prevalent (46.3%), followed by GT (41.4%) and TT (12.2%). Among Haitians, the GT genotype was most
prevalent (64.3%), followed by GG (21.4%) and TT (14.3%). Among Caucasians, 54.5% were GG, 36.4% were
GT, and 9.1% were TT. There was a
significant difference in the proportion of rapid metabolizers (GG) between
Africans and Haitians (46.3% vs 21.4%, p=0.04), with an equal distribution of
the GG genotype between patients from West Africa (43%) and Sub-Saharan Africa
(44%). The highest proportion of slow
metabolizers (TT) was among West Africans (21.5%), while the highest proportion
of rapid metabolizers was among European Caucasians (75%). Among children treated
with standard (weight/kg) doses of Efavirenz for whom unadjusted drug levels
were available, 4/6 (67%) of GG genotype had trough drug levels in the lower
therapeutic range (1-2 mg/L) at steady state, as compared to only 3/8 (38%)
among the GT genotype. The single child
with TT genotype had supra-therapeutic levels (>10mg/L) on standard dosing.
Conclusions: In this study population, the heterozygous GT
genotype dominated, though there were significant differences within the predominant
ethnic groups represented. Population-based knowledge of these genotypes may
help tailor standard NNRTI dosing regimens to optimize their efficacy.
F. Kakkar1,2, S. Valois1, D.G. Ramsey3, A.M. Rezgui3, V. Gagne3, V. Lamarre1,2, N. Lapointe1, H. Soudeyns1,4,5, P. Ovetchkine2, M. Krajinovic6
1Centre Maternel et Infantil sur le SIDA (CMIS), CHU Sainte-Justine, Montreal, Canada, 2CHU Sainte-Justine, Université de Montreal, Infectious Diseases, Montreal, Canada, 3Centre de Recherche, CHU Sainte-Justine, Montreal, Canada, 4Université de Montréal, Department of Microbiology, Infectiology & Immunology, Montreal, Canada, 5Unité d'Immunopathologie Virale, Centre de Recherche du CHU Sainte-Justine, Montreal, Canada, 6Division of Hematology-Oncology, CHU Sainte-Justine, Université de Montréal, Department of Pediatrics, Montreal, Canada