13th Annual Conference of the British HIV Association 29 March–1 April 2007, Brighton, UK

NOVEL AND KNOWN SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) DESCRIBED IN CYTOCHROME P450 2B6 (CYP2B6) AMONG DIVERSE AFRICAN POPULATIONS: POTENTIAL IMPLICATIONS FOR EFAVIRENZ METABOLISM

HIV Med 2007; 8(Suppl. 1):4 (abstract no. O14)

Tariq Sadiq¹, Yalda Jamshidi¹, Lorna Tinworth¹, Michelle Moreton¹, Shalini Andrews¹, Denise Mckeown², Muchanetta Ndorro² and David Holt^1
1St George’s, University of London, London, UK, ²St George’s Healthcare NHS Trust, London, UK

AIM: Because Africans exhibit wide genetic diversity, we are sequencing CYP2B6 in selected HIV-1-infected African populations to determine frequencies of novel and known SNPs that may critically affect metabolism of efavirenz.

METHODS: Ugandan and Zimbabwean HIV-1-infected patients were prospectively recruited. Nested PCR was used to amplify the exonic regions of CYP2B6 from whole blood. Efavirenz trough concentrations (ETC) were measured in those receiving efavirenz.

RESULTS: A total of 115 patients were recruited (64 Ugandan and 38 Zimbabwean) and 48 sequenced to date; female 77/115; median age 38; CD4 count 368/mm³ (IQR 244–490); HIV-1 RNA load <50 copies/mL (<50– 10⁶); 86 and 28% were receiving antiretroviral therapy or efavirenz respectively. SNPs were found either heterozygously or homozygously in 66.7% (95% CI 51.5–79.1), 59.3% (45.1–72.1) and 9.3% (3.7–21.6) for 516G>T 785A>G and 983T>C respectively comparing historically to 48.8, 47.5, and 6.6% respectively in Ghanaians; 27.8, 29.8 and 4.4% respectively in African Americans; 25.5, 28.7 and 0% respectively in Caucasians. A novel mutation was discovered in one patient in the hetrerozygous state, (G1048T), resulting in a switch from glutamic acid to a stop codon, E350X. This patient had ETC of 1520 ng/mL implying adequate function of the wild-type allele. ETC of the study group are currently being measured.

CONCLUSIONS: In this group of Ugandans and Zimbabweans higher frequencies of key CYP2B6 SNPs are observed compared with African-American and other Black African populations. A novel SNP resulting in premature termination of CYP2B6 transcription, with the potential to markedly affect efavirenz metabolism, is described.

2007-03-29
O14

Copyright © 2007 - British HIV Association (BHIVA) Reproduction of this abstract (other than one copy for personal reference) must be cleared through the BHIVA Organising Secretariat 1 Mountview Court, 310 Friern Barnet Lane, London N20 0LD