CYP2B6 GENOTYPE BASED EFAVIRENZ DOSE RECOMMENDATIONS DURING RIFAMPICIN-BASED ANTITUBERCULOSIS CO-TREATMENT FOR A SUB-SAHARAN AFRICA POPULATION

Background Pharmacogenetics is a major determinant of the EFV–rifampicin interaction during HIV-TB co-treatment. We assessed genetic factors that influence EFV PK, treatment outcomes and provide genotype-based EFV dose recommendations for adult TB-HIV-1 co-infected Ugandans receiving rifampicin based anti-tuberculosis co-treatment. Methods Steady state plasma EFV concentrations (n=1216) from 158 HIV-TB co-infected patients (76 females) treated with efavirenz/lamivudine/zidovidine and rifampicin-based TB treatment were analysed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEMTM) was used to estimate genotype effects on EFV PK. Population genotype-frequency-based PK simulations predicted AUCs and trough concentrations were compared between the product label / known reference values and different dose simulations. Results Compared to CYP2B6*1/*1, EFV post-induction CL/F was 2.5 and 1.7 times higher in CYP2B6*6/*6 and CYP2B6*1*/6, respectively. A 23% increase in F1 was observed for the variant ABCB1 c.4046A>G. EFV mean AUC was significantly higher in CYP2B6*6/*6 genotypes compared to CYP2B6*1/*1 (p< 0.0001). Simulated AUCs for a 600 mg EFV dose were 1.2 and 2.4 times greater than the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes, respectively. EFV daily doses of 450 mg and 250 mg for the general population and CYP2B6*6/*6 genotypes respectively yielded simulated exposures that were comparable to the product label. Overall, only 8.9% patients had HIV RNA >40 copies/mL after 84 days of treatment. Conclusions During rifampicin co-treatment, daily doses of 450 mg and 250 mg might meet the EFV dosing needs of HIV-TB infected Ugandans in general and CYP2B6*6 homozygous variants, respectively.