Two African trials reported more weight gain with dolutegravir (DTG) than efavirenz (EFV), especially in women. EFV is toxic to mitochondria and is associated with lipoatrophy. We hypothesised that CYP2B6 metaboliser genotype, which predicts EFV exposure, would determine amount of weight gained and fat distribution in patients starting EFV-based ART.
Participants enrolled in the EFV/TDF/FTC arm of the ADVANCE trial who consented to genetic testing were included. CYP2B6 metaboliser genotype was classified as extensive, intermediate, and slow. Outcomes included change in weight gain and trunk and limb fat on DXA from baseline to week 48 by CYP2B6 genotype. Weight gain was compared between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm.
171 participants had genetic testing done. CYP2B6 metaboliser genotypes were 51 extensive, 74 intermediate, and 46 slow; median age 32 years (IQR 28–37); 57% women; median BMI 23.7 kg/m2 (IQR 20.2–27.5); and median CD4 count 292 cells/uL (IQR 172–406). The percentage change in weight from baseline over 48 weeks differed by CYP2B6 metaboliser genotype (p=0.004; Kruskal-Wallis), but differences were more marked in women over time (see figure). In men CYP2B6 metaboliser genotype was associated with percentage change in weight initially (week 12 p=0.007; week 24 p=0.053), but the effect attenuated over time. The percentage change in limb fat on DXA (n=148) from baseline to 48 weeks differed significantly by CYP2B6 metaboliser genotype in women (p=0.008), with highest percentage increase in extensive metabolisers, but not in men (p=0.680). Percentage change in trunk fat on DXA from baseline to 48 weeks was not significantly different by CYP2B6 metaboliser genotype in women (p=0.082) or men (p=0.732). The percentage change in weight from baseline to 48 weeks was similar between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm (p=0.939).
In Africans starting EFV-based ART CYP2B6 metaboliser genotype was associated with weight gain and, in women, with changes in limb fat. The similar weight gain observed between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm suggests off-target effects (e.g. mitochondrial toxicity) impairing weight gain in EFV slow/intermediate metabolisers could explain the greater weight gain observed with DTG in African trials.