CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz

Abstract

Background Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART). Methods We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm. Results There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

Weight changes after antiretroviral therapy initiation in CoRIS (Spain): a prospective multicentre cohort study

“…Regarding NNRTIs, RPV has been associated with more weight gain than EFV [5]. In the ADVANCE study, data found that CYP2B6 was identified as a relevant factor: Slow EFV metabolizers on EFV had minimal weight gain, whereas rapid metabolizers gained as much weight as those on DTG, arguing that it was the lack of EFV toxicity that accounted for the difference, rather than a direct DTG effect [15]. Regarding the comparison between INSTIs and PIs, the recent pooled analysis of eight ART-na€ ıve randomized clinical trials [5] revealed a greater average weight gain at two years among patients treated with INSTIs, with 3.2 kg versus 1.9 kg among those treated with NNRTIs and 1.7 kg with PIs.…”

Concentration–response relationships of dolutegravir and efavirenz with weight change after starting antiretroviral therapy

“…We calculated percentage change in weight from baseline to week 48. Body composition measures using DXA (Discovery DXA System, software version APEX 4.6.0.1, Hologic, Bedford, MA, USA) at baseline and week 48 were used to estimate changes in abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) 12,15 . The percentage change in mass from baseline to week 48 was calculated for VAT and SAT.…”

Excess Weight Gain With Integrase Inhibitors and Tenofovir Alafenamide: What Is the Mechanism and Does It Matter?

“…Multiple investigators have assessed the effects of individual genetic variations on weight change with EFV in treatment initiation and switch studies. For example, researchers compared weight change after treatment initiation with EFV or DTG based on CYP2B6 genetic loss-of-function polymorphism, which leads to higher EFV concentrations [ 65 ]. Based on 342 participants receiving DTG and 168 receiving EFV, the CYP2B6 EFV metabolizer genotype significantly influenced likelihood of weight gain while taking EFV; extensive metabolizers gained similar amounts of weight to the group taking DTG.…”