Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor–Containing Regimens

Abstract

Background Unwanted weight gain affects some people living with HIV who are prescribed integrase strand transfer inhibitors (INSTI). Mechanisms and risk factors are incompletely understood. Methods We utilized two cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naïve participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142 and A5202 and did not receive INSTIs. Results In the observational cohort (N=61), CYP2B6 slow metabolizers had greater weight gain after switch (p=0.01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (N=462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (p=0.001) but not those receiving efavirenz with abacavir (p=0.65). Findings were consistent when stratified by race/ethnicity and by sex. Conclusions Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

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

“…A separate analysis of data that included ACTG 5202 results found that CYP2B6 genotype predicted weight change from EFV, with higher EFV levels suppressing weight, which will be discussed in more detail later [ 37 ]. Relevant to NRTI considerations, the association was present only when EFV was combined with TDF and not when combined with ABC.…”

“…Investigators assessed weight gain 48 weeks after switch from EFV to an INSTI in 2 cohorts (61 individuals from an observational cohort and 462 from a clinical trial cohort) and evaluated whether the CYP2B6 and UGT1A1 genotypes were associated with weight change following the ART switch (both genotypes are associated with ART metabolism and drug levels) [ 37 ]. Interestingly, the results demonstrated that CYP2B6 EFV slow metabolizers experienced significantly greater weight gain after the switch from EFV to EVG or RAL, but not DTG.…”

Case Report: Reversal of Integrase Inhibitor– and Tenofovir Alafenamide–Related Weight Gain After Switching Back to Efavirenz/Emtricitabine/Tenofovir DF

“…There is growing research regarding pharmacogenetics predicting weight gain or loss with specific ARVs. In a retrospective investigation, patients with CYP2B6 polymorphisms (slow metabolizers of EFV) gained more weight following a switch from an EFV- to INSTI-based regimen, potentially reflecting withdrawal of the inhibitory effect of higher EFV concentrations on weight gain [ 20 ]. Conversely, patients with CYP2B6 genotypes associated with extensive metabolism of EFV experienced similar weight gain with EFV-based ART as patients with an INSTI-based regimen [ 21 ].…”

Integrase Strand Transfer Inhibitors Play the Main Role in Greater Weight Gain Among Men With Acute and Early HIV Infection

“…Besides, similar to several previous reports [ 1 , 4 , 9 , 12 ], our findings show that INSTI users had greater weight gain than NNRTI users, even though the most prevalent INSTI in our study was elvitegravir, which was associated with less weight gain than dolutegravir or bictegravir [ 1 , 9 ]. These findings may partly be explained by the effect of efavirenz on weight suppression as efavirenz accounted for 93% of NNRTIs in this study [ 27 , 28 ]. Our results did not, however, support the hypothesis that the greater weight gain caused by INSTI was due to a more rapid return-to-health effect.…”