Among HIV-infected patients who switched from efavirenz- to integrase strand transfer inhibitor (INSTI)-based therapies, the genotype CYP2B6 was associated with weight gain, according to data published in Clinical Infectious Diseases. Investigators say this finding possibly reflects the withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain.
To better understand the mechanisms and risk factors behind unwanted weight gain in HIV-infected patients prescribed INSTIs, investigators used 2 cohorts to study the pharmacogenetics of weight gain after the switch from efavirenz- to INSTI-based regimens. In an observational cohort, the authors investigated weight gain at 48 weeks after the switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for ≥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, weight gain at 48 weeks was examined among treatment-naïve participants who did not receive INSTIs and were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202.
The observational cohort contained 61 individuals, and the data revealed that CYP2B6 slow metabolizers had greater weight gain after the switch (P =.01). This was observed after patients switched to elvitegravir or raltegravir but not dolutegravir. There were no associations found with the UGT1A1 genotype. In the clinical trial cohort of 462 patients, the CYP2B6 slow metabolizers had less weight gain at 48 weeks among those receiving efavirenz with tenofovir disoproxil fumarate (TDF) (P =.001) but not among those receiving efavirenz with abacavir (P =.65). The findings remained consistent when stratified for race/ethnicity and sex.
This study was limited by the small size of the observational cohort, which may be reflected in the lack of association between the UGT1A1 genotype and weight gain, and between the CYP2B6 genotype and weight gain among black participants. Furthermore, Asian individuals were not represented. The clinical cohort was also insufficient to carry out some subgroup analyses. It was also not possible to discern the relative contributions of lamivudine and emtricitabine because these were almost always prescribed with abacavir and TDF, respectively.
According to investigators, “among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with change in weight at week 48, likely because greater efavirenz exposure causes less weight gain during the pre-switch regimen.” However, the association of weight gain and the CYP2B6 genotype with concomitant TDF but not abacavir was unexpected and remains unexplained.
Leonard MA, Cindi Z, Bradford Y, et al. Efavirenz pharmacogenetics and weight gain following switch to integrase inhibitor-containing regimens [published online August 23, 2020]. Clin Infect Dis. doi:10.1093/cid/ciaa1219