Dataset Information

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

ABSTRACT:

Background

Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants.

Methods

Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change.

Results

A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant ( P < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain.

Conclusion

CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

SUBMITTER: Wu K

PROVIDER: S-EPMC10732300 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

Wu Kunling K Koethe John J Hulgan Todd T Brown Todd T Bares Sara H SH Tassiopoulos Katherine K Lake Jordan E JE Leonard Michael M Samuels David C DC Erlandson Kristine K Haas David W DW

Pharmacogenetics and genomics 20231101 2

<h4>Background</h4>Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants.<h4>Methods</h4>Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed ...[more]

PMID: 37910437

Similar Datasets

Project description:BackgroundThe biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV.SettingTwo single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017.MethodsTwenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses.ResultsNP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4 and CD8 HLA-DR-/CD38 subsets both increased (P = 0.05, 0.02).ConclusionsEven asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.

Project description:BackgroundThis study explored the relationship between integrase strand transfer inhibitor (INSTI)-based anti-retroviral agents and weight gain over time, and the risk factors for weight gain in Korean people living with human immunodeficiency virus (PLWH).Materials and methodsThe study was conducted retrospectively in PLWHs 18 years of age or older who took one of three INSTI-based single-tablet regimens (STRs) (tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat [TDF/F/EVG/c], tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat [TAF/F/EVG/c], and abacavir/lamivudine/dolutegravir [ABC/3TC/DTG]) for more than 2 years at three university-affiliated hospitals in South Korea from May 2014 to December 2020. Analysis was performed in the treatment-naïve and treatment-experienced groups, respectively.ResultsIndividual INSTI-based STRs were associated with weight gain at the 24-month follow up in both treatment-naïve (n = 179) and treatment-experienced (n = 290) groups. Body mass index (BMI) categories changed over time for TAF/F/EVG/c and ABC/3TC/DTG, with significant increases in the rates of overweight and obesity in treatment-naïve patients, whereas there was no change for TDF/F/EVG/c. TAF/F/EVG/c significantly increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) compared to other regimens over 24 months. In the treatment-naïve group, a baseline CD4+ T cell count <100 cells/mm3, human immunodeficiency virus (HIV) viral load (VL) ≥100,000 copies/mL, no physical exercise, and TAF/F/EVG/c (vs. TDF/F/EVF/c) were risk factors for ≥10% weight gain. In the treatment-experienced group, age <45 years, BMI <25 kg/m², and no physical exercise were risk factors for ≥5% weight gain.ConclusionINSTI-based STR continued to increase body weight at the 24-month follow up in treated and untreated Korean PLWH. Exercise, together with demographic-, HIV-, and anti-retroviral therapy-related factors, influenced weight gain. Therefore, when prescribing an INSTI-based STR, weight gain and metabolic changes should be closely monitored in PLWH with these risk factors.

Project description:BackgroundIntegrase strand transfer inhibitor (INSTI)-based antiretroviral (ARV) therapies have been associated with greater weight gain in people with human immunodeficiency virus (HIV) versus those on protease inhibitor (PI)-based regimens. The DEFINE study investigated whether switching from an INSTI- to a PI-based regimen could mitigate/reverse weight gain.MethodsDEFINE (NCT04442737) was a randomized, 48-week, open-label, prospective, phase 4 study in virologically suppressed adults with HIV-1 and ≥10% weight gain on INSTI + tenofovir alafenamide (TAF)/emtricitabine (FTC; <36 months prescreening). Participants either switched immediately to darunavir/cobicistat/FTC/TAF (D/C/F/TAF) or continued INSTI + TAF/FTC during weeks 0-24 then switched to D/C/F/TAF for weeks 24-48. The primary endpoint was least squares (LS) mean (95% confidence interval [CI]) percent weight change from baseline to week 24.ResultsOverall, 103 adults were randomized (D/C/F/TAF, n = 53; INSTI + TAF/FTC, n = 50); 30% were female, and 61% were Black/African American. No significant difference in weight change was observed at week 24 (LS mean change: D/C/F/TAF, 0.63% [95% CI, -.44% to 1.70%] vs INSTI + TAF/FTC, -0.24% [95% CI, -1.35% to .87%]; P = .24); however, a trend toward weight loss was observed with extended time post-ARV switch to D/C/F/TAF (baseline to week 48, -0.36% [95% CI, -1.77% to 1.06%]), particularly in subgroups at higher weight gain risk (eg, female and Black/African American participants). Metabolic endpoints paralleled weight change over time. D/C/F/TAF was well tolerated, with comparable virologic efficacy between arms.ConclusionsWhile no significant change in body weight was observed at 24 weeks after switching from INSTI + TAF/FTC to D/C/F/TAF among adults with weight gain, a trend toward weight loss emerged with longer time post-ARV switch, supporting further investigation of ARV selection/switch for weight management. Clinical Trials Registration. NCT04442737.

Dataset Information

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

Background

Methods

Results

Conclusion

Publications

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets