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

2020 ◽  
Author(s):  
Michael A Leonard ◽  
Zinhle Cindi ◽  
Yuki Bradford ◽  
Kassem Bourgi ◽  
John Koethe ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Weight Gain ◽  
Integrase Inhibitor ◽  
The United States ◽  
Inhibitory Effect ◽  
Strand Transfer ◽  
Treatment Naïve ◽  
Observational Cohort ◽  
The Difference ◽  
Slow Metabolizers

Abstract Background Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood. Methods We utilized 2 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-naive 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 = .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 = .001), but not those receiving efavirenz with abacavir (P = .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.

scholarly journals 893. Evaluating Weight Gain in Treatment-naïve, HIV-infected Patients Started on Antiretroviral Therapy

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S538-S538
Author(s):  
Nimra Chaudhry ◽  
Eris Cani ◽  
Lendelle Raymond ◽  
Tae Park ◽  
Timothy Kanter
Keyword(s):  
Weight Gain ◽  
Primary Objective ◽  
Average Weight ◽  
City Hospital ◽  
Strand Transfer ◽  
Art Initiation ◽  
Average Change ◽  
Treatment Naïve ◽  
The Difference ◽  
Tenofovir Alafenamide

Abstract Background There is increasing evidence that integrase strand transfer inhibitors (INSTIs) are associated with more weight gain when compared to other antiretroviral (ART) classes. Thus, the primary objective of the study was to evaluate the difference in weight gain at 6 and 18 months among treatment-naïve patients started on an INSTI-based versus a non-INSTI-based ART regimen. Methods This was a retrospective cohort study of ART-naive adults who were initiated and maintained on INSTI and non-INSTI based regimens for at least 18 months at an HIV clinic in an inner-city hospital from January 2013 to June 2019. The non-INSTI-based regimens were darunavir (DRV) or rilpivirine (RPV)-based. Data collected included patient demographics, ART regimen, pre- and post-ART initiation weight in kilograms (kg), body mass index (BMI), CD4 count, and viral load. A two-tailed t-test was used to compare change in weight in INSTI-based versus non-INSTI-based regimens. Sub-group analyses were conducted using the ANOVA test. Results Out of 170 patients, 60% were initiated on an INSTI-based regimen, 7.1% on a DRV-based regimen, and 32.9% on a RPV-based regimen. Of the patients initiated on INSTI-based regimens, 73.5% were on elvitegravir (EVG),16.7% on dolutegravir, 8.8% on bictegravir, and 0.98% on raltegravir. The mean age at ART initiation was 38 years with majority of the patients described as Black. More male patients received an INSTI-based regimen compared to females (77.5% vs. 32%). The average change in weight at 6 and 18 months in the INSTI-based group vs non-INSTI-based group was +3.6 kg vs. +2.9 kg (95% CI -2.2-0.7, p=0.317) and +5.7 kg vs.+4.8 kg (95% CI -3.2-1.2, p=0.357) respectively. There was no significant average change in weight among the INSTI-based regimens (+3.6 kg), vs DRV (+5.3 kg), or RPV (+2.4 kg) based regimens at 6 months (p=0.108) and 18 months [(+5.7 kg) vs (+7.2 kg), vs (+4.3 kg) (p=0.186) respectively]. Among the INSTIs, EVG was associated with the highest increase in weight at both 6 and 18 months (+3.9 kg and +5.8 kg). Forty-six percent of patients in the INSTI group were on tenofovir alafenamide (TAF) while no patients received TAF in the non-INSTI groups. Conclusion When comparing INSTI-based to DRV or RPV-based regimens, there was no significant increase in average weight at 6 and 18 months. Disclosures All Authors: No reported disclosures

scholarly journals Short-term Increase in Risk of Overweight and Concomitant Systolic Blood Pressure Elevation in Treatment Naïve Persons Starting INSTI-based Antiretroviral Therapy

2019 ◽  
Author(s):  
Ronald Galdamez ◽  
José A García ◽  
Marta Fernández ◽  
Catalina Robledano ◽  
Vanessa Agulló ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Weight Gain ◽  
Ldl Cholesterol ◽  
University Hospital ◽  
Strand Transfer ◽  
Metabolic Disturbances ◽  
Short Term ◽  
Metabolic Markers ◽  
Blood Pressure Elevation ◽  
Treatment Naïve

Abstract Background Integrase strand transfer inhibitors (INSTI) have been associated with weight gain, but their effect on short-term overweight/obesity incidence, blood pressure(BP) and metabolic markers change has not been described in treatment-naïve people with HIV(PWH). Methods Medical records of treatment-naïve persons starting ART at the HIV Clinic of University Hospital of Elche(Spain), between January 2007 and July 2019 were retrospectively reviewed. Standard procedures included measurements of weight, BP and metabolic assessment. Data at baseline, 48, 72, and 96 weeks post ART initiation were analysed. We used Cox mixed-effects model to generate predictions of BMI over time and Generalized Additive Mixed Models(GAMM) to relax the linearity assumptions and generate 95% confidence intervals in the multivariable adjust. Results Among 219 (median age 44.0 years, IQR=37.0-53.5; 46 females) participants. Baseline weight mean(SD) was 70.4(13.7)kg without difference between regimens; 66% had a BMI <25 kg/mt2. The incidence of overweight/obesity was significantly greater in persons starting INSTI-based regimens: 15(36.6%) of 41 patients treated with INSTI vs 30(28.9%) of 104 treated with other ART regimens(HR 2.3, 95%CI, 1.2–4.4;p=0.011). In contrast to other ART regimens, patients treated with INSTI showed a significant increase in systolic BP(SBP) (adjusted increase 7.0 mmHg, 95%CI, 0.3–13.7;p=0.039) that was correlated with weight gain (r=0.13, 95%CI, 0.10-0.16;p<0.001). Patients who reached overweight/obesity in INSTI-based ART showed a significant increase in LDL cholesterol. Conclusions INSTI-based ART was associated in the short-term with a greater risk of overweight/obesity and SBP elevation. Patients developing overweight/obesity increased LDL cholesterol with no other metabolic disturbances.

scholarly journals Weight Gain After Switch from Efavirenz-Based to Integrase Inhibitor-Based Regimens

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S433-S433 ◽  
Author(s):  
Jamison Norwood ◽  
Megan Turner ◽  
Carmen Bofill ◽  
Cathy Jenkins ◽  
Sally Bebawy ◽  
...  
Keyword(s):  
Weight Gain ◽  
Group Analysis ◽  
Integrase Inhibitor ◽  
Fixed Dose ◽  
Virologic Suppression ◽  
Strand Transfer ◽  
Persons Living With Hiv ◽  
Virologic Control ◽  
Hiv 1 ◽  
Over Time

Abstract Background Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) offers persons living with HIV a potent new treatment option. Recently, local HIV clinicians noted weight gain in patients who switched from daily, fixed-dose efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) to fixed-dose dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). To assess whether regimen switch was significantly associated with weight gain, we evaluated body weight over time among patients with sustained virologic suppression who switched from EFV/TDF/FTC to an INSTI-containing regimen, including DTG/ABC/3TC. Methods We analyzed data from adult patients on EFV/TDF/FTC for &gt;=2 years with consistent plasma HIV-1 RNA &lt;1000 copies/mL prior to date of switch (or date of sham switch for those who remained on EFV/TDF/FTC). All maintained HIV-1 RNA &lt;1000 copies/mL for &gt;=18 months post-switch. We assessed weight change over 18 months in patients switched to an INSTI-containing regimen or a protease inhibitor (PI)-containing regimen vs. those remaining on EFV/TDF/FTC over the same period. In a sub-group analysis, we compared patients switched to DTG/ABC/3TC vs. raltegravir- or elvitegravir-containing regimens. Linear mixed effects models assessed mean differences in weight over time, adjusting for baseline age, sex, race, CD4+ count and weight. Results Among 495 patients, 136 switched to an INSTI-containing regimen, 34 switched to a PI-containing regimen, and 325 remained on EFV/TDF/FTC. Patients switched to an INSTI-containing regimen gained an average of 2.9 kilograms (kg) at 18 months compared with 0.9 kg among those continued on EFV/TDF/FTC (P = 0.003, Figure a), while those switched to a PI regimen gained 0.7 kg (P = 0.81, Figure b). Among INSTI regimens, those switched to DTG/ABC/3TC gained 5.3 kg at 18 months, which was more than raltegravir or elvitegravir regimens (P = 0.19, Figure c) and significantly more than those continued on EFV/TDF/FTC (P = 0.001, Figure d). Conclusion Switching from daily, fixed-dose EFV/TDF/FTC to an INSTI-containing regimen among patients with virologic control was associated with weight gain at 18 months. This weight gain was particularly profound among those switching to DTG/ABC/3TC. Disclosures All authors: No reported disclosures.

scholarly journals 633. Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) Efficacy in Participants with Pre-Existing Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S376-S377
Author(s):  
Michelle L D’Antoni ◽  
Kristen Andreatta ◽  
Rima K Acosta ◽  
Silvia Chang ◽  
Ross Martin ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Pooled Analysis ◽  
Baseline Viral Load ◽  
Virologic Suppression ◽  
Strand Transfer ◽  
Viral Loads ◽  
Subtype B ◽  
Treatment Naïve ◽  
Inhibitor Resistance

Abstract Background Pre-existing drug resistance can affect the efficacy of antiretroviral therapy. Studies in treatment-naïve and virologically suppressed participants have demonstrated safety and efficacy of B/F/TAF, including in patients with M184V/I mutations. In this pooled analysis, we investigated virologic outcomes after 48 weeks of B/F/TAF treatment in individuals with pre-existing integrase strand transfer inhibitor resistance (INSTI-R). Methods Although INSTI-R was prohibited per study entry criteria, pre-existing INSTI-R (T66A/I/K, E92G/Q, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H/S, R263K) was evaluated in participants from studies 1489, 1490, 1844, 1878, 4030. INSTI-R was assessed by historical genotypes and/or retrospective deepType HIV assay (Seq-IT, Germany), GenoSure IN, GenoSure Archive (Monogram Biosciences). Virologic outcomes were defined by last on-treatment observation carried forward (LOCF) method. Results Pre-existing primary INSTI-R substitutions were detected in 20/1907 participants (1.0%) after enrolment. Of the 20, 75% were male, 30% white, and 85% had HIV-1 subtype B, baseline median CD4 counts of 594 (IQR 517, 700), and median age of 52 (43, 59) years. One participant was treatment-naïve with a baseline viral load of 30,000 copies/ml and had Q148H (+ G140S on plasma RNA genotype) and was sensitive to bictegravir (&lt; 2.5-fold change). The other 19 participants were virologically suppressed and had E92G (n=3), Y143C (n=2), Y143H (n=4), S147G (n=2), N155S (n=1), Q148H (n=3), Q148K (n=1), Q148R (n=1), or R263K (n=2) INSTI-R mutations by DNA genotype. The treatment-naïve individual was suppressed by Week 4 and maintained viral loads of &lt; 50 copies/mL through Week 48. All suppressed participants had HIV RNA &lt; 50 copies/mL throughout Week 48. All study participants had virologic success by LOCF (&lt; 50 copies/mL) at Week 48. Conclusion Participants with primary INSTI-R substitutions had or maintained virologic suppression through 48 weeks of B/F/TAF treatment. Consistent with the potent in vitro activity of bictegravir against many INSTI-R mutations, these virologic outcomes suggest that B/F/TAF may have potential as a treatment option for some patients with pre-existing INSTI-R, if confirmed by further studies. Disclosures Michelle L. D’Antoni, PhD, Gilead Sciences (Employee, Shareholder) Kristen Andreatta, MSc, Gilead Sciences (Employee, Shareholder) Rima K. Acosta, BS, Gilead Sciences, Inc. (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc. (Employee, Shareholder)

scholarly journals Integrase Strand Transfer Inhibitors and Weight Gain in Children and Youth with Perinatal HIV in the DC Cohort

2021 ◽  
Author(s):  
Wei Li A Koay ◽  
Sahera Dirajlal-Fargo ◽  
Matthew E Levy ◽  
Paige Kulie ◽  
Anne Monroe ◽  
...  
Keyword(s):  
United States ◽  
Weight Gain ◽  
The United States ◽  
Rate Of Change ◽  
Children And Youth ◽  
Strand Transfer ◽  
Z Score ◽  
Perinatal Hiv ◽  
Integrase Strand Transfer Inhibitors

Abstract We conducted a retrospective analysis of 38 children and youth with HIV (aged 0-&lt;20 years) in the United States and report an increased rate of change of BMI-for-age z-score after initiating integrase strand transfer inhibitors (+0.19 z-score units/year, 95% CI 0.01, 0.37, p=0.036) for a median follow-up of 527.5 days.

scholarly journals Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy

2019 ◽  
Vol 70 (7) ◽  
pp. 1267-1274 ◽  
Author(s):  
Kassem Bourgi ◽  
Peter F Rebeiro ◽  
Megan Turner ◽  
Jessica L Castilho ◽  
Todd Hulgan ◽  
...  
Keyword(s):  
Weight Gain ◽  
Antiretroviral Therapy ◽  
Transcriptase Inhibitor ◽  
Virologic Suppression ◽  
Strand Transfer ◽  
Care Clinic ◽  
Art Initiation ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Restricted Cubic Splines

Abstract Background Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)–based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens. Methods Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)–, and nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals. Results Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/μL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P &lt; .05), and 0.5 kg for elvitegravir (P &lt; .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant. Conclusions Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.

Integrase Inhibitor-Based Antiretroviral Therapy Among Women Living with HIV: Data from the OPERA Cohort

2019 ◽  
Vol 17 (4) ◽  
pp. 266-276
Author(s):  
Jennifer Fusco ◽  
Cassidy Henegar ◽  
Evelyn Byrd Quinlivan ◽  
Vani Vannappagari ◽  
Michael Aboud ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Cox Regression ◽  
Integrase Inhibitor ◽  
Virologic Response ◽  
Hiv Treatment ◽  
Strand Transfer ◽  
Women Living With Hiv ◽  
Treatment Naïve ◽  
Hiv Women ◽  
Living With Hiv

Background: Women face unique complexities in HIV treatment yet are underrepresented in antiretroviral therapy (ART) studies. Objective: This analysis assessed the one-year durability of the first integrase strand transfer inhibitor (INSTI)-based regimens prescribed to women in a large cohort of patients living with HIV in care. Methods: Women with HIV who initiated their first INSTI-containing regimen between 08/12/2013 and 11/30/2015 were identified in the OPERA cohort, a collaboration of 79 US outpatient clinics. Discontinuation within the first year of treatment with an INSTI was compared between dolutegravir (DTG), raltegravir (RAL) and elvitegravir (EVG), using multivariable Cox regression and Kaplan- Meier estimates. Virologic response and regimen modifications were described and compared across INSTIs. Results: A total of 537 treatment-naïve (DTG: 39%, EVG: 48%, RAL: 13%) and 878 treatmentexperienced (DTG: 57%, EVG: 29%, RAL: 13%) women were analyzed. In the first twelve months after initiation, women taking EVG or RAL were more likely to discontinue their initial INSTI than those taking DTG among both treatment-naïve (adjusted hazard ratio EVG vs. DTG: 1.59 (95% CI: 1.09, 2.39); RAL vs. DTG: 2.46 (1.49, 4.05)) and treatment-experienced women (EVG vs. DTG: 1.39 (1.02, 1.88); RAL vs. DTG: 2.17 (1.51, 3.12)). Following discontinuation of the initial INSTI, women commonly switched to a regimen containing a different drug from the INSTI class (treatment-naïve DTG: 34%, RAL: 33% EVG: 41%; treatment-experienced DTG: 23%, RAL: 19% EVG: 41%). Conclusion: In treatment-naïve and treatment-experienced women living with HIV, women taking DTG had the lowest risk for early (≤1 year) discontinuation.

scholarly journals 881. Long-term Weight Gain After Initiating Combination Antiretroviral Therapy in Treatment-naïve Asian People Living with HIV

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S532-S533
Author(s):  
Naokatsu Ando ◽  
Takeshi Nishijima ◽  
Daisuke Mizushima ◽  
Yosuke Inaba ◽  
Yohei Kawasaki ◽  
...  
Keyword(s):  
Weight Gain ◽  
Antiretroviral Therapy ◽  
Transcriptase Inhibitor ◽  
People Living With Hiv ◽  
Strand Transfer ◽  
Clinical Issue ◽  
Asian Populations ◽  
Asian Patients ◽  
Treatment Naïve ◽  
Tenofovir Alafenamide

Abstract Background Weight gain after the initiation of antiretroviral therapy (ART) is becoming a major clinical issue in treatment-naïve people living with human immunodeficiency virus (PLWH). However, limited data exist for the Asian populations. We aimed to investigate changes in weight after the initiation of ART therapy in treatment-naïve Asian patients. Methods We evaluated adult, treatment-naïve Asian PLWH who started integrase strand transfer inhibitor (INSTI)-, protease inhibitor (PI)-, or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART at AIDS Clinical Center, Tokyo, between January 2005 and February 2019. They were followed up until October 2019. Multivariate linear mixed-effects models were used to generate marginal predictions of weight over time. Predicted weight by ART class (INSTI, PI, and NNRTI), each key drug (dolutegravir [DTG], elvitegravir [EVG], raltegravir [RAL], and darunavir [DRV]), and each key drug with or without the use of tenofovir alafenamide (TAF)/emtricitabine (FTC) was reported at 3-month intervals until censoring or 5 years. Results Among the 1,579 study patients, 610 (38.6%), 929 (58.8%), and 40 (2.5%) started INSTI-, PI-, and NNRTI-based ART. After 5 years, PLWH who initiated DTG- (5.3 kg), DRV- (4.0 kg), and EVG-based treatment (4.6 kg) gained more weight than those who initiated RAL-based treatment (1.8 kg). PLWH who initiated DTG plus TAF/FTC (6.7 kg) gained the largest weight. Conclusion In the Asian PLWH population, ART-associated weight gain continues to increase for 5 years after treatment initiation. DTG plus TAF/FTC was associated with the largest weight gain. Disclosures All Authors: No reported disclosures

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