Tipping the Scales: Is ART adding pounds to our patients? Matthew - PDF document

12/13/19 Tipping the Scales: Is ART adding pounds to our patients? Matthew D. Hickey, MD 1 Conflict of Interest • I have no disclosures 2 1

12/13/19 1. Recent trends in weight gain 2. Weight gain after ART start and ART switch 3. Two RCTs of DTG +/- TAF in Sub- Saharan Africa 4. RCT data on bictegravir, dolutegravir, and TAF 5. Health consequences of weight gain and possible mechanisms Roadmap 3 First, a case (Audience Response) • 37 year old man with a recent diagnosis of HIV (CD4 280, VL 20,000) who is presenting to establish care. • He also has hypertension and takes hydrochlorothiazide “most of the time”. HLA-B*5701 is negative. • Prior to seeing you, he read on the internet that HIV medications could make him gain weight and tells you that he absolutely wants to avoid weight gain. • What do you start? A. DTG + TAF/FTC B. DTG + TDF/FTC C. DTG/3TC/ABC D. BIC/TAF/FTC E. DRV/c/TAF/FTC 4 2

12/13/19 Weight increasing at ART start • Over time, BMI at ART start has increased at rate faster than general US population • Prevalence of obesity: • PLHIV: 9% (1998) -> 18% (2010) • US Pop: 22% (1998) -> 27% (2010) Koethe et al. AIDS Res Human Retrov. 2016 5 Weight gain after ART start • Significant weight gain after starting ART • Especially seen in men and non-white women • Some weight gain due to ‘return to health’ • 18% treatment-emergent obesity • Key questions: • How much of this weight gain is ‘return to health’? • Does ART cause weight gain beyond ‘return to health’? • Do some ART drugs cause more weight gain than others? Koethe et al. AIDS Res Human Retrov. 2016 6 3

12/13/19 Weight gain among aïve patients tr trea eatmen tment t naïv starting ART 7 Unexpected finding: Weight gain with RAL vs boosted-PI • Randomized trial to see if Risk for severe weight gain (>10% body weight) raltegravir had improved Factor Adjusted 95% CI p-value metabolic profile compared to Odds Ratio protease inhibitors ATV/r vs. RAL 0.72 (0.53 to 0.99) p=0.04 • Surprisingly, weight gain worse DRV/r vs. RAL 0.73 (0.53 to 0.99) p=0.04 with RAL, even when excluding Black 1.55 (1.10 to 2.20) p=0.01 (non-Hispanic) baseline underweight Baseline log10 2.52 (2.00 to 3.16) p<0.0001 • More weight gain among: HIV-RNA • Low CD4 – return to health? Baseline CD4 count 0.78 (1.18 to 1.39) p<0.0001 (100 cells/uL) • Black people, high viral load Bhagwat et al. CROI 2017 Oral #695. Slide credit: John R Koethe, CROI 2019 8 4

12/13/19 Greater weight gain with INSTI start 21,866 ART-naïve patients starting ART in US/Canada from 2007-2016 Bourgi et al. CROI 2019 Poster #670. 9 Weight gain among ced patients treatment experience switching to an INSTI 10 5

12/13/19 Greater weight gain with switch to INSTI DTG/ABC/3TC versus EFV/TDF/FTC Integrase inhibitor regimens versus EFV/TDF/FTC Weight Change (kg) DTG/ABC/3TC Integrase Inhibitor Weight Change (kg) EFV/TDF/FTC EFV/TDF/FTC Time from Regimen Switch (months) Time from Regimen Switch (months) • Single center in southern US (n=495) • Patients virally suppressed on EFV/TDF/FTC prior to switch • Weight gain greatest after switch to DTG/ABC/3TC Norwood. JAIDS. 2017 Slide credit: John R Koethe, CROI 2019 11 Weight gain after switch to DTG from boosted protease inhibitor (NICE-022) Weight gain after switch from boosted-PI to dolutegravir 2 DTG Switch Randomized trial of patients with DTG Switch Weight changes (kg) 1.5 +0.98 kg high cardiovascular risk on boosted PI (n=415) who were switched to: +0.03 kg 1 • DTG immediate started at week 0 +0.82 kg • DTG delayed started at week 48 0.5 g k 5 . 2 0 + 0 0 48 96 Weeks DTG delayed DTG immediate Waters, HIV Drug Therapy 2018 #102 12 6

12/13/19 Weight increases after switch to INSTI • Among patients suppressed at time of switch to INSTI, weight stable pre-switch and increased post-switch (n=691) • Weight gain greatest with switch to dolutegravir • Greater weight gain among women, black people, older people Lake. CROI 2019. Poster 669. 13 Randomized Trials of DTG in Sub-Saharan Africa • Two randomized trials of Dolutegravir vs standard of care (EFV/TDF/FTC) in treatment naïve patients • ADVANCE in South Africa • NAMSAL in Cameroon Venter. NEJM. 2019. NAMSAL ANRS 12313 Study Group. NEJM. 2019. 14 7

12/13/19 ADVANCE Study: DTG vs EFV in South Africa • Randomized trial in treatment naïve patients (n=1,053) 100 TDF/FTC+DTG, 85% comparing: 90 80 • EFV + TDF/FTC (n=351) 70 • DTG + TDF/FTC (n=351) TAF/FTC+DTG, 84% Participants (%) 60 • DTG + TAF/FTC (n=351) 50 TDF/FTC/EFV, 79% 40 • Over half of participants were 30 women 20 • Overall, high rates of viral 10 suppression 0 0 4 8 12 16 20 24 28 32 36 40 44 48 4 12 24 36 48 Week 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019. 15 Greater weight gain with DTG + TAF/FTC TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV Mean change in weight (kg) +6 kg +3 kg +1 kg Week 48 +8 kg +5 kg +2 kg Week 96 Treatment-emergent overweight, n (%) 23% 14% 9% Week 48 25% 13% 11% Week 96 Treatment-emergent obesity, n (%) 14% 7% 6% Week 48 19% 8% 4% Week 96 Highly significant differences in weight change between arms, p<0.001 Clinical obesity (BMI ≥ 30 kg/m 2 ). TAF/FTC+DTG higher than other 2 groups (p<0.01) 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019. 16 8

12/13/19 Not just ‘return to health’: weight gain differences greatest in baseline normal and overweight BMI TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV (n=351) (n=351) (n=351) Underweight, kg (% change) +4.8 (9%) +2.6 (5%) +3.1 (6%) Week 48 +4.5 (8%) +4.0 (8%) +3.2 (6%) Week 96 Normal, kg (% change) +5.6 (9%) +3.0 (5%) +1.1 (2%) Week 48 +8.1 (13%) +3.9 (6%) +2.2 (4%) Week 96 Overweight, kg (% change) +7.0 (9%) +3.6 (5%) +1.0 (1%) Week 48 +9.0 (12%) +4.6 (6%) +1.0 (1%) Week 96 Obese, kg (% change) +4.4 (5%) +3.2 (4%) 0.9 (1%) Week 48 +4.6 (5%) +6.3 (7%) +2.6 (3%) Week 96 McCann. European AIDS Conference 2019. Abstr. PS3/3. 17 Women gained more weight than men Men Women Similar results when excluding those with GI adverse events 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019. 18 9

12/13/19 Generalized increase in body fat Women Week 48 Week 96 TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV (n=158) (n=156) (n=137) (n=60) (n=53) (n=48) 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019. 19 Increase in metabolic syndrome with DTG+TAF TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV (n=351) (n=351) (n=351) 16/350 (5%) 21/351 (6%) 14/351 (4%) Baseline prevalence Treatment-emergent metabolic syndrome 20/290 (7%) 16/297 (5%) 9/275 (3%) Week 48 17/189 (9%) 9/189 (5%) 6/180 (3%) Week 96 Statistically significant differences between TAF/FTC+DTG and TDF/FTC/EVF at week 96, p=0.025 Metabolic syndrome defined as obesity AND any two of: elevated triglycerides, low HDL, hypertension, diabetes 1. McCann. European AIDS Conference 2019. Abstr. PS3/3. 2. Venter. NEJM. 2019. 20 10

12/13/19 NAMSAL Study: DTG vs EFV in Cameroon • Randomized trial in treatment naïve patients (n=613) DTG+ TDF/3TC 75% comparing: • EFV + TDF/3TC (n=310) • DTG + TDF/3TC (n=303) EFV+ TDF/3TC 69% • Nearly two thirds of participants were women • Lower rates of viral suppression, largely due to higher baseline viral loads NAMSAL ANRS 12313 Study Group. NEJM. 2019. 21 Greater weight gain seen with DTG, again TDF/3TC+DTG TDF/3TC+EFV400 p-value for Week 48 (n=293) (n=278) difference Mean change from baseline: +5 +3 <0.001 Weight (kg) +1.7 +1.2 <0.001 BMI (kg/m 2 ) 1. NAMSAL ANRS 12313 Study Group. NEJM. 2019. 2. Hill. IAS 2019. Abstr MOAX0102LB 22 11

12/13/19 Substantial treatment-emergent obesity in men ≥ 10% change from baseline Treatment emergent obesity weight (Week 48) (Week 48) p<0.05 20 p<0.01 50 n.s. 44% 18 45 n.s. 16 14% 40 34% 14 12% % participants 35 % participants 12 26% 30 10 25 7% 19% 8 20 6 15 4 2% 10 2 5 0 0 TDF/3 TDF/3 TC/EF TDF/3 TDF/3 TC/EF TC+D TC+D TDF/ TDF/ TDF/ 3TC+ 3TC/ TDF/ 3TC+ 3TC/ DTG EFV DTG EFV TG TG V V Men Women Men Women 1. NAMSAL ANRS 12313 Study Group. NEJM. 2019. 2. Hill. IAS 2019. Abstr MOAX0102LB 23 Summary from ADVANCE and NAMSAL • Dolutegravir is associated with increased weight gain and obesity in both men and women • Weight gain is greater in women and when DTG is combined with TAF/FTC • Is this due to weight loss associated with TDF? Or weight gain with TAF? • In women, weight gain does not plateau by 2 years of follow up, unknown whether weight continues to rise • Modest increase in metabolic syndrome with DTG+TAF/FTC • One question: Is bictegravir associated with similar weight gain? 24 12

12/13/19 Pooled analysis of 8 RCTs in ART naïve patients: INSTI associated with greater increases in weight Sax et al Clin Inf Dis Oct 2019 25 Dolutegravir and Bictegravir associated with largest weight gain Sax et al Clin Inf Dis Oct 2019 26 13

12/13/19 TAF also associated with greater weight gain than TDF Sax et al Clin Inf Dis Oct 2019 27 Greater weight gain with INSTI+TAF Mean weight change (kg) over 1 year Direct study comparisons • Greater weight gain with EVG/c/TAF/FTC than EVG/c/TDF/FTC Sax et al Clin Inf Dis Oct 2019 28 14