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

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

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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

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Tipping the Scales: Is ART adding pounds to

  • ur patients?

Matthew D. Hickey, MD 1

Conflict of Interest

  • I have no disclosures

2

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Roadmap

  • 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

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

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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

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  • 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

Weight gain after ART start

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Weight gain among tr trea eatmen tment t naïv aïve patients starting ART

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Unexpected finding: Weight gain with RAL vs boosted-PI

  • Randomized trial to see if

raltegravir had improved metabolic profile compared to protease inhibitors

  • Surprisingly, weight gain worse

with RAL, even when excluding baseline underweight

  • More weight gain among:
  • Low CD4 – return to health?
  • Black people, high viral load

Risk for severe weight gain (>10% body weight)

Bhagwat et al. CROI 2017 Oral #695.

Slide credit: John R Koethe, CROI 2019

Factor Adjusted Odds Ratio 95% CI p-value ATV/r vs. RAL 0.72 (0.53 to 0.99) p=0.04 DRV/r vs. RAL 0.73 (0.53 to 0.99) p=0.04 Black (non-Hispanic) 1.55 (1.10 to 2.20) p=0.01 Baseline log10 HIV-RNA 2.52 (2.00 to 3.16) p<0.0001 Baseline CD4 count (100 cells/uL) 0.78 (1.18 to 1.39) p<0.0001

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Greater weight gain with INSTI start

Bourgi et al. CROI 2019 Poster #670.

21,866 ART-naïve patients starting ART in US/Canada from 2007-2016

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Weight gain among treatment experience ced patients switching to an INSTI

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Slide credit: John R Koethe, CROI 2019

Greater weight gain with switch to INSTI

  • Norwood. JAIDS. 2017
  • 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

Integrase inhibitor regimens versus EFV/TDF/FTC DTG/ABC/3TC versus EFV/TDF/FTC Weight Change (kg) Weight Change (kg) Time from Regimen Switch (months) Time from Regimen Switch (months) Integrase Inhibitor EFV/TDF/FTC DTG/ABC/3TC EFV/TDF/FTC

11

Weight gain after switch to DTG from boosted protease inhibitor (NICE-022)

Waters, HIV Drug Therapy 2018 #102

Randomized trial of patients with high cardiovascular risk on boosted PI (n=415) who were switched to:

  • DTG immediate started at week 0
  • DTG delayed started at week 48

0.5 1 1.5 2 48 96 Weight changes (kg) Weeks

Weight gain after switch from boosted-PI to dolutegravir

DTG delayed DTG immediate +0.82 kg + . 2 5 k g +0.03 kg +0.98 kg DTG Switch DTG Switch

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  • Lake. CROI 2019. Poster 669.
  • 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

Weight increases after switch to INSTI

13

  • Two randomized trials of

Dolutegravir vs standard

  • f care (EFV/TDF/FTC) in

treatment naïve patients

  • ADVANCE in South Africa
  • NAMSAL in Cameroon

Randomized Trials of DTG in Sub-Saharan Africa

  • Venter. NEJM. 2019. NAMSAL ANRS 12313 Study Group. NEJM. 2019.

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ADVANCE Study: DTG vs EFV in South Africa

  • Randomized trial in treatment

naïve patients (n=1,053) comparing:

  • EFV + TDF/FTC (n=351)
  • DTG + TDF/FTC (n=351)
  • DTG + TAF/FTC (n=351)
  • Over half of participants were

women

  • Overall, high rates of viral

suppression

TAF/FTC+DTG, 84% TDF/FTC+DTG, 85% TDF/FTC/EFV, 79% 4 12 24 36 48 10 20 30 40 50 60 70 80 90 100

4 8 12 16 20 24 28 32 36 40 44 48

Participants (%) Week

  • 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019.

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Greater weight gain with DTG + TAF/FTC

  • 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019.

TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV Mean change in weight (kg) Week 48 +6 kg +3 kg +1 kg Week 96 +8 kg +5 kg +2 kg Treatment-emergent overweight, n (%) Week 48 23% 14% 9% Week 96 25% 13% 11% Treatment-emergent obesity, n (%) Week 48 14% 7% 6% Week 96 19% 8% 4%

Highly significant differences in weight change between arms, p<0.001 Clinical obesity (BMI ≥ 30 kg/m2). TAF/FTC+DTG higher than other 2 groups (p<0.01)

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TAF/FTC+DTG (n=351) TDF/FTC+DTG (n=351) TDF/FTC/EFV (n=351) Underweight, kg (% change) Week 48 +4.8 (9%) +2.6 (5%) +3.1 (6%) Week 96 +4.5 (8%) +4.0 (8%) +3.2 (6%) Normal, kg (% change) Week 48 +5.6 (9%) +3.0 (5%) +1.1 (2%) Week 96 +8.1 (13%) +3.9 (6%) +2.2 (4%) Overweight, kg (% change) Week 48 +7.0 (9%) +3.6 (5%) +1.0 (1%) Week 96 +9.0 (12%) +4.6 (6%) +1.0 (1%) Obese, kg (% change) Week 48 +4.4 (5%) +3.2 (4%) 0.9 (1%) Week 96 +4.6 (5%) +6.3 (7%) +2.6 (3%)

  • McCann. European AIDS Conference 2019. Abstr. PS3/3.

Not just ‘return to health’: weight gain differences greatest in baseline normal and overweight BMI

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Women gained more weight than men

Men Women

  • 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019.

Similar results when excluding those with GI adverse events

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Week 48 Week 96

TAF/FTC+DTG (n=158) TDF/FTC+DTG (n=156) TDF/FTC/EFV (n=137) TAF/FTC+DTG (n=60) TDF/FTC+DTG (n=53) TDF/FTC/EFV (n=48)

  • 1. Hill. IAS 2019. Abstr MOAX0102LB. 2. Venter. NEJM. 2019.

Generalized increase in body fat

Women

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TAF/FTC+DTG (n=351) TDF/FTC+DTG (n=351) TDF/FTC/EFV (n=351) Baseline prevalence 16/350 (5%) 21/351 (6%) 14/351 (4%) Treatment-emergent metabolic syndrome Week 48 20/290 (7%) 16/297 (5%) 9/275 (3%) Week 96 17/189 (9%) 9/189 (5%) 6/180 (3%) 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.

Increase in metabolic syndrome with DTG+TAF

20

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NAMSAL Study: DTG vs EFV in Cameroon

  • Randomized trial in treatment

naïve patients (n=613) comparing:

  • EFV + TDF/3TC (n=310)
  • DTG + TDF/3TC (n=303)
  • 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.

DTG+ TDF/3TC 75% EFV+ TDF/3TC 69%

21

Greater weight gain seen with DTG, again

Week 48 TDF/3TC+DTG (n=293) TDF/3TC+EFV400 (n=278) p-value for difference Mean change from baseline: Weight (kg) +5 +3 <0.001 BMI (kg/m2) +1.7 +1.2 <0.001

  • 1. NAMSAL ANRS 12313 Study Group. NEJM. 2019. 2. Hill. IAS 2019. Abstr MOAX0102LB

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≥ 10% change from baseline weight (Week 48)

p<0.05 p<0.01 n.s.

Treatment emergent obesity (Week 48)

  • 1. NAMSAL ANRS 12313 Study Group. NEJM. 2019. 2. Hill. IAS 2019. Abstr MOAX0102LB

26% 19% 44% 34%

5 10 15 20 25 30 35 40 45 50

TDF/ 3TC+ DTG TDF/ 3TC/ EFV TDF/ 3TC+ DTG TDF/ 3TC/ EFV

Men Women % participants 14% 2% 12% 7%

2 4 6 8 10 12 14 16 18 20

TDF/3 TC+D TG TDF/3 TC/EF V TDF/3 TC+D TG TDF/3 TC/EF V

Men Women % participants

Substantial treatment-emergent obesity in men

n.s.

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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?

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Pooled analysis of 8 RCTs in ART naïve patients: INSTI associated with greater increases in weight

Sax et al Clin Inf Dis Oct 2019

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Dolutegravir and Bictegravir associated with largest weight gain

Sax et al Clin Inf Dis Oct 2019

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TAF also associated with greater weight gain than TDF

Sax et al Clin Inf Dis Oct 2019

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Sax et al Clin Inf Dis Oct 2019

Greater weight gain with INSTI+TAF

Direct study comparisons

  • Greater weight gain with

EVG/c/TAF/FTC than EVG/c/TDF/FTC

Mean weight change (kg) over 1 year

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Sax et al Clin Inf Dis Oct 2019

Greater weight gain with INSTI+TAF

Direct study comparisons

  • Greater weight gain with

EVG/c/TAF/FTC than EVG/c/TDF/FTC

  • Greater weight gain with

BIC/TAF/FTC than DTG/ABC/3TC

Mean weight change (kg) over 1 year

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Sax et al Clin Inf Dis Oct 2019

Greater weight gain with INSTI+TAF

Direct study comparisons

  • Greater weight gain with

EVG/c/TAF/FTC than EVG/c/TDF/FTC

  • Greater weight gain with

BIC/TAF/FTC than DTG/ABC/3TC

  • Similar weight gain in DTG vs

BIC when combined with TAF/FTC

Mean weight change (kg) over 1 year

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Sax et al Clin Inf Dis Oct 2019

Greater weight gain with INSTI+TAF

Direct study comparisons

  • Greater weight gain with

EVG/c/TAF/FTC than EVG/c/TDF/FTC

  • Greater weight gain with

BIC/TAF/FTC than DTG/ABC/3TC

  • Similar weight gain in DTG vs

BIC when combined with TAF/FTC

Mean weight change (kg) over 1 year

~0.9kg weight gain/year among average adult aged 20-40

Hill 2003 Science

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Patients gain weight with ART… so what?

  • ADVANCE showed small increased prevalence of metabolic syndrome

in DTG+TAF/FTC compared to DTG+TDF/FTC or EFV+TDF/FTC1

  • Pooled analysis of 8 RCTs showed no increase in diabetes or

hypertension; very small decreases in HDL cholesterol2

  • Several cohort studies with conflicting results regarding incident

dyslipidemia and diabetes with INSTI or TAF-associated weight gain3-5

  • Follow up time may not be sufficient in studies conducted to date to

fully appreciate metabolic consequences of ART-associated weight gain

  • 1. McCann. European AIDS Conference 2019. Abstract PS3/3. 2. Sax et al Clin Inf Dis Oct 2019.
  • 3. Rebeiro IDWeek 2019. Abstract LB9. 4. Zimmerman IDWeek 2019. Abstract 981. 5. Schafer IDWeek 2019 Abstract 979.

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What we know and what we don’t

  • What we know
  • Greater weight gain with INSTIs in randomized trials among ART-naïve patients
  • Greater weight gain when TAF combined with INSTI among ART-naïve patients
  • Likely weight gain from switch to INSTI or TAF, though lower quality evidence
  • Risk of weight gain higher in women, black people (in US-based studies), high

viral load

  • What we don’t know
  • Mechanism of action for INSTI and TAF associated weight gain
  • Possible measures to prevent weight gain
  • Reversibility of weight gain
  • Long-term clinical consequences of ART-associated weight gain

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Hypothesized mechanisms: INSTI

  • Promotion of adipose tissue growth and insulin resistance?
  • DTG/RAL associated with increased adipocyte growth and insulin resistance1
  • Case reports of acute-onset diabetes with INSTI switch2,3
  • Better virus elimination and reduction of catabolism?
  • More rapid viral suppression with INSTI
  • Better penetration into adipocytes4
  • Lack of weight gain with cabotegravir for PrEP5
  • 1. Gorwood. Intl Co-morbidities & Adverse Drug Reactions Workshop 2019. 2. Fong, IJSA 2017. 3. Horikawa TJECM 2018.
  • 4. Couturier Antiviral Res 2018. 5. CROI 2019 Abstract #034.

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Decisions we’re facing now in clinic

  • How do we counsel patients on possibility of weight gain without

scaring them away from ART?

  • Should some patients be switched from TAF to TDF?
  • Should we consider DTG/ABC/3TC for some patients for whom we are

worried about renal/bone toxicity and weight gain?

  • Is there less weight gain with two-drug therapy and should we be

thinking about this for selected patients (e.g. DTG/3TC, DTG/RPV)?

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Back to the case…

  • 37 year old man with a recent diagnosis of HIV (CD4 280, VL 20,000)

who is presenting to establish care. He has hypertension and takes hydrochlorothiazide “most of the time”. HLA-B*5701 is negative. He is worried about weight gain

  • Did your answer change?
  • A. DTG + TAF/FTC
  • B. DTG + TDF/FTC
  • C. DTG/3TC/ABC
  • D. BIC/TAF/FTC
  • E. DRV/c/TAF/FTC

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Answer: A-E are all reasonable options

We will be discussing further in the debate!

  • A. DTG + TAF/FTC
  • B. DTG + TDF/FTC
  • C. DTG/3TC/ABC
  • D. BIC/TAF/FTC
  • E. DRV/c/TAF/FTC

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Thank you!

Many thanks to the conference organizers for the opportunity to speak and to everyone who helped me prepare this talk:

Matt.Hickey@ucsf.edu

Diane Havlir Annie Luetkemeyer Carina Marquez Vivek Jain Ayesha Appa Meg Newman Ashley McMullen

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