Dolutegravir transition and weight gain:

an updateAug 2020

Professor Francois Venter

Ezintsha, University of the Witwatersrand

Case studies: (1)

• 1) A healthy person starts the new dolutegravir-containing regimen. They gain 20kg, and are classified “obese”, but there are no other complications. The person is satisfied and wants to continue the treatment, but the nurse is worried.

Case studies (2)

• Previous case but:• Person now morbidly obese, with hypertension and has

developed diabetes;

• Nurse insisting on taking her off treatment, but she is saying she is happy with her weight and gaining more and is fine with the risk.

• What to do?

ADVANCE: Study design

Inclusion criteria: treatment-naïve, HIV-1 RNA level ≥ 500 copies/mL, no TB or

pregnancy, no baseline genotyping

Open-label, 96-week study in Johannesburg, South Africa

Study visits at Baseline, Week 4, 12, 24, 36, 48, 60, 72, 84, and 96

1053 Participants

TAF/FTC+DTG

N=351

TDF/FTC/EFV

N=351

TDF/FTC+DTG

N=351

96 weeks

Baseline characteristics (1/2)

CharacteristicTAF/FTC+DTG

(n=351)

TDF/FTC+DTG

(n=351)

TDF/FTC/EFV

(n=351)

Age, mean (SD), years 33 ± 8 32 ± 8 32 ± 7

Female 61% 59% 57%

Black 99% 100% 100%

Baseline HIV-1 RNA

≤100,000 copies/mL 78% 80% 77%

>100,000 copies/mL 22% 20% 23%

CD4+ cell count, mean (SD),

cells/mm3349 ± 225 323 ± 234 337 ± 222

And representative by race and gender and geography

Baseline characteristics (2/2)

CharacteristicTAF/FTC+DTG

(n=351)

TDF/FTC+DTG

(n=351)

TDF/FTC/EFV

(n=351)

Weight, mean (kg)

Male 67.9 67.1 67.3

Female 68.8 69.5 70.2

BMI, mean (kg/m2)

Male 21.7 21.6 21.8

Female 25.6 26.1 26.1

Categories of BMI, n (%)

Underweight (< 18.5) 42 (12%) 35 (10%) 37 (11%)

Normal (18.5-25) 177 (51%) 190 (54%) 193 (55%)

Overweight (25-30) 96 (27%) 78 (22%) 77 (22%)

Obese (> 30) 35 (10%) 48 (14%) 44 (13%)

Weight was high even pre-ART!

Mean change in weight (kg) to Week 96: women

n= 606 590 563 546 519532 206 152513 379 164506 493

+8,2 kg

+12,3 kg

TAF/FTC+DTG

+4,6 kg

+7,4 kg

TDF/FTC+DTG

+3,2 kg

+5,5 kg TDF/FTC/EFV

0 4 12 24 36 48 60 72 84 96 108 120 132 144

0

2

4

6

8

10

12

14

Wei

gh

t (k

g)

Week

+5,2 kg

+7,2 kg

TAF/FTC+DTG

+3,6 kg

+5,5 kg

TDF/FTC+DTG

+1,4 kg

+2,6 kg TDF/FTC/EFV

0 4 12 24 36 48 60 72 84 96 108 120 132 144-1

1

3

5

7

9

Wei

gh

t (k

g)

Week

Mean change in weight (kg) to Week 96: men

n= 419 403 388 377 369375 144 113357 292 119355 344

Treatment-Emergent Obesity at Week 96

27%

7%

17%

3%

11%

2%

0

5

10

15

20

25

30

Women Men

Pe

rce

nt

of

pa

tie

nts

(%

)

TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV

% Weight Change from Baseline to Week 144

-5

0

5

10

15

20

0 4

12

24

36

48

60

72

84

96

108

120

132

144

Weig

ht

change f

rom

baselin

e (

%)

Week

TAF/FTC + DTG TDF/FTC + DTG

+ 11.1%

+ 18.3%

+7.7%

Week

TAF/FTC + DTG TDF/FTC + DTG

+ 10.6%

+8.6%

+ 3.9%

MalesFemales

Linear regression model: predicted mean percentage

change in weight from baseline over 5 years in females

-5

0

5

10

15

20

25

30

35

40

0 4

12

24

36

48

60

72

84

96

10

8

12

0

13

2

14

4

15

6

16

8

18

0

19

2

20

4

21

6

22

8

24

0

25

2

26

4

We

igh

t g

ain

fro

m b

ase

line

(%

)

Week

Predicted: TAF arm Predicted: TDF arm

+32.2%

+18.7%

+14.9%

Predicted 10-year risks of diabetes and cardiovascular disease

in the ADVANCE trial

Andrew Hill1, Kaitlyn McCann2, Ambar Qavi2, Bryony Simmons2 ,Victoria Pilkington2,Michelle Moorhouse3, Godspower Akopmiemie3, , Simiso Sokhela3, Celicia Serenata3, Alinda Vos4,

Francois Venter3

1 Liverpool University, Pharmacology, Liverpool, United Kingdom, 2 Imperial College London, Faculty of Medicine, London, United Kingdom 3 Ezintsha, Wits Reproductive Health and HIV Institute, Johannesburg, South Africa; 4 University Medical Center Utrecht, Epidemiology, Utrecht,

Netherlands

QDIABETES Equation Results: Females (Linear Predictions)

*TAF/FTC/DTG risk significantly higher than TDF/FTC/DTG at Week 96 (p=0.028); Year 3 (p= 0.025); Year 4 (p= 0.015); Year 5 (p= 0.014)

Treatment arm / 10 year diabetes risk

Median change from baseline to:

Baseline Week 96 (Observed)

Year 3 Year 4 Year 5

TAF/FTC/DTGn = 120

0.30% +1.20% +1.40% +2.00% +2.50%

TDF/FTC/DTGn = 111

0.40% +0.50% +0.60% +0.90% +1.30%

TDF/FTC/EFVn = 116

0.30% +0.80% +1.00% +1.30% +1.50%

12 additional cases of diabetes in TAF vs TDF per 1000 females over 30 treated for 5 years

OPERA: Longitudinal Prospective Cohort Analysis

Routine EHR data collected from ~ 8% of US PWH receiving care (> 115,000 individuals across 65 cities in 19 states and Puerto Rico)

Current analysis restricted to adults receiving TDF-containing 3-drug ART at BL with ≥ 2 consecutive HIV-1 RNA < 200 copies/mL who switched TDF to TAF

Mallon. AIDS 2020. Abstr OAB0604. Slide credit: clinicaloptions.com

Anchor Agent by Class, % (n) Maintained Other ARVs (n = 5479)

INSTIs (n = 3281)

Elvitegravir/cobicista

t

Dolutegravir

Raltegravir

73 (2389)

20 (643)

8 (249)

NNRTIs (n = 1452)

Rilpivirine

Nevirapine

Efavirenz

Etravirine

85 (1238)

12 (176)

2 (26)

1 (12)

Boosted PIs (n = 746)

Darunavir

Atazanavir

Lopinavir

Fosamprenavir

68 (504)

28 (211)

3 (22)

1 (9)

OPERA: Weight Change With Switch From TDF to TAF

While Also Switching to an INSTI

Mallon. AIDS 2020. Abstr OAB0604. Reproduced with permission. Slide credit: clinicaloptions.com

Mos From Switch

We

igh

t (k

g)

92

90

88

86

84

82

80

78

0-60-54 -48-42 -36-30-24-18-12 -6 0 6 12 18 24 30 36 42 48

EVG/c

BIC

DTG

Estimated Weight

Δ by Time From

TDF to TAF Switch,

kg/yr (95% CI)

EVG/c

(n = 1120)

DTG

(n = 174)

BIC

(n = 129)

-60 to 0 mos0.24

(0.04 to 0.43)

0.22

(-0.08 to 0.52)

0.01

(-0.38 to 0.39)

0 to 9 mos2.55

(1.86 to 3.24)

3.09

(1.26 to 4.93)

4.47

(0.81 to 8.13)

9+ mos0.26

(-0.10 to 0.61)

-0.23

(-1.62 to 1.16)

-9.97

(-23.79 to

3.85)

Integrase inhibitors associated with larger rises in weight

Sax et al Clin Inf Dis Sept 2019

Dolutegravir and bictegravir associated with largest rises in weight

Sax et al Clin Inf Dis Sept 2019

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz

Rulan Griesel, Gary Maartens, Simiso Sokhela, Godspower Akpomiemie, Francois Venter, Michelle Moorhouse, Phumla Sinxadi

How on earth did we get here?

• Uganda/ US/ UK – ‘higher life expectancy that matched populations

• HIV positive people are going to get old

Thanks: Julie Fox, Guys

So HIV-positive people are leading normal lives – which means they will gain weight

Lots of people stand to gain or lose from this being a side effect

• Pharmaceutical companies

• Governments, donors and budgets

• Researchers

People make a LOT of money from making you feel horrible about your

body – implicated in everything from depression to anorexia

And we aren’t really sure what is a “healthy diet”

Nature, 2013

Weight is culturally sensitive…

• Different communities = different perceptions of what is healthy, desirable, sexy

• Stigma that skinny = HIV, TB, other illness

• Advertising and magazines – steadily skinnier models

• Self-perception is important (and flawed)

But obesity IS an issue…

“The associations of both overweight and obesity with

higher all-cause mortality were broadly consistent in four

continents.”

Being obese is linked to lots of issues

• Diabetes (glucose)

• Hypertension (blood pressure)

• Lipids (cholesterol, LDL (‘bad cholesterol’)

• Strokes

• Heart attacks

• Cancer

• Joint pain

• Mental health issues

• Poor COVID outcomes

Conference on Retroviruses and Opportunistic Infections 2020

CHANGES IN BODY MASS INDEX AND THE RISK OF

CARDIOVASCULAR DISEASE: THE D:A:D STUDY

Kathy Petoumenos, Locadiah Kuwanda, Lene Ryom, Amanda Mocroft, Peter

Reiss, Stephane De Wit, Christian Pradier, Andrew Philips, Camilla I

Hatleberg, Antonella d’Arminio Monforte, Rainer Weber, Caroline Sabin, Jens

Lundgren, Matthew G Law

On behalf of the D:A:D Study group

Conclusion

• Increases in BMI across all levels of baseline BMI were consistently associated with increased risk of DM

• Increases in BMI across all levels of baseline BMI were not associated with an increased risk of CVD

Some evidence of an increased risk of CVD with a decrease in BMI (especially at low baseline BMI)

• The extent to which these results apply to PLHIV with increased weight while receiving contemporary ART are uncertain

• Further analysis of weight change, INSTI/TAF and clinical events is needed

African HIV Burden

First-line for >30 million people…

XTCTDF EFV

Toxicity driver

Pill size

Low genetic barrier

Cost

Contraception drug

interactions

Desirable Property EFV/TDF/FTC

High resistance barrier No

Well tolerated Not initially

No lab tox monitoring TDF creat

Safe in pregnancy Yes

Low pill burden Yes FDC

Once a day Yes

Use with TB (rif) Yes

Toxicity

Pill size

Cost

Why INSTI?

• All well tolerated

• Highly effective

• New reference for ‘’third drug’’

Which INSTI agents are we talking about?

• Raltegravir • Well studied, relatively widely registered

• Can be used in paeds (>4 weeks)

• Had a role in PEP, Rx

• Expensive, high mg, twice daily till recently, no FDC

• Use in lower income countries largely confined to third line

• Unlikely to change in next 5 years – cost, co-formulation, TB, resistance barrier

• Role in children

• ? Any role in adults

• Elvitegravir • QUAD-Stribild

• First drug registered as FDC

• ’Boosted’’ – lots of drug interactions

• Limited registration, Gilead drug

• Expensive, but potential for price reduction

• Unlikely to change in next 5 years – cost, TB, pregnancy

• In fact, unlikely to be around!

• Bictegravir• Very similar to dolutegravir

• Co-formulated with TAF

• Very limited data in Africa

• Almost no pregnancy data

• TB data – high drug interaction potential

• ?role in our setting

• Cabotegravir

• Phase 2-3 as prevention and treatment

• Injectable

• 4 or 8 weekly

• For treatment: switch strategy with injectable rilpivirine

• Remarkably well tolerated! May be a more popular than first blush

Why dolutegravir?

• Very well tolerated

• Highly effective• Low mg, co-formulation with TDF and TAF by generics (ABC

co-formulation registered)

• Resistance profile compelling

• Creatinine clearance issue?

• TB a problem, but ?double dosing

“Dolutegravir in first line therapy has by far the highest impact in getting to the last 90 for South Africa”

Professor Gesine Meyer-Rath -Boston

University/HE2RO

WHO 2019 guidelines

Population First-line regimens Second-line regimens Third-line regimens

Adults and adolescents

(incl. women of childbearing

potential and

pregnant women)

Two NRTIs + DTG Two NRTIs + (ATV/r or LPV/r)

DRV/r + DTG + 1–2 NRTIs

(if possible, consider

optimisation using

genotyping)

Two NRTIs + EFV Two NRTIs + DTG

Children (0–10 years) Two NRTIs + DTG Two NRTIs + (ATV/r or LPV/r)

Two NRTIs + LPV/r Two NRTIs + DTG

Two NRTIs + NNRTI Two NRTIs + DTG

• Guidelines include recommendations on the selection of ARV drugs in response to high levels of

DR1

− Recommend countries consider changing their first-line ART regimens away from NNRTIs if

levels of NNRTI DR reach 10%

1. http://www.who.int/hiv/pub/arv/arv-2016/en/World Health Organization. HIV treatment interim guidance. Accessed August 2018

What about drug interactions?

InSTI Backbone Key drug interactions

All regimens

Polyvalent cation–containing

supplements/medication

(including antacids), rifampicin

BIC FTC/TAF Metformin

DTG

ABC/3TC

FTC/TAF

FTC/TDF

Metformin

RPV Metformin, PPIs

EVG/

COBI

FTC/TAFStatins, inhaled/injected/systemic steroids

FTC/TDF

RALFTC/TAF

FTC/TDF

DTG 50 mg daily

TB: DTG and rifampicin

Dooley KE et al, JAIDS 2013;62:21−7

AUC0-24 DTG 50 mg/d 32.1

DTG 50 mg 12 hourly + rifampicin 42.6

DTG 50 mg 12 hourly + rifampicin

DT

G c

on

cen

tra

tio

n

Time after dose (h)

Ceiling price agreement announced

• This ceiling price agreement could yield billions of rand in savings through TLD rollout and enable widespread access to a clinically superior regimen

• The TLD agreement lasts four years: 01 April 2018 – 31 March 2022

• Applies to over 90 countries

• Results of collaboration from many partners: Governments of Kenya and South

Africa, the Bill & Melinda Gates Foundation; Clinton Health Access Initiative;

Global Fund to Fight AIDS, Tuberculosis and Malaria; President’s Emergency

Plan for AIDS Relief (PEPFAR); United Kingdom’s Department for International

Development; Unitaid; UNAIDS; and USAID, with Mylan Laboratories and

Aurobindo Pharma.

2002

d4T/3TC/NVP

$280 $240 $300 $75

Historical launch prices for new regimens2006

AZT/3TC/NVP

2010

TDF/3TC/EFV

2018

TDF/3TC/DTG

Works in first line, works in second line….

• Cheaper and better!

• Massive move to DTG – double dose in TB, safe if started in pregnancy

• Investment by PEPFAR, Global Fund, other agencies –unprecedented switch

• 2 million in Africa on DTG/TDF/3TC often in absence of VL

• 3-4 million South Africans about to transition

New drugs in the REAL real world…

Discontinuation due to neuropsychiatric AE

Factors associated with DTG discontinuation

Hoffmann et al. HIV Medicine 2017; Libre et al. CROI 2017 abstract #615; Hsu et al. CROI 2017 abstract #664

AIDS 2016

DTG in the real world…

Discontinuation due to neuropsychiatric AE

Factors associated with DTG discontinuation

Hoffmann et al. HIV Medicine 2017; Libre et al. CROI 2017 abstract

#615;

Hsu et al. CROI 2017 abstract #664

The recent signal

Zash R, et al.AIDS 2018 Session TUSY15.

NTDs: neural tube defects

• 4 cases of severe NTDs among 426 women in women on DTG periconception

• Approx 45% of all births• ± 600 more exposures

• 0.9% versus 0.1%

• No clear time trend or obvious explanation

Efavirenz controversy: conflicting evidence

Preclinical data

• NTDs in primate study

Clinical data: T1 EFV exposure

• 4 retrospective • 1 prospective

case report of NTDs in humans

1. Ford N, et al. AIDS. 2011;25:2301-2304. .

Meta analysis (2011):

1 NTD

Incidence: 0.7 (95% CI 0.002 – 0.39%)

= NO association

Overall health benefit DALYs and cost-adjusted (net) DALYs averted per year compared with TLE

mean over 3 month periods from 2018-2038; cost adjustment based on cost effectiveness threshold $500 / DALY averted

Policy option

TLE

TLD VL dependent in men /

TLE in women

TLD in men / TLE in women

TLD VL dependent

TLD

Number

net DALYs

DALYs

Tsepamo Update: Prevalence of NTDs by ARV Exposure

Zash. AIDS 2020. Abstr OAXLB01. Slide credit: clinicaloptions.com

Parameter

Conception PregnancyHIV Negative

(n = 119,630)DTG

(n = 3591)

Non-DTG

(n = 19,361)

EFV

(n = 10,958)

DTG

(n = 4581)

Total NTDs per exposures, n/N 7/3591 21/19,361 8/10,958 2/4581 87/119,630

NTD prevalence, % (95% CI)

April 2019

April 2020

0.30

(0.13-0.69)

0.19

(0.09-0.40)

0.10

(0.06-0.17)

0.11

(0.07-0.17)

0.04

(0.01-0.11)

0.07

(0.03-0.17)

0.03

(0.00-0.15)

0.04

(0.01-0.16)

0.08

(0.06-0.10)

0.07

(0.06-0.09)

Prevalence diff. with DTG

conception, Apr 2020, % (95%

CI)

Ref0.09

(-0.03 to 0.30)

0.12

(0 to 0.32)

0.15

(0 to 0.36)

0.12

(0.01 to 32.0)

NTDs per exposures between

April 2019 and April 2020, n/N2/1908* 6/4569 5/2999 1/741 17/30,258

*Includes 1 lumbosacral myelomeningocele (spina bifida) and 1 encephalocele.

Weight gain likely to have a much greater impact…

On pregnancy outcomes than DTG teratogenicity!

Predicting the risk of adverse pregnancy outcomes due to ART-induced weight gain

Sumbul Asif1, Evangelina Baxevanidi1, Andrew Hill2, Celicia Serenata3, WD Francois Venter3,

Lee Fairlie3, Masebole Masenya3, Nomathemba Chandiwana3, Simiso Sokhela3

1. Imperial College London, Faculty of Medicine, London, United Kingdom, 2. Liverpool University, Department of Translational Medicine, Liverpool, United Kingdom, 3. Ezintsha, Wits RHI, University of the Witwatersrand, Johannesburg, South Africa

APO

Baseline TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV

96-weeks 96-weeks 96-weeks

Preterm delivery 70 73 71 70

Gestational Hypertension 28 39 34 29

Gestational diabetes mellitus 16 23 19 16

Pre-eclampsia 25 35 30 26

Postpartum haemorrhage 112 115 114 112

Caesarean section 213 232 224 215

Small-for-gestational-age infants 89 87 88 89

Large-for-gestational-age infants 134 154 145 137

Low birthweight infants 64 65 64 64

Macrosomia 31 37 34 31

Stillbirth 4 4 4 4

Neonatal death 2 2 2 2

Neural tube defect 0 0 0 0

So what are the issues in moving from EFV to DTG?

• Resistance – what if failing virologically?

• Side effects• Pregnancy – issues re teratogenicity

• CNS

• Weight gain

• Cape Town model – if you act on detectable viral loads FAST, >1/2 will suppress!

Outcomes after HIV RNA >50 at Week 48

TAF/FTC + DTG arm

Outcomes after HIV RNA >50 at Week 48

TDF/FTC + DTG arm

Proportion of participants with HIV-1 RNA level

But…

• Deenan Pillay (CID): Rising NNRTI resistance in

large rural community, poor virological outcomes

• But didn’t affect response to NNRTI-based

treatment!

Addressing pretreatment TDR

Potent fixed-dose

combination

regimens

• Suppress HIV-RNA

• High adherence

• Promptly switch individuals with confirmed VF to

second-line treatment

• Minimize time spent on a failing regimen with

resistant virus

• Perform viral load monitoring

• HIV-DR testing with failure

VL monitoring

• Change first-line regimen at a national level,

from an NNRTI-based regimen to DTG- or bPI–

based regimen

Use agents with

high genetic barrier

• Which is the more cost-effective strategy?

Improve adherence • Strengthen adherence support

↓ chance of transmitting resistant virus

http://apps.who.int/iris/bitstream/handle/10665/255896/9789241512831-eng.pdf

Conclusions for me

• Weight gain is real – definitely associated with DTG, and with TAF

• DTG may not be as perfect as we hoped – but at the moment, only have efavirenz!

• No data on what to do if someone is gaining weight on either DTG or EFV (or anything else)

• When can we say “too much weight” and stop treatment (against the patient’s wishes)?

• Summary: switch when VL undetectable ideally (in context of drug stock outs); counsel re side effects –and probably try EFV/rilp until newer drugs come out

Thank you!