Dolutegravir transition and weight gain: an update - Aug 2020
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Dolutegravir transition and weight gain:
an update
Aug 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
TAF/FTC+DTG
N=351
TDF/FTC+DTG
1053 Participants
N=351
TDF/FTC/EFV
N=351
96 weeks
Open-label, 96-week study in Johannesburg, South Africa
Study visits at Baseline, Week 4, 12, 24, 36, 48, 60, 72, 84, and 96
And representative by race and gender and geography
Baseline characteristics (1/2)
TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV
Characteristic
(n=351) (n=351) (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),
349 ± 225 323 ± 234 337 ± 222
cells/mm3
Weight was high even pre-ART!
Baseline characteristics (2/2)
TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV
Characteristic
(n=351) (n=351) (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%)
Mean change in weight (kg) to Week 96: women
14
+12,3 kg
12 TAF/FTC+DTG
10 +8,2 kg
Weight (kg)
8 +7,4 kg
TDF/FTC+DTG
6 +4,6 kg +5,5 kg
TDF/FTC/EFV
4 +3,2 kg
2
0
n= 0 4606 12
590 24
563 36
546 48
532 60
519 72
513 84
506 96
493 108
379 120
164 132
206 144
152
Week
Mean change in weight (kg) to Week 96: men
9
+7,2 kg
7
TAF/FTC+DTG
+5,2 kg +5,5 kg
Weight (kg)
5 TDF/FTC+DTG
+3,6 kg
3 +2,6 kg
+1,4 kg TDF/FTC/EFV
1
-1
0 4 12 24 36 48 60 72 84 96 108 120 132 144
n= 419 403 388 377 375 369 357 355 344 292 119 144 113
Week
Treatment-Emergent Obesity at Week 96
30 27%
Percent of patients (%)
25
20 17%
15
11%
10 7%
5 3% 2%
0
Women Men
TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV% Weight Change from Baseline to Week 144
Females Males
20 + 18.3%
Weight change from
baseline (%)
15
+ 11.1% + 10.6%
10 +8.6%
+7.7%
5 + 3.9%
0
0
4
12
24
36
48
60
72
84
96
108
120
132
144
Week Week
-5 TAF/FTC + DTG TDF/FTC + DTG TAF/FTC + DTG TDF/FTC + DTGLinear regression model: predicted mean percentage
change in weight from baseline over 5 years in females
40
35
Weight gain from baseline (% )
+32.2
30
%
25
20 +18.7%
15 +14.9%
10
5
0
0
4
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
192
204
216
228
240
252
264
-5
Week
Predicted: TAF arm Predicted: TDF armPredicted 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,
NetherlandsQDIABETES Equation Results: Females (Linear Predictions)
Median change from baseline to:
Treatment arm / 10
year diabetes risk Week 96
Baseline Year 3 Year 4 Year 5
(Observed)
TAF/FTC/DTG 0.30% +1.20% +1.40% +2.00% +2.50%
n = 120
TDF/FTC/DTG 0.40% +0.50% +0.60% +0.90% +1.30%
n = 111
TDF/FTC/EFV 0.30% +0.80% +1.00% +1.30% +1.50%
n = 116
*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)
12 additional cases of diabetes in TAF vs TDF per 1000 females over 30 treated for 5 yearsOPERA: 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
Anchor Agent by Class, % (n) Maintained Other ARVs (n = 5479)
Elvitegravir/cobicista
73 (2389)
t
INSTIs (n = 3281) 20 (643)
Dolutegravir
8 (249)
Raltegravir
Rilpivirine 85 (1238)
Nevirapine 12 (176)
NNRTIs (n = 1452)
Efavirenz 2 (26)
Etravirine 1 (12)
Darunavir 68 (504)
Atazanavir 28 (211)
Boosted PIs (n = 746)
Lopinavir 3 (22)
Mallon. AIDS 2020. Abstr OAB0604. Fosamprenavir 1 (9) Slide credit: clinicaloptions.comOPERA: Weight Change With Switch From TDF to TAF
While Also Switching to an INSTI
92 Estimated Weight
90 Δ by Time From EVG/c DTG BIC
88 DTG TDF to TAF Switch, (n = 1120) (n = 174) (n = 129)
EVG/c kg/yr (95% CI)
Weight (kg)
86
0.24 0.22 0.01
84 -60 to 0 mos
BIC (0.04 to 0.43) (-0.08 to 0.52) (-0.38 to 0.39)
82
2.55 3.09 4.47
80 0 to 9 mos
(1.86 to 3.24) (1.26 to 4.93) (0.81 to 8.13)
78
-9.97
0.26 -0.23
0 9+ mos (-23.79 to
(-0.10 to 0.61) (-1.62 to 1.16)
-60-54 -48 -42 -36-30-24-18 -12 -6 0 6 12 18 24 30 36 42 48 3.85)
Mos From Switch
Mallon. AIDS 2020. Abstr OAB0604. Reproduced with permission. Slide credit: clinicaloptions.comIntegrase inhibitors associated with
larger rises in weight
Sax et al Clin Inf Dis Sept 2019Dolutegravir and bictegravir associated with largest
rises in weight
Sax et al Clin Inf Dis Sept 2019CYP2B6 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
• ResearchersPeople 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 groupConclusion
• 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 neededAfrican HIV Burden
First-line for >30 million people…
TDF XTC EFV
Desirable Property EFV/TDF/FTC
High resistance barrier No
Well tolerated Not initially Toxicity driver
Toxicity No lab tox monitoring TDF creat Pill size
Pill size Safe in pregnancy Yes Low genetic barrier
Cost Low pill burden Yes FDC Cost
Once a day Yes Contraception drug
Use with TB (rif) Yes interactionsWhy 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 blushWhy 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/HE2ROWHO 2019 guidelines
Population First-line regimens Second-line regimens Third-line regimens
Adults and adolescents Two NRTIs + DTG Two NRTIs + (ATV/r or LPV/r)
(incl. women of childbearing
potential and Two NRTIs + EFV Two NRTIs + DTG
pregnant women)
DRV/r + DTG + 1–2 NRTIs
(if possible, consider
optimisation using
Children (0–10 years) Two NRTIs + DTG Two NRTIs + (ATV/r or LPV/r)
genotyping)
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 2018What about drug interactions?
InSTI Backbone Key drug interactions
Polyvalent cation–containing
All regimens supplements/medication
(including antacids), rifampicin
BIC FTC/TAF Metformin
ABC/3TC
FTC/TAF Metformin
DTG FTC/TDF
RPV Metformin, PPIs
EVG/ FTC/TAF
Statins, inhaled/injected/systemic steroids
COBI FTC/TDF
FTC/TAF
RAL
FTC/TDFTB: DTG and rifampicin
DTG 50 mg 12 hourly + rifampicin
DTG concentration
DTG 50 mg daily
Time after dose (h)
AUC0-24 DTG 50 mg/d 32.1
DTG 50 mg 12 hourly + rifampicin 42.6
Dooley KE et al, JAIDS 2013;62:21−7Ceiling 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
Historical launch prices for new regimens
2002 2006 2010 2018
d4T/3TC/NVP AZT/3TC/NVP TDF/3TC/EFV TDF/3TC/DTG
$280 $240 $300 $75
• 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.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 transitionNew drugs in the REAL real world…
Discontinuation due to
neuropsychiatric AE Factors associated with DTG discontinuation
AIDS 2016
Hoffmann et al. HIV Medicine 2017; Libre et al. CROI 2017 abstract #615; Hsu et al. CROI 2017 abstract #664DTG in the real world…
Discontinuation due to Factors associated with DTG
neuropsychiatric AE discontinuation
Hoffmann et al. HIV Medicine 2017; Libre et al. CROI 2017 abstract
#615;
Hsu et al. CROI 2017 abstract #664The recent signal
• 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
NTDs: neural tube defects
Zash R, et al.AIDS 2018 Session TUSY15.Efavirenz controversy: conflicting evidence
Preclinical data Clinical data: T1 EFV exposure
• NTDs in primate study • 4 retrospective
• 1 prospective
case report of NTDs
in humans
Meta analysis (2011):
1 NTD
Incidence: 0.7 (95% CI 0.002 – 0.39%)
= NO association
1. Ford N, et al. AIDS. 2011;25:2301-2304. .Overall health benefit
DALYs and cost-adjusted (net) DALYs averted per year compared with TLE
Policy option
net DALYs
TLE DALYs
TLD VL dependent in men /
TLE in women
TLD in men / TLE in women
TLD VL dependent
TLD
Number
mean over 3 month periods from 2018-2038; cost adjustment based on cost effectiveness threshold $500 / DALY avertedTsepamo Update: Prevalence of NTDs by ARV Exposure
Conception Pregnancy
HIV Negative
Parameter DTG Non-DTG EFV DTG (n = 119,630)
(n = 3591) (n = 19,361) (n = 10,958) (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 0.30 0.10 0.04 0.03 0.08
(0.13-0.69) (0.06-0.17) (0.01-0.11) (0.00-0.15) (0.06-0.10)
April 2020 0.19 0.11 0.07 0.04 0.07
(0.09-0.40) (0.07-0.17) (0.03-0.17) (0.01-0.16) (0.06-0.09)
Prevalence diff. with DTG
0.09 0.12 0.15 0.12
conception, Apr 2020, % (95% Ref
(-0.03 to 0.30) (0 to 0.32) (0 to 0.36) (0.01 to 32.0)
CI)
NTDs per exposures between
2/1908* 6/4569 5/2999 1/741 17/30,258
April 2019 and April 2020, n/N
Zash. AIDS 2020. Abstr OAXLB01. Slide credit: clinicaloptions.com
*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
TAF/FTC+DTG TDF/FTC+DTG TDF/FTC/EFV
Baseline
APO 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 0So 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
↓ chance of transmitting resistant virus
Improve adherence • Strengthen adherence support
Potent fixed-dose • Suppress HIV-RNA
combination • High adherence
regimens
• Promptly switch individuals with confirmed VF to • Which is
second-line treatment the more
VL monitoring
• Minimize time spent on a failing regimen with cost-
resistant virus effective
• Perform viral load monitoring strategy?
• HIV-DR testing with failure
Use agents with • Change first-line regimen at a national level,
high genetic barrier from an NNRTI-based regimen to DTG- or bPI–
based regimen
http://apps.who.int/iris/bitstream/handle/10665/255896/9789241512831-eng.pdfConclusions 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!
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