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UK CAB 2018
Dr Nadine Chamay, PhD
Medical Advisor
ViiV Healthcare, UK
UK/HIVP/0009/18
Date of preparation October 2018
Rationale for 2DR
Agenda
2DR, the rationale
o Gemini 1&2
o SWORD 1&2
Pregnancy: an update
ViiV pipeline
Your questions
TPV
ETR
1987 1988…1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
AZT
SQV
RTV
IDV
Core agents
Backbone therapies
NVP
NFV*EFV
APV*LPV
ENF
EVGDTG
ATV
FPV
DRV
MVC
RAL
ddC*
Year of EMA approval of ARVs used in the treatment of HIV
d4T
3TC ABCddl
TDFFTC
TAF
Evolution of the backbone 1987–1996 HAART: Rise of the core agents 1996–2007 Core agents driving advancements 2007+
10
No.
of b
ackb
one
agen
ts d
evel
oped
No.
of c
ore
agen
ts d
evel
oped
8
6
4
2
0
0
2
4
6
8
10
12
14
16
18
20
*No longer marketed in the European Union
Licence dates from individual SmPCs, available upon request
RPV
The evolution of new ARV agents
ABC, abacavir; APV, amprenavir; ARV, antiretroviral; ATV, atazanavir; AZT, azidothymidine;
d4T, stavudine; ddC, zalcitabine; ddl, didanosine; DRV, darunavir; DTG, dolutegravir; EMA,
European Medicines Agency; ENF, enfuvirtide; ETR, etravirine; EFV, efavirenz; EVG,
elvitegravir; FPV, fosamprenavir; FTC, emtricitabine; HAART, highly active antiretroviral
therapy; IDV, indinavir; LPV, lopinavir; MVC, maraviroc; NFV, nelfinavir; NVP, nevirapine;
RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; SQV, saquinavir; TAF, tenofovir alafenamide;
TDF, tenofovir disoproxil fumarate; TPV, tipranavir; 3TC lamivudine
*No longer available in the European Union
Why 2DR?
AE, adverse event; DDI, drug-drug interaction; HCP, healthcare professional; SoC, standard of care
Reduce potential impact of long-term
exposure to multiple ARVs
Less potential for AEs?
“As much as needed, as little as possible”
“Why take 3 (or 4), when 2 can do?”
Why 2DR?
Potential to reduce DDIs
Ageing patients
Co-morbidities
Potential preservation of future
treatment options
Clinical profile of newer agents allow
us to investigate 2DR
High expectations – HCPs and patients
Establishing new treatment paradigms
and evolving the SoC
Costs
ART, antiretroviral therapy; ARV, antiretroviral; EFV, efavirenz; FDA, Food and Drug Administration; FTC, emtricitabine; HAART, highly active antiretroviral therapy; INI, integrase
inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor; TDF, tenofovir disoproxil fumarate.
Adapted from: 1. Lacey et al. Available from: http://truvenhealth.com/Portals/0/Assets/Life-Sciences/White-Papers/pharma-innovation-hiv-aids-treatment.pdf. 2. Palmisano et al. Ann Ist
Super Sanità 2011;47:44–8. 3. Drugs.com. Available from https://www.drugs.com/history/atripla.html. 4. Drugs.com. Available from: https://www.drugs.com/history/isentress.html. 5.
Drugs.com. Available from: https://www.drugs.com/newdrugs/fda-approves-tivicay-dolutegravir-hiv-infection-3867.html. All URLs accessed May 2018.
Significant medical advances in HIV therapy have
changed the focus from saving lives to chronic
management1
1987The first ARV, an
NRTI, is approved,
for the treatment of
HIV2
1995–1996The introduction
of third agents
marked the
beginning of the era
of HAART2
2006The FDA approves the
single-tablet triple
regimen
(EFV/FTC/TDF)3
2007The FDA approves
the first INI,
raltegravir4
2013The first ARV with head-to-
head data in multiple patient
populations at approval
launches, dolutegravir5
2018A new advance in
HIV management
Antiretroviral therapy coverage and number
of AIDS-related deaths, globally, 2000–2015
Adapted from: Global AIDS Update 2016, UNAIDS 2016.
An
tire
tro
vir
al
the
rap
y c
ove
rag
e (
%)
Nu
mb
er
of
AID
S-r
ela
ted
de
ath
s (
mil
lio
ns
)
Life expectancy among PLHIV is
approaching normal
ART, antiretroviral therapy; ARV, antiretroviral; PLHIV, people living with HIV.
Adapted from: 1. Antiretroviral Therapy Cohort Collaboration. Lancet HIV 2017;4:e349–56. 2. Marcus et al. JAIDS 2016;73:39–46. 3. Nakagawa et al. AIDS 2012;26:335–43.
Life expectancy in patients on ART has increased to near normal1
However, even with early treatment and access to care, an 11.8-year
gap in life expectancy remains for HIV-infected compared with HIV-
uninfected individuals2
PLHIV will be on ARV therapy for decades; the mean estimated
duration of lifetime treatment in 2012 was 39.1 years3
Adapted from: 1. Hasse et al. Clin Infect Dis 2011;53:1130–9.
Among PLHIV, the prevalence of comorbidities and
comedication use increases with age1
Proportion of patients having ≥ 1 comorbidity or receiving
≥ 1 comedication increased with age1
As part of the Swiss HIV Cohort Study, Hasse et al. investigated how the number of
comorbidities and the number of non-AIDS comedications taken by HIV-positive patients
differed with age (8444 PLHIV in cohort)
Comedications Comorbidities
Age
groups
Age
groups
Pa
rtic
ipa
nts
(%
)
n =
5761
n =
2233
n =
450
n =
5761
n =
2233
n =
450
PLHIV, people living with HIV.
Patients are being exposed to drugs
for decades longer than previously
Boosted triple-therapy regimen
(QD)
Unboosted triple therapy
(QD)
Unboosted 2DR (QD)
No. of drug
doses/year1460 1095 730
No. of drug
doses per
39.1 years1
57,086 42,815 28,543
2DR, two-drug regimen; QD, once-daily.
Adapted from: 1. Nakagawa et al. AIDS 2012;26:335–43.
There are many potential benefits
to reducing ARV drug exposure
AE, adverse event; ARV, antiretroviral.
Adapted from: 1. Saint-Marc et al. AIDS 1999;13:2188–9. 2. Saint-Marc et al. AIDS 1999;13:1659–67. 3. Fris-Moller et al. N Engl J Med 2003;349:1993–2003. 4. D:A:D
Study Group. Lancet 2008;371:1417–26. 5. Cooper et al. Clin Infect Dis 2010;51:496–505. 6. Bedimo et al. AIDS 2012;26:825–31. 7. Lee et al. JAIDS 2013;62:525–33. 8.
Mollan et al. Presented at IDWeek 2013; Abstract 670. 9. Hill. Curr Opin HIV AIDS 2013;8:34–40. 10. Girouard et al. Clin Infect Dis 2016;62:784–91. 11. Eron et al.
Presented at IAS 2017; Slides MOAX0205LB.
Drug preservation
• Preservation of drug effect for
ARVs not included in regimen
Reduced cost9,10
• Reduced drug costs, and long-
term care/societal costs
• Improvements in accessImproved quality of life11
• Improvements in patient
satisfaction
Reduced toxicity and AEs1–8
• Short- and long-term tolerability/AEs
• Unknown toxicities, including organ
dysfunction
Potential benefits of
reducing ARV exposure
ARV, antiretroviral.
Three strategies are being explored
to reduce ARV exposure
1. Dose reduction
2. Reduce the frequencyof drug administration
3. Reduce the number of ARV drugs given
CD4 BINDING
CO-RECEPTOR
BINDING
FUSIONBUDDING
HIV
viron
gp120
CD4
Assembly
Translation
Viral RNAs
Transcription
Proviral DNA
Reverse transcription
of viral RNA genome
Integration
Chemokine
Co-receptor
(CCR5 or
CXCR4)
ssRNA
MATURATION
NEW HIV VIRON
Targeting the HIV life-cycle
CCR5, C-C chemokine receptor type 5; CD4, cluster of differentiation 4; CXCR4,
C-X-C chemokine receptor type 4; ssRNA, single-strand RNA.
Figure adapted from Reyskens et al. Biochim Biophys Acta
2014;1842:256–68.
1Fundación Huésped, Buenos Aires, Argentina; 2Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,
Mexico City, Mexico; 3Hospital La Paz, Madrid, Spain; 4Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani,
Rome, Italy; 5Bliss Healthcare Services, Orlando, FL, USA; 6Royal Sussex County Hospital, Brighton, UK; 7National Taiwan University Hospital, Taipei, Taiwan, Province of China; 8Rheinische Friedrich-Wilhelms Universität,
Bonn, Germany; 9Hôpital Saint Antoine, Paris, France; 10ViiV Healthcare, Research Triangle Park, NC, USA;
11ViiV Healthcare, Brentford, UK; 12GlaxoSmithKline, Stockley Park, UK
Non-Inferior Efficacy of Dolutegravir (DTG) PlusLamivudine (3TC) vs DTG Plus Tenofovir/Emtricitabine (TDF/FTC) Fixed-Dose Combination in Antiretroviral Treatment–Naive Adults With HIV-1 Infection—Week 48 Results From the GEMINI Studies
P. Cahn,1 J. Sierra Madero,2 J. Arribas,3 A. Antinori,4 R. Ortiz,5 A. Clarke,6
C.-C. Hung,7 J. Rockstroh,8 P.-M. Girard,9 C. Man,10 J. Sievers,11 A. Currie,12
M. Underwood,10 A. Tenorio,10 K. Pappa,10 B. Wynne,10 M. Gartland,10
M. Aboud,11 K. Smith10
a−10% non-inferiority margin for individual studies.
Methods: GEMINI-1 and -2 Phase III Study
Design
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
DTG + 3TC (N=716)
Day
1
Screening
(28 d)
Identically designed, randomized, double-blind, parallel-group,
multicentre, non-inferiority studies
DTG + TDF/FTC (N=717)
DTG + 3TC
Week
48
Primary endpoint
at Week 48:
participants with
HIV-1 RNA <50 c/mL
(ITT-E snapshot)a
Double-blind
phase
Open-label
phase
Continuation
phase
CountriesArgentina Australia Belgium
Canada France Germany
Italy Republic of Korea Mexico
Netherlands Peru Poland
Portugal Romania Russian Federation
South Africa Spain Switzerland
Taiwan United Kingdom United States
Week
144
Week
24
Week
96
• ART-naive adults
• VL 1000-500,000 c/mL
1:1
Eligibility criteria• ≤10 days of prior ART
• No evidence of pre-existing viral resistance
based on presence of any major resistance-
associated mutation
• No HBV infection or need for HCV therapy
Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).
Methods: Demographic and Baseline Characteristics for
the Pooled GEMINI-1 and -2 Population
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands.
Slides TUAB0106LB.
Characteristic
DTG + 3TC
(N=716)
DTG + TDF/FTC
(N=717)
Age, median (range), y
≥50 y, n (%)
32.0 (18-72)
65 (9)
33.0 (18-70)
80 (11)
Female, n (%) 113 (16) 98 (14)
Race, n (%)
African American/African heritage
Asian
White
Other
Ethnicity, n (%)
Hispanic or Latino
Not Hispanic or Latino
99 (14)
71 (10)
480 (67)
66 (9)
215 (30)
501 (70)
76 (11)
72 (10)
497 (69)
72 (10)
232 (32)
485 (68)
HIV-1 RNA, median (range), log10 c/mL
≤100,000
>100,000a
4.43 (1.59-6.27)
576 (80)
140 (20)
4.46 (2.11-6.37)
564 (79)
153 (21)
CD4+ cell count, median (range), cells/mm3
>200
≤200
427.0 (19-1399)
653 (91)
63 (9)
438.0 (19-1497)
662 (92)
55 (8)
a2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL
Results: Pooled Snapshot Outcomes at Week
48: ITT-E and Per Protocol Populations
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1
RNA (≤100,000 c/mL vs >100,000 c/mL), CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). bPP, per protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could
potentially affect efficacy outcomes as determined by the medical monitor prior to database lock.
Virologic outcome Adjusted treatment difference (95% CI)a
DTG + TDF/FTC DTG + 3TC
-10 -8 -6 -4 -2 0 2 4 6 8 10
-4.4 1.1
-1.7
Percentage-point difference
DTG + 3TC is non-inferior to DTG +
TDF/FTC with respect to proportion
<50 c/mL at Week 48 (snapshot, ITT-E
population) in both studies
-1.3
-3.9 1.2
ITT-E
PP
91
36
93
25
93
25
94
14
0
20
40
60
80
100
Virologicsuccess
Virologicnonresponse
No virologicdata
HIV
-1 R
NA
<50
c/m
L, %
ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717)
PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693)
Results: Snapshot Analysis by Visit:
Pooled ITT-E Population
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
0
70
85 89
90
93
91 93
72
87 89
88
93
9091
-20
0
20
40
60
80
100
-4 0 4 8 12 16 20 24 28 32 36 40 44 48
HIV
-1 R
NA
<50 c
/mL, %
Study visit
CD4+ cell count (cells/mm3)
Adjusted mean change
from baseline at Week 48a
DTG + 3TC 224
DTG + TDF/FTC 218
DTG + 3TC (n=716)
DTG + TDF/FTC (n=717)
aCalculated from a repeated measures model adjusting for study, treatment, visit (repeated factor), baseline plasma HIV -1 RNA,
baseline CD4+ cell count, treatment and visit interaction, and baseline CD4+ cell count and visit interaction.
98 9898 9899 9897 100
0
20
40
60
80
100
Wit
ho
ut
TR
DF,
%
TRDF Analysis
566
576
>100,000≤100,000 >200 ≤200
Baseline HIV-1
RNA, c/mL
Baseline CD4+
cell count, cell/mm3
Results: Pooled Outcomes at Week 48 Stratified by Baseline
HIV-1 RNA and CD4+ Cell Count: Snapshot and TRDF
Analysis
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands.
Slides TUAB0106LB.
91 9394 9392
79
9093
0
20
40
60
80
100
HIV
-1 R
NA
<5
0 c
/mL
, %
Snapshot Analysis
• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL
• Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal
due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria
• DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB,
Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated)
• DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed)
DTG + 3TC DTG + TDF/FTC
>100,000≤100,000 >200 ≤200
Baseline HIV-1
RNA, c/mL
Baseline CD4+
cell count, cell/mm3
553
564
138
140
149
153
642
653
647
662
62
63
55
55
526
576
531
564
129
140
138
153
605
653
618
662
50
63
51
55
DTG + 3TC CD4 <200 Snapshot non-response (n=13):
o 1 CVW,
o 3 with VL >50 in window (2 of 3 re-suppressed),
o 2 discontinued due to AE (TB, Chagas disease),
o 2 protocol violations
o 2 lost to follow-up
o 1 withdrew consent
o 1 withdrew to start HCV treatment
o 1 change in ART (incarcerated)
DTG + TDF/FTC < 200 Snapshot non-response (n=4):o 1 investigator discretion
o 1 withdrew consent
o 1 lost to follow-up
o 1 VL >50 (re-suppressed)
Results: Confirmed Virologic Withdrawals
Through Week 48: ITT-E Population
GEMINI 1 GEMINI 2 Pooled
Variable, n (%)
DTG + 3TC
(N=356)
DTG +
TDF/FTC
(N=358)
DTG + 3TC
(N=360)
DTG +
TDF/FTC
(N=359)
DTG + 3TC
(N=716)
DTG +
TDF/FTC
(N=717)
CVW 4 (1) 2 (<1) 2 (<1) 2 (<1) 6 (<1) 4 (<1)
Treatment-emergent
resistance
0 0 0 0 0 0
• Low rates of virologic withdrawals were observed at Week 48
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
• No treatment-emergent INSTI mutations or NRTI mutations were
observed among participants who met CVW (confirmed virologic
withdrawal) criteria
Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound. Virologic non-response is defined as either a decrease in
plasma HIV-1 RNA of less than 1 log10 c/mL by Week 12 with subsequent confirmation unless plasma HIV-1 RNA is <200 c/mL, or confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24.
Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL after prior confirmed suppression to <200 c/mL.
.
Results: Adverse Events − Pooled ITT-E
Population
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
n (%)
DTG +
3TC
(N=716)
DTG +
TDF/FTC
(N=717)
Any AE 543 (76) 579 (81)
AE occurring in ≥5% of participants in either group
Headache
Diarrhea
Nasopharyngitis
Upper respiratory tract infection
Nausea
Insomnia
Pharyngitis
Back pain
71 (10)
68 (9)
55 (8)
56 (8)
27 (4)
27 (4)
36 (5)
35 (5)
75 (10)
77 (11)
78 (11)
44 (6)
53 (7)
45 (6)
32 (4)
31 (4)
Drug-related AE
Grade 2-4 AE occurring in ≥1% of participants
Headache
126 (18)
42 (6)
8 (1)
169 (24)
47 (7)
8 (1)
AE leading to withdrawal from the study
Neuropsychiatric AEs leading to withdrawal
15 (2)
6 (<1)
16 (2)
4 (<1)
Any serious AEa 50 (7) 55 (8)
a2 deaths (acute myocardial infarction, n=1; Burkitt’s lymphoma, n=1) in the GEMINI-2 study; both were in the DTG + 3TC group and were
considered unrelated to the study drug regimen.
Results: Change in Renal Biomarkers at
Week 48: Pooled ITT-E Population
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
6.3
10.4
-12.1
4.1
13.5
-15.5
-20
-15
-10
-5
0
5
10
15
Ad
jus
ted
me
an
ch
an
ge f
rom
ba
se
lin
ea
GFR from
cystatin C,
CKD-EPI
(mL/min/
1.73 m2)
GFR from
creatinine,
CKD-EPI
(mL/min/1.73 m2)
Creatinine
(µmol/L)
aEstimated mean change from baseline at Week 48 in each arm calculated from ANCOVA model adjusting for: study, treatment, baseline
plasma HIV-1 RNA, baseline CD4+ cell count, age, sex, race, presence of diabetes mellitus, presence of hypertension, and baseline
biomarker value. Multiple imputed dataset (missing at random). bEstimated from geometric mean ratio for baseline and Week 48.
Plasma/Serum markers
-13.1
-7.4 -7.7
2.9
11.4
31.2
-20
-10
0
10
20
30
40
Ch
an
ge f
rom
ba
se
lin
e, %
b
Urine markers
Protein/
Creatinine
(g/mol)
Retinol-binding
protein/
Creatinine
(µg/mmol)
Beta-2
microglobulin/
Creatinine
(mg/mmol)
DTG + 3TC (n=716) DTG + TDF/FTC (n=717)
*
*
*
*
*
*
*p<0.001a
Results: Change in Bone Markers at
Week 48: Pooled ITT-E Population
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
1.220.60 0.40 0.14
4.07
6.17
13.10
0.330
5
10
15
Serum bone specificalkaline phosphatase
Serumosteocalcin
Serum procollagen 1N-terminal propeptide
Serum type 1 collagenC-telopeptide
Ad
jus
ted
me
an
ch
an
ge
fro
m
ba
se
lin
e (
µg
/L)a
aEstimated mean change from baseline at Week 48 in each arm calculated from ANCOVA model adjusting for study, treatment, baseline
plasma HIV-1 RNA, baseline CD4+ cell count, age, sex, race, BMI, smoking status, current vitamin D use, and baseline biomarker value.
Multiple imputed dataset (missing at random).
DTG + 3TC (n=716)
DTG + TDF/FTC (n=717)
*
*
*
*
*p<0.001
Orkin C et al. HIV Glasgow 2018; Glasgow,
UK. Slides P021.
Subanalysis
• GEMINI-1 and-2 results demonstrate non-inferior virologic efficacy for the 2DR
DTG + 3TC vs the 3DR DTG + TDF/FTC at Week 48
• Both DTG + 3TC and DTG + TDF/FTC were associated with low rates of
confirmed virologic withdrawals through Week 48
– No treatment-emergent INSTI or NRTI mutations were observed among participants
who met CVW criteria
• Overall safety and tolerability profile at Week 48 was comparable between the
2 regimens
– Fewer drug-related AEs with DTG + 3TC
– Change in renal and bone biomarkers significantly favors DTG + 3TC
• These data support DTG + 3TC as an effective option for the treatment of HIV-1
infection
Conclusions
Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
Phase III, randomised, multicentre, parallel-group, non-inferiority study
• Objective: to demonstrate non-inferior antiviral activity of switching to DTG + 3TC QD compared with
continuation of current ARV regimen over 48 weeks in HIV-1-infected ART-experienced subjects
• Primary endpoint: the proportion of participants who meet the Snapshot virologic failure criteria at
Week 48 using the ITT-E population
– non-inferiority margin = 4%; Week 48 primary endpoint
TANGO: Switch Study
TAF-based
regimens
Randomisation
1:1N=600
DTG + 3TC
Primary
endpoints
Secondary
endpoints
Baseline Week 24 Week 48 Week 96 Week 144
TAF-based regimens
North America + EU + international
TANGO. Available from: https://clinicaltrials.gov/ct2/show/NCT03446573 Accessed May 2018
Phase III, randomised, multicentre, parallel-group, non-inferiority study
• Objective: to demonstrate the non-inferior antiviral activity of switching to DTG/3TC QD compared
with continuation of current ART regimen over 48 weeks in HIV-1 infected patients (n= 600)
• Primary endpoint: the proportion of participants who meet the snapshot virological failure criteria at
Week 48, using the ITT-E population
– Non-inferiority margin = 4%; Week 48 primary endpoint
• Planned start: H1 2019
SALSA: Second Switch Study Design
ViiV Healthcare, data on file 2018
VL <50 c/mL
on INI, NNRTI,
or PI + 2 NRTIs
1:1
Baseline Week 52 Week 100
CAR
DTG/3TC
Primary endpoint at Week 48:
subjects with VL <50 c/mL (ITT-E snapshot)
DTG/3TC
• HIV-1 infected patients
• On stable CAR for >6
months before screening
• 1st or 2nd ART with no
change in prior regimen
due to VF
• Confirmed HIV-1 RNA
<50 c/mL during the 12
months before screening
• HBV negative
Screening Early switch Late switch
Proposed study: Information not yet published
Dolutegravir + Rilpivirine
1ViiV Healthcare, Brentford, UK; 2Barts Health NHS Trust, London, UK; 3Hospital Universitari de Bellvitge,
Barcelona, Spain; 4Hospital of the University of Munich, Munich, Germany; 5East Sydney Doctors, Darlinghurst,
Sydney, Australia; 6CHG - Hôpital Delafontaine, Saint Denis Cedex, France; 7Central West Clinical Research, St
Louis, MO, USA; 8GlaxoSmithKline, Uxbridge, UK; 9ViiV Healthcare, Research Triangle Park, NC, USA;
10ViiV Healthcare, Collegeville, PA, USA; 11Janssen Pharmaceutica NV, Beerse, Belgium
Durable Suppression 2 Years After
Switch to DTG + RPV 2-Drug Regimen:
SWORD-1 and SWORD-2 Studies
Aboud M,1 Orkin C,2 Podzamczer D,3 Bogner J,4 Baker D,5
Khuong-Josses M-A,6 Parks D,7 Angelis K,8 Kahl L,1 Blair E,9
Underwood M, 9 Wynne B,10 Vandermeulen K,11 Gartland M,9 Smith K9
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands. Slides THPEB047.
Study Design
• SWORD-1 and SWORD-2 are identically designed, randomized, multicentre,
open-label, parallel-group, non-inferiority phase III studies
– A full description of the study design, including eligibility criteria and endpoints, has
been previously reported1
Methods (1)
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.
Slides THPEB047.Llibre et al. Lancet. 2018;391:839-849.
Study Populations
• Participants randomized to DTG + RPV on Day 1 who received at least 1
dose of DTG + RPV (early-switch group)
• Participants randomized to continue their current antiretroviral regimen (CAR)
on Day 1, completed early-switch phase at Week 52, and received at least 1
dose of DTG + RPV upon switching at Week 52 (late-switch group)
Methods (2)
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.
Slides THPEB047.
• Through 100 weeks of treatment, DTG + RPV continued to be efficacious in the
early-switch group
• Virologic efficacy in the late-switch group at Week 100 was similar to that of the early-
switch group at Week 481
Results: virologic efficacy (1)
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.
Slides THPEB047.
1. Llibre et al. Lancet. 2018;391:839-849.
aOther reasons for discontinuation while treated with DTG + RPV were lost to follow-up,
n=3; protocol deviation, n=5 (prohibited medication use, n=3; pregnancy, n=2);
withdrawal of consent, n=18 (participant relocated, n=5; travel burden, n=2; other, n=9);
and investigator discretion, n=2.
HIV-1 RNA <50 c/mL (FDA Snapshot) at Week 48 and Week 100
• Through Week 100, there
was a low number of
confirmed virologic
withdrawals (CVWs)
across study populations
(1%; 10/990)
• CVWs with resistance-
associated treatment-
emergent mutations were
low across both groups
and detected in 3
participants, all receiving
DTG + RPV (0.3%; 3/990)
– In all 3 participants, at least
1 NNRTI resistance–
associated mutation was
detected
Results: virologic efficacy (2)
Adapted from: Aboud et al. AIDS 2018;
Amsterdam, the Netherlands. Slides THPEB047.
aShading represents participants with treatment-emergent NNRTI resistance–associated mutations. bUnderlined value denotes viral load when participant met virologic withdrawal.cHIV-1 baseline resistance testing was performed on integrated HIV-1 proviral DNA using GenoSure
Archive® assay (Monogram Biosciences, South San Francisco, CA). On-study resistance testing
used standard plasma-based genotypic and phenotypic resistance testing.dParticipants in the late-switch group. eResistance testing not performed because of low viral load.
DTG + RPV: Low Rates of CVW Through Week 100
• Cumulative AEs reported in the early-switch group were consistent with the
respective antiretroviral drugs
Results: safety and tolerability
Adapted from: Aboud et al. AIDS 2018;
Amsterdam, the Netherlands. Slides
THPEB047.
aPreferred term coding based on MedDRA version 20.1 rather than 19.1 used in the Week 48 analysis, wherein “cold” and
“common cold” changed in preferred term from “nasopharyngitis” to “viral upper respiratory tract infection.” bThere were no grade
2-4 drug-related AEs of ≥2% frequency in any group. cA participant might have had >1 AE that led to discontinuation. dGrouped
term includes multiple adverse events. Psychiatric AEs that led to discontinuation in the early switch group were anxiety (n=4),
suicidal ideation (n=4), insomnia (n=2), depression (n=2), affective disorder, depressed mood, nightmare, and completed suicide
(n=1 each); those in the late-switch group were insomnia (n=3), depression (n=2), abulia, confusional state, loss of libido, major
depression, and suicidal ideation (n=1 each).
Adverse Events (Grades 1-4) at Week 48 and Week 100
• All bone turnover biomarkers
were decreased from baseline
at Week 100 except
procollagen 1 N-terminal
propeptide in the early-switch
group
• DTG + RPV was associated
with a neutral effect on
atherogenesis and
inflammation biomarkers, with
no pattern of change noted at
Week 100
• No further changes at Week
100 compared with Week 48,
as previously presented1
Results: biomarker analyses (1)
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.
Slides THPEB047.
Llibre et al. Lancet. 2018;391:839-849.aLast pre-switch data (usually Week 48) used for late-switch baseline. *P<0.05 vs
baseline. **P<0.001 vs baseline.
Bone Turnover Biomarkers at Week 48 and Week 100
• Improvements in renal tubular function, as measured by changes from baseline in urine
retinol-binding protein/creatinine ratio and urine beta-2 microglobulin/creatinine ratio
(not shown), were maintained at Week 100 in the early-switch group
Results: biomarker analyses (2)
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.
Slides THPEB047.
Change From Baseline in Retinol-Binding Protein/Creatinine Ratios at Week 48 and Week 100
• No discernable pattern of changes from baseline in mean serum concentration of lipids
(total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein
cholesterol, or triglycerides) was noted in the early- or late-switch groups
Results: biomarker analyses (3)
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.
Slides THPEB047.aLast pre-switch data (usually Week 48) used for late-switch baseline.
Total Cholesterol/HDL Cholesterol Ratio at Week 48 and Week 100
• Durable efficacy: high level of virologic suppression maintained through 100
weeks in the early-switch group
• Reproducible outcomes: 93% efficacy in the late-switch group (48 weeks after
switching to DTG + RPV), consistent with 95% efficacy in the early-switch
group at Week 48
• No CVWs with INSTI mutations; CVWs with NNRTI mutations rare (0.3%;
3/990 through Week 100), with minimal impact on future treatment options
• Safety profile of late-switch group similar to early-switch group 48 weeks post-
switch
• Switching to DTG + RPV had a favourable effect on renal tubular function as
evidenced by changes from baseline in retinol-binding protein/creatinine ratio
and beta-2 microglobulin/creatinine ratio
• Data through Week 100 support efficacy and safety of switching to once-daily
DTG + RPV for patients with HIV-1 on stable, suppressive 3- or 4-drug ART
Conclusions
Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.
Slides THPEB047.
Dolutegravir and Neural Tube
Defects (NTDs)
The data to be presented is in response to an unsolicited request.
This includes information on unlicensed indications.
UK/DGR/0016/18
Date of Preparation May 2018
• NTDs are congenital abnormalities affecting the brain, spine, or
spinal cord and result from failure of complete closure of the neural
tube, which usually occurs by Day 28 of pregnancy.
• Most common NTDs are spina bifida (usually compatible with life)
and anencephaly (usually incompatible with life).
• Diagnosis is through imaging or blood tests during pregnancy, or
made at birth.
• Risk factors include: Genetic factors, Folate/B12 deficiency,
Obesity, Diabetes, Medications (e.g. anti-epileptics)
• Prevalence rates of NTDs can vary widely between regions
– UK: 0.13%
– Europe: 0.09%
– USA: 0.02 – 0.2%
– India: 0.45%
– Africa: 0.05 – 0.75%
What are NTDs?
Wilde J et al Annu Rev Genet 2014;48:583-611; Relton C et al J Med Genet 2004;41:256-260; Morris JK et al http:dx.doi.org/10:1136/archdischild-2015-309226; Khoshnood
B et al. BMJ 2015;351:h5949; MMWR August 25,1995;44(SS-4):1-13; Allagh et al PLoS One 2015;10(3):e0118961; Zaganjor I et al PLoS One 2016;11(4):e0151586
• A number of data sources describe the use of DTG in pregnancy*:
– ViiV sponsored clinical trials: 74 pregnancies - no NTDs reported.
– Post-marketing reports: Approximately 500 pregnancy outcomes - 3 NTDs
reported.
– Non-ViiV Data: Approximately 4,150 pregnancies with approximately 880
exposed at time of conception. From the Botswana cohort: 4 NTDs with
exposure at conception, 1 NTD with exposure during pregnancy (8 weeks
GA).
* Due to potential for double reporting of individual cases into different sources,
these numbers should not be combined
DTG use in pregnancy: Additional data
ViiV Data on File
Surveillance for Neural Tube Defects following Antiretroviral Exposure from Conception
Rebecca Zash, Lewis Holmes, Joseph Makhema, Modiegi Diseko, Denise L. Jacobson, Gloria Mayondi, Mompati Mmalane, Lynne Mofenson, Tendani Gaolathe, Chipo Petlo, Max Essex, Shahin
Lockman and Roger L Shapiro
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
• The Tsepamo Study started in August 2014– Birth Outcomes Surveillance
– Funding: NIH/NICHD (R01, R Shapiro PI)
• Primary aims::– (1) Evaluate adverse birth outcomes by HIV-status and
ART regimen
– (2) Determine if there is an increased risk of neural tube defects (NTDs) among infants exposed to efavirenz (EFV) from conception
Background
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
Study Setting: Botswana
1. Ability to capture outcomes
• Antenatal record available at
delivery for >99% of women
• >95% of women deliver in a
healthcare facility
• Early termination extremely rare
2. Large # of exposures
• High HIV prevalence (~25%)
• High uptake of ART in pregnancy
(>90%)
• Multiple ART regimens in use
concurrently
• 52% start prior to conception
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
GHANZI
MAUN
SELEBI-PHIKWE
SEROWE
MAHALAPYE
MOLEPOLOLE
FRANCISTOWN
Study Population: Methods
Tsepamo takes place at 8 of the largest maternity wards in Botswana• ~45% of the total births in the
country
Research assistants abstract data from the obstetric cards for all in-hospital deliveries.
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
• Compared to EFV, no increased risk of adverse birth outcomes (stillbirth, preterm birth, small for gestational age, or neonatal death) among 1729 women who started DTG during pregnancy1
– No increased risk of major congenital abnormalities identified in the small number (N=280) who started DTG during the first trimester
Recent results from DTG started during pregnancy
1. Zash et al Lancet Global Health 2018;6:e804-810
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
Results: Neural Tube Defect by Exposure
Deliveries up to 1 MAY 2018• DTG at conception:
• 4/426 (0.94%; 95%CI 0.37%, 2.4%)• Non-DTG ART at conception:
• 14/11,300 (0.12%; 95%CI 0.07%, 0.21%) • EFV at conception:
• 3/5787 (0.05%; 95%CI 0.02%, 0.15%) • DTG started during pregnancy:
• 0/2812 (0.00%; 95%CI 0.0%, 0.13%) • Non-DTG ART started during pregnancy:
• 3/5624 (0.05%, 95% CI 0.02%, 0.16%)• HIV-uninfected
• 61/66057 (0.09%, 95%CI 0.07%, 0.12%) Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
Neural Tube Defects on DTG at conception
• The 4 defects identified were all pre-specified as NTDs, and included: – encephalocele (with photo)
– anencephaly (no photo)
– myelomeningocele (with photo)
– iniencephaly (with photo)
• None of the women were reported to be on folate supplementation PRIOR to pregnancy – Botswana does not fortify grains with folate
• Review of maternal data found no other risk factor for NTD present
NEJM Botto 1999
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
0
5
10
Sep
t
Dec
Mar
Jun
e
Sep
t
Dec
Mar
Jun
e
Sep
t
Dec
Mar
Jun
e
Sep
t
Dec
Mar
Jun
e
Other
2014 2015 2016 2017 2018
• From 1 May-15 July, there were 2 more NTDs; 1 in an infant exposed to DTG started during pregnancy (8 weeks GA) and 1 birth to an HIV-uninfected woman- NTDs in DTG started in pregnancy: 1/3104 (0.03%, 95% CI
0.01%, 0.18%)
Update since 1 May 2018
Updated prevalence of DTG exposure at conception is 4/596 (0.67%, 95% CI 0.26%, 1.7%)-- 95% CI still does not overlap with any other exposure group
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
Updated Analysis Plan
• Next formal analysis will occur after 31 March 2019– Will include women already exposed to DTG from conception
prior to recent guideline change
– Plans in place to expand from 8 to 18 sites, increasing from 45% to 72% of births in the country
• Final analysis in 2019 to include:– NTDs
– All major malformations
– Other adverse birth outcomes (stillbirth, preterm, SGA, NND)
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
Projections for March 2019
• With expanded surveillance to 18 sites, we estimate ~ 1226 births with exposure to DTG from conception by end of March 2019
With 0 more NTDs, the lower CI overlaps with the upper CI for other ART at conception (0.21%), EFV at conception (0.15%) and with HIV-uninfected (0.13%)
With 1 more NTD, the lower CI overlaps with the upper CI for other ART at conception (0.21%)
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
Conclusion
• We have identified a concerning preliminary early signal for DTG and neural tube defects that requires further data to confirm or refute– Based on only 4 cases (though 95% confidence intervals do
not overlap with other exposure groups)
– Absolute prevalence difference is small (~ 0.8%)
– The 4 different defects among infants exposed to DTG at conception is unusual
Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15
Overview of ViiV Pipeline
Name
Medical Advisor
ViiV Healthcare
UK/HIVP/0004/18 March 2018
Key Ongoing Trials with DTG (Adults)
1. http://clinicaltrials.gov/ct2/show/NCT02227238; 2. http://clinicaltrials.gov/ct2/show/NCT02178592 3. https://clinicaltrials.gov/ct2/show/NCT02429791; 4. http://clinicaltrials.gov/show/NCT02422797
5. https://clinicaltrials.gov/ct2/show/NCT02831673; 6. https://clinicaltrials.gov/ct2/show/NCT02831764
3TC, lamivudine; ATV/r, atazanavir; c/mL, copies/mL; DTG, dolutegravir; FTC, emtricitabine; LPV, lopinavir; NRTI, nucleoside reverse transcriptase inhibitor; QD, once-daily; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate
N=125
N=612
N>500
each
N=700
each
Phase IIIb, randomised, open-label study to assess
the safety and efficacy of DTG or EFV in adults
starting treatment for rifampicin-sensitive TB
Phase IIIb, open-label, non-inferiority,
randomised, second-line study of:
• DTG 50 mg QD + 2 NRTIs
• LPV/r (800/200 mg QD or 400/100 mg BID) +
2 NRTIs
Phase III, randomised, open-label study to assess the safety
and efficacy of switching to DTG + RPV versus continuing
current antiretroviral regimen
Phase III, randomised, multicentre, non-inferiority studies to
evaluate the efficacy, safety, and tolerability of DTG + 3TC QD
versus DTG + TDF/FTC FDC over 148 weeks5,6
INSPIRING2
Treatment-naïve,
TB co-infected
DAWNING1
Treatment-experienced,
failing on first-line
therapy
SWORD-13 and
SWORD-24
Virologically
suppressed adults
GEMINI 15 and 26
Treatment-naïve adults
Trials Starting in 2018-19 with DTG (Adults)
N=600
N=766
Phase III, randomised, non-inferiority study to assess the safety and efficacy of switching to DTG + 3TC versus continuing witha triple therapy regimen
Phase III, randomised, non-inferiority study to assess the safety and efficacy of switching to DTG + 3TC versus continuing with a triple TAF-containing regimen
Study 2080902
Treatment-experienced, stable patients
TANGO1
Treatment-experienced,stable patients
1. ViiV Healthcare. TANGO Protocol 2. ViiV Healthcare. Study 208090 Protocol
2017 20192018 2020
SWORD
SWORD DEXA W48
Anticipated Data Readouts
W144
GEMINI
W144W96W48
W24 W96W48 W144
Tango W48 W96
DAWNING
INSPIRING W24 W48
W24
First available congress presentation =
Interim Analysis=
Key Ongoing Trials with DTG (Paediatrics)
1. http://clinicaltrials.gov/show/NCT01302847; 2. Hazra R, et al. IAS 2012. Abstract TUAB0203 3. Viani RM, et al. Pediatr Infect Dis J 2015;34:1207–13; 4. https://clinicaltrials.gov/ct2/show/NCT02259127
PK, pharmacokinetics
N=700
N=160
Phase II/III, open label, multicentre, randomised (1:1), non-inferiority clinical trial in paediatric subjects (≥6–18 years) of first- or second-line: • DTG QD + 2 NRTIs vs • SOC (NNRTI or PI + 2 or 3 NRTIs)
Phase I/II, multicentre, open-label, non-comparative intensive PK andsafety study in paediatric subjects aged ≥4 weeks–<18 years(in age descending cohorts) receiving DTG as tablets or paediatric formulation
ODYSSEY4
ARV-naïve or experienced (first- or second-line)
paediatric
P10931–3
Treatment-experienced, INI-naïve paediatric
ViiV Healthcare: HIV Pipeline
ViiV Healthcare, Available from: https://www.viivhealthcare.com/our-medicines/medicines-in-development.aspx Accessed February 2018LA, long-acting; IM, intramuscular
Product Class Phase
DTG + RPV INSTI + NNRTI III
DTG + 3TC INSTI + NRTI III
LA CAB + LA RPV* (for IM injection)
INSTI + NNRTIIII
(for treatment of HIV infection)
LA CAB (for IM injection)
INSTIIII
(for prevention of HIV infection)
Fostemsavir Attachment inhibitor III
Combinectin(GSK3732394)
Entry Inhibitor Pre-clinical
GSK3640254 Maturation Inhibitor I
Cabotegravir nanosuspension
• Drug crystal suspended in aqueous vehicle
• Nanomilled to increase surface area and drug dissolution rate
– Wet bead milling with terminal sterilisation by gamma irradiation
• Higher drug loading versus matrix approaches for lower injection volume
16th HIV-HEPPK Müller RH et al. Eur J Pharm Biopharm 2011:78;1–959
CAB LA 200 mg/mL
Component Function
Cabotegravir free acid(d50 ~200 nm)
Active drug
Mannitol Tonicity agent
Surfactant system Wetting agent/stabiliser
Water for injection Solvent
16th European AIDS Conference; October 25-27, 2017; Milan, Italy
gp160
gp120 trimer gp41 trimer
CD4 binding site
CD4 receptor
CCR5/CXCR4
TemsavirTemsavir binds near
the CD4 binding site
Temsavir prevents gp120 conformational change, inhibiting HIV-1 attachment
Attachment inhibited
Temsavir Proposed Mode of Action
Conceptualization and Design by Max Lataillade (ViiV Healthcare) and John Wong (Nucleus Global), funded by ViiV Healthcare
16th European AIDS Conference; October 25-27, 2017; Milan, Italy
Viruses accumulate in
extracellular space
and are subsequently
removed by the host
immune system
Viruses accumulate in
extracellular space…
Conceptualization and Design by Max Lataillade (ViiV Healthcare) and John Wong (Nucleus Global), funded by ViiV Healthcare
ViiV Healthcare: Pipeline
• *Investigational treatments; †Subject to validation by appropriate regulatory authorities
• CAB, cabotegravir; RPV, rilpivirine
Long-acting two-drug regimensCAB + RPV*
PreventionCabotegravir*
Search for remission
and cureCollaborations
Advanced therapeutics Tivicay®
Legacy ARV drug portfolio Epzicom/Kivexa®
and Celsentri/Selzentry®
Dolutegravir regimensTriumeq®
Two-drug regimensDTG/RPV
DTG/3TC
Attachment inhibitor*† for heavily
treatment-experienced patients
Maturation inhibitor*† with possible
combinations with DTG and/or CAB
Next-generation*† agents
DTG and Weight Gain – Summary
See slide notes for references
• Weight gain has been associated with ARV use,1–6 and is mentioned in the SmPCs of many
commonly used ARVs7–18
• Increased weight is not mentioned in the Tivicay (DTG) SmPC19
• Despite ART-related weight gain, HIV-positive patients generally have similar or lower weight
than HIV-negative persons of a similar age5,6,20
• Data are not available to determine whether observed weight gain is reflective of a return to
health or is clinically significant
• Data on weight gain with DTG are limited, largely consisting of case reports21 and
retrospective, observational studies22–24
• Two comparative studies reported weight/BMI gain with DTG-based regimens23,24
‒ One large study found significant BMI increases after 12 months of treatment with DTG, EVG,
RAL, DRV and RPV, with little difference between them23
‒ Another study found significantly greater weight gains with INI- or PI-based regimens versus EFV,
with most notable increases after 18 months of DTG/ABC/3TC24
• In a post-hoc weight analysis of the NEAT-022 study in virologically suppressed patients with high
CV risk, switch from Pl/r to DTG was associated with a small but statistically significant weight &
BMI gain over 48 weeks; risk of weight gain was higher amongst individuals switching from
darunavir/r vs other protease inhibitors.25
• Weight changes will continue to be monitored and evaluated in current and future DTG RCTs
Weight/BMI Gain in ART-naïve
Patients: Summary
ACTG, AIDS Clinical Trial Group; INI, integrase inhibitor
Adapted from: 1. Lakey W, et al. AIDS Res Hum Retroviruses 2013;29:435–40; 2. Erlandson KM, et al. AIDS 2013;27:2069–79. 3. Bhagwat P, et al. CROI 2017. Poster 695; 4. McComsey GA, et al. Clin Infect Dis 2016;62:853–62. . Bakal D, et al. J
Antimicrob Chemother 2018;73:2177–85; 6. Nguyen A, et al. HIV Med 2008;9:142–150
Group Duration
Weight Change
(kg)
BMI change
(kg/m2)
Significant change
from baseline
Duke clinic1 (HIV+ n=92)
Overall
12 months
+4.4 +1.5
All significantly
increased
Women +8.6 –
Men +3.6 –
PI/r +9.0 –
Non-PI/r +2.7 –
ACTG 5224s Substudy A52022
(N=269)Overall 96 weeks +4.8 – Significantly increased
ATV/r
versus EFV96 weeks Difference +3.35
Difference
+0.88
Significantly greater
gains with ATV vs EFV
ACTG 52573 (N=1,809)Overall 96 weeks +3.8 +1.3
Greater risk of severe weight gain with RAL vs ATV/r (p=0.0427) or DRV/r (p=0.0555)
ACTG 5260s Substudy A52574
(N=328)
Overall 96 weeks – +3.8–4.7%
No significant difference between ATV/r, DRV/r or RAL
Brazil5 (N=1,794)
Overall
Median 4.1
years
– +2.4 Significantly increased
INI – +1.6INI use associated with
development of obesityPI/r – +0.4
NNRTI – +0.4
Swiss Cohort6 (N=5,427) ATV and LPV associated with risk of >5 kg weight gain (DRV and INIs not tested)
Published
Literature
ART-naive
Weight/BMI Gain in ART-experienced
Patients: Summary
Published
Literature ART-
experienced
Adapted from: 1. Currier J, et al. AIDS Patient Care STDS 2011;25:333–40; 2. Menard A, et al. AIDS.2017;31:1499–1500
3. Taramasso L, et al. Open Forum Infect Dis 2017;4:ofx2394. Norwood J, et al. J Acquir Immune Defic Syndr 2017;76:527–31
Group Duration
Weight change
(kg)
BMI change
(kg/m2)
Significant change
from baseline
GRACE1
DRV/r + OBT (N=429)
Women 48
weeks
+3.2 +1.2 Significant in women
not menMen +1.8 +0.5
Marseille2
DTG (N=462)
OverallMean
276 days
+3 +1Significant in women
not menWomen +4 +2
Men +2 +1
SCOLTA3
(N=1118)
DRV
12
months
– +0.48
All significantly
increased
DTG – +0.37
EVG – +0.42
RAL – +0.36
RPV – +0.30
Vanderbilt4
(N=495)
EFV
18
months
+0.9 –
Significant increase
with INI versus EFV
INI +2.9 –
PI/r +0.7 –
DTG/ABC/3TC +5.3
RAL or EVG +2.8
GRACE, Gender, Race And Clinical Experience; /r, ritonavir boosterSCOLTA, surveillance cohort long-term toxicity antiretrovirals
Questions?
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