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Dr. José M. Miró Servicio de Enfermedades Infecciosas
Hospital Clínic - IDIBAPSUniversidad de Barcelona
Barcelona
Correo electrónico: [email protected]
Nuevas Modalidades de Tratamiento Antirretroviral
X Congreso Nacional de GESIDA
Sesión PlenariaGESIDA 2018
Potential conflict of interest
Dr. José M Miró has received honoraria for speaking or
participating in Advisory Boards and/or research grants from
the following Pharmaceutical Companies:
Merck
Novartis
Pfizer
Roche
Theravance
ViiV Healthcare
Abbvie
Contrafect
Cubist
Genentech
Gilead Sciences
Jansen-Cilag
GESIDA 2018
New Modalities of Antiretroviral Treatment
Where we come from: 1 - 2 - 3
Where we are now: TT regimens
New regimens: 2D oral
New regimens: 2D long-acting
Monotherapy
Take home messages
GESIDA 2018
THE EVOLUTION OF HIV THERAPY >30 ARTS
FDA. Antiretroviral drugs used in the treatment of HIV infection http://www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment/ucm118915.htm Accessed August 2015
FDA news release November 2015 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm Accessed November 2015
1984 2018
Retrovir 100 mg capsule
<50 cop./mL
InSTI
STR
GESIDA 2018
Hosp. Clinic-IDIBAPS-Univ. of Barcelona, Barcelona, Spain
Hospital Clinic of Barcelona
HIV cohort (1983-2018)8,500 patients (historical cohort)
5,300 active patients
5,100 (95%) on ART (>95% VL BDL)
GESIDA 2018
Number of new and accumulated HIV-infected patients and
patients on ART at the H. Clinic of Barcelona (1986-2017)
5267 patients
98% on
ART
PrEP !!!
GESIDA 2018
Percentage of patients with undetectable HIV RNA viral load
(<400 c/mL) on ART at the H. Clinic of Barcelona (1995-2017)
50%
97%
0%
80-90%
Lee FJ et al PLoS One 2014;9:e97482; Carr A et al. Glasgow 2018 P#51
GESIDA 2018
Annual mortality rates in the cohort of HIV-infected
patients of the H. Clinic of Barcelona (1986-2017)
20%
<1%
GESIDA 2018
The Constant Evolution of Initial ART at the
Hospital Clinic of Barcelona, Spain (1990-2017)
InSTI = 60%12/r/c
GESIDA 2018
New Modalities of Antiretroviral Treatment
Where we come from: 1 - 2 - 3
Where we are now: TT regimens
New regimens: 2D oral
New regimens: 2D long-acting
Monotherapy
Take home messages
GESIDA 2018
Saag MS et al. JAMA. 2018; 320:379-396
GESIDA 2018
Recommended Initial ART Regimens for
Treating HIV Infection in 2018Saag MS et al. JAMA. 2018;320:379-396.GESIDA 2018
Alternative ART Regimens for Treating
HIV Infection in 2018 Saag MS et al. JAMA. 2018;320:379-396.GESIDA 2018
B/F/TAF vs. DTG/3TC/ABC
B/F/TAF vs. DTG
plus TAF/FTC
96 wk. Results Presented at the IDWeek
and HIV Glasgow Meetings in 2018GESIDA 2018
B/F/TAF vs. DTG/3TC/ABC
Gallant J, et al. Lancet. 2017;390:2063-2072 & Wohl D et al. IDWeek. October 3-7, 2018
GESIDA 2018
B/F/TAF vs. DTG/3TC/ABC
Gallant J, et al. Lancet. 2017;390:2063-2072 & Wohl D et al. IDWeek. October 3-7, 2018
GESIDA 2018
No R mutations
AE D/C = 0/5
92% vs. 93% at W48
B/F/TAF vs. DTG/3TC/ABC
Gallant J, et al. Lancet. 2017;390:2063-2072 & Wohl D et al. IDWeek. October 3-7, 2018
GESIDA 2018
GS-US-380-1490 Study Design
Phase 3, randomized, double-blind, active-controlled study
– Stratified by HIV-1 RNA, CD4 cell count, geographic region (USA vs non-USA)
– North America, Europe, Australia, and Latin America
– Chronic hepatitis B and/or C virus (HBV/HCV) infection allowed
Primary endpoint: proportion with HIV-1 RNA <50 copies/mL at Week 48
– B/F/TAF 89.4% vs DTG + F/TAF 92.9% with HIV-1 RNA <50 c/mL (p=0.12)1
Secondary endpoint: proportion with HIV-1 RNA <50 copies/mL at Week 96
– Noninferiority margin of 12% based on FDA Snapshot algorithm
18
ClinicalTrials.gov NCT02607956. c, copies; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault equation.
1. Sax et al. Lancet 2017; 390:2073-82.
48Week 0 144
Treatment-Naïve Adults
HIV-1 RNA ≥500 c/mL
eGFRCG ≥30 mL/min
n=320
n=325
1 Endpoint
96
DTG + F/TAF Placebo QD
B/F/TAF QD
B/F/TAF Placebo QD
DTG + F/TAF QD
1:1
2º Endpoint
B/F/TAF vs. DTG plus TAF/FTC
Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018
GESIDA 2018
Baseline Characteristics
19
c, copies; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault; IQR, interquartile range.
* Positive HBV surface antigen; isolated positive HBV core antigen, with quantifiable HBV DNA (ie, ≥20 IU/mL) on or prior to 1st dose.† Positive HCV antibody and quantifiable HCV RNA (ie, ≥15 IU/mL) prior to 1st dose of study drug.
B/F/TAF
n=320
DTG + F/TAF
n=325
Median age, y (range) 33 (18–71) 34 (18–77)
Male, % 88 89
Race/ethnicity, %
Black or African descent 30 31
White 57 60
Hispanic/Latino 26 25
Median HIV-1 RNA, log10 copies/mL (Q1, Q3) 4.43 (3.95, 4.90) 4.45 (4.03, 4.84)
HIV-1 RNA >100,000 copies/mL, % 21 17
Median CD4 cell count, cells/µL (Q1, Q3) 440 (289, 591) 441 (297, 597)
CD4 count <200 cells/µL, % 14 10
HBV*/HCV† coinfection, % 3/2 2/2
Median eGFRCG, mL/min (Q1, Q3) 120 (101, 142) 121 (103, 145)
Sax PE, et al. Lancet. 2017;390:2073-2082 & Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018
B/F/TAF vs. DTG plus TAF/FTCGESIDA 2018
Virologic Outcome at Week 96Snapshot analysis
At Week 96, B/F/TAF was noninferior to DTG + F/TAF by FDA Snapshot analysis
– Per protocol analysis: B/F/TAF 100% vs DTG + F/TAF 98%
Mean CD4 increase from baseline at Week 96:
– B/F/TAF +237 cells/µL vs DTG + F/TAF +281 cells/µL (p=0.008)
– Mean CD4 % change B/F/TAF 11% vs DTG + F/TAF 11% (p=0.37)
– Mean absolute CD4 B/F/TAF 693 vs DTG + F/TAF 733 (p=0.13)
20
P-value was from analysis of variance (ANOVA) model adjusted by the baseline HIV-1 RNA and region stratum.
% Treatment Difference (95% CI)
-7.9 3.2
-2.3
-12 120-6 6
Favors
DTG + F/TAF
Favors
B/F/TAF
84
412
86
311
0
20
40
60
80
100
HIV-1 RNA
<50 copies/mL
HIV-1 RNA
≥50 copies/mL
No Virologic
Data
DTG + F/TAF (n=325)
B/F/TAF (n=320)
Pro
po
rtio
n o
f p
art
icip
ants
, %
Virologic Outcome
269
320
281
325
14
320
9
325
35
325
37
320
No R mutations
AE D/C = 6/5
89% vs. 93% at W48
B/F/TAF vs. DTG plus TAF/FTC
Sax PE, et al. Lancet. 2017;390:2073-2082 & Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018
GESIDA 2018
B/F/TAF vs. DTG/3TC/ABC
vs. DTG
plus TAF/FTC
Pros- Same day T&T w/STR
- HBV
Cons- Acute infection
- Advanced Infection
- Avoid in TB/HIV
- Less long-term data
Pros- More long-term data
- TB/HIV
Cons- HLA-B*5701 testing
- Same day T&T w/TAF/FTC
- HBV w/TAF/FTC
- Advanced Infection
- NRC (DTG) and CVD (ABC) issues
- Teratogenicity (e.g. NTD)
GESIDA 2018
Evolution of ART regimens over time
2
1984-2018 Future
112/r/c
GESIDA 2018
New Modalities of Antiretroviral Treatment
Where we come from: 1 - 2 - 3
Where we are now: TT regimens
New regimens: 2D oral
New regimens: 2D long-acting
Monotherapy
Take home messages
GESIDA 2018
What are the reasons to start/switch to 2DC
• To avoid potential NRTI-related toxicity
- Bone
- Kidney
- Cardiovascular
- Other
• Less exposure to ART drugs throughout life
• Economic cost
• Naïve or virologically suppressed patients
• No antiretroviral-resistance mutations
• Never do it in HBV/HIV coinfected patients
GESIDA 2018
2D vs. TT RCT
Naïve
- GARDEL (LPV/r + 3TC)
- KALEA (LPV/r + TDF)
- NEAT001/ANRS143 (DRV/r + RAL)*
- ANDES (DRV/r + 3TC)
Switching
- OLE (LPV/r + 3TC)
- ATLAS-M (ATV/r + 3TC)
- SALT (ATV/r + 3TC)
- DUAL-GESIDA (DRV/r + 3TC)
r/PI-based 2DC
*Not recommended if plasma HIV RNA VL
>100.000 copies/mL and CD4 < 200/mm3
GESIDA 2018
bPI-based 2DC: Trial Designs
StudyFollow Up
WeekDual Triple Treatment History
GARDEL (n=306) 96 LPV/r + 3TC LPV/r + 2 NRTI Naïve
KALEAD (n=152) 24 LPV/r + TDF LPV/r + 2 NRTI Naïve
ANDES (n=145) 48 DRV/r + 3TC DRV/r + 3TC/TDF Naïve
OLE (n=250) 48 LPV/r + 3TC LPV/r + 2 NRTI Switch
ATLAS-M (n=266) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch
SALT (n=267) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch
DUAL-GESIDA (n=249) 48 DRV/r + 3TC DRV/r + 2 NRTI Switch
Total (n=1635)
Liev Z et al. HIV Glasgow. October 28-31, 2018
GESIDA 2018
bPI-based 2DC: HIV-RNA <50 copies/mL
StudyFollow Up
WeekDual Triple
RD, 95% Confidence Interval
GARDEL (n=306) 96 90.3% 84.4% +6% (-2%, +13%)
KALEAD (n=152) 24 69.4% 70.0% -1% (-15%, +14%)
ANDES (n=145) 48 93.3% 94.2% -1% (-9%, +7%)
OLE (n=250) 48 87.8% 86.6% +1% (-7%, +9%)
ATLAS-M (n=266) 96 77.4% 65.4% +12% (1 %, +23%)
SALT (n=267) 96 74.4% 73.4% +1% (-10%, +11%)
DUAL-GESIDA (n=249) 48 88.9% 92.7% -4% (-11% , +3%)
Total (n=1635) p=0.40 83.6% 80.6% +2% (-2%, +6%)
Liev Z et al. HIV Glasgow. October 28-31, 2018
GESIDA 2018
bPI-based 2DC: Virological failure (PDVF)
StudyFollow Up
WeekDual Triple
RD, 95% Confidence Interval
GARDEL (n=306) 96 7.3% 6.4% +1% (5%, +7%)
KALEAD (n=152) 24 15.3% 8.8% -7% (-4%, +17%)
ANDES (n=145) 48 0.0% 1.4% -1% (-5%, +2%)
OLE (n=250) 48 2.4% 2.4% 0% (-4%, +4%)
ATLAS-M (n=266) 96 1.5% 6.8% -5% (-10%, - 1%)
SALT (n=267) 96 6.8% 3.7% +3% (-2%, +8%)
DUAL-GESIDA (n=249) 48 3.2% 1.6% +2% (-2%, +8%)
Total (n=1635) p=0.98 5.0% 4.5% 0% (-2%,+2%)
Liev Z et al. HIV Glasgow. October 28-31, 2018
GESIDA 2018
Treatment Emergent Resistance Mutations
StudyFollow Up
WeekDual Triple
RD, 95% Confidence Interval
GARDEL (n=306) 96 2.4% 2.1% -1% (-5%, +2%)
KALEAD (n=152) 24 0.0% 1.3% -1% (-5%, +2%)
OLE (n=250) 48 0.8% 0.0% +1% (-1%, +1%)
ATLAS-M (n=266) 96 0.0% 0.0% 0% (-1%, +1%)
SALT (n=267) 96 0.0% 0.7% -1% (-3%, +1%)
DUAL-GESIDA (n=249) 48 0.0% 0.0% -1% (-1%, +1%)
Total (n=1490) p=0.89 0.7% 0.7% 0% (-1%, +1%)
Only few NRTI mutations in 2D and TT arms (M184V). No major PI mutations.
Liev Z et al. HIV Glasgow. October 28-31, 2018
GESIDA 2018
Discontinuations due to Adverse Events
StudyFollow Up
WeekDual Triple
RD, 95% Confidence Interval
KALEAD (n=152) 24 11.1% 7.5% +4% (-6%, +13%)
TDF (n=152) p=0.45 11.1% 7.5% +4% (-6%, 13%)
GARDEL (n=306) 96 0.6% 2.8% -2% (-5%, +1%)
OLE (n=250) 48 0.8% 3.1% -2% (-6%, +1%)
ATLAS-M (n=266) 96 1.5% 2.3% -1% (-4%, +3%)
SALT (n=281) 96 5.0% 7.1% -2% (-8%, +3%)
DUAL-GESIDA (n=249) 48 0.8% 1.6% -1% (-4%, +2%)
3TC (n=1352) p=0.04 1.7% 3.5% -2% (-3%, 0%)
GESIDA 2018
0
20
40
60
80
100
<50cp/ml PDVF Resistance D/AE
bPI-based 2DC: Summary Findings
HIV-RNA <50 copies/mL
Protocol Defined Virological Failure
Resistance Mutations
Discontinuations due to adverse
events
Dual
DualDual
Dual
Triple
TripleTriple
Triple
83.6% 80.6%
5.0% 4.5%0.7% 0.7%
2.7% 3.9%
Perc
enta
ge o
f p
atie
nts
wh
o a
chie
ved
en
dp
oin
t (
%)
GESIDA 2018
2D vs. TT RCT
Naïve
- GARDEL (LPV/r + 3TC)
- KALEA (LPV/r + TDF)
- NEAT001/ANRS143 (DRV/r + RAL)
- ANDES (DRV/r + 3TC)
Switching
- OLE (LPV/r + 3TC)
- ATLAS-M (ATV/r + 3TC)
- SALT (ATV/r + 3TC)
- DUAL-GESIDA (DRV/r + 3TC)
r/PI-based 2DC DTG-based 2DC
Naïve (+ 3TC)
- PADDLE (single arm)
- ACTG A5353 (single arm)
- GEMINI 1+2 (DTG + 3TC)
Switching
- SWORD 1+2 (DTG + RPV)
- ASPIRE (DTG + 3TC)
- ANRS 167 LAMIDOL
(single arm DTG + 3TC)
GESIDA 2018
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
a−10% noninferiority margin for individual studies.
GEMINI-1 and -2 Phase III Study Design
Cahn P 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,
multicenter, noninferiority 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).
GESIDA 2018
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
Demographic and Baseline Characteristics for the
Pooled GEMINI-1 and -2 Population
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
Cahn P et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
up to 500,000
GESIDA 2018
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
Pooled Snapshot Outcomes at Week 48: ITT-E and Per Protocol Populations
Cahn P 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
-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
ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717)
PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693)
GESIDA 2018
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
TRDF Analysis
566
576
>100,000≤100,000 >200 ≤200
Baseline HIV-1
RNA, c/mL
Baseline CD4+
cell count, cell/mm3
Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and
CD4+ Cell Count: Snapshot and TRDF Analysis
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
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
GESIDA 2018
22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands
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
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 failure) 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.
.
GESIDA 2018
SWORD-1 and -2: Phase III Study Design
*8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies
HBV, hepatitis B virus; ITT(-E), intent to treat (- exposed); NRTI, nucleoside reverse transcriptase inhibitor
Inclusion criteria
• On stable CAR 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
DTG + RPV (N=513)
Day 1
Screening
Week 148
Identically designed, randomised, multicentre, open-label,
parallel-group, non-inferiority studies
CAR (N=511) DTG + RPV
VL <50 c/mL on INI, NNRTI,or PI + 2 NRTIs
1:1
DTG + RPV
Week 52
Primary endpoint
at 48 weeks:
subjects with
VL <50 c/mL
(ITT-E snapshot)*
Early-switch phase Late-switch phase Continuation phase
Countries:
Argentina Australia Belgium Canada
France Germany Italy Netherlands
Russia Spain Taiwan United Kingdom
United States
Llibre JM, et al. CROI 2017. Oral Presentation 44LB
GESIDA 2018
SWORD-1 and -2: Demographics and
Baseline Characteristics
Llibre JM, et al. CROI 2017. Oral Presentation 44LB
Data pooled across SWORD-1 and -2
DTG + RPV
(n=513)
n (%)
CAR
(n=511)
n (%)
Age, mean (SD)
≥50 years
43 (11)
147 (29)
43 (10)
142 (28)
Female 120 (23) 108 (21)
Race, non-white 92 (18) 111 (22)
CD4+ cell count, cells/mm3 (median)
≤500
>500
611
165 (32)
348 (68)
638
149 (29)
362 (71)
Baseline third-agent class
PI
NNRTI
INI
133 (26)
275 (54)
105 (20)
136 (27)
278 (54)
97 (19)
Baseline TDF use 374 (73) 359 (70)
Median duration of ART prior to Day 1, months 51 53
GESIDA 2018
SWORD-1 and -2: Snapshot Outcomes at Week 48
Llibre JM, et al. CROI 2017. Oral Presentation 44LB
*Adjusted for age and baseline third agent
CAR DTG + RPV
–4.3 3.0
SWORD-1
SWORD-2
–3.9 4.2
SWORD-1
SWORD-2
95 96 94 94
<1 <1 <1 2 4 4 5 4
0.2
–0.6
Percentage-point difference
DTG + RPV is non-inferior to CAR with
respect to snapshot in the ITT-E population
(<50 c/mL) at Week 48 in both studies
0
Virologic outcomes
Adjusted treatment
difference (95% CI)*
GESIDA 2018
SWORD-1 and -2: Confirmed Virologic Withdrawals
Llibre JM, et al. CROI 2017. Oral Presentation 44LB
• One subject on DTG + RPV meeting virologic withdrawal criteria had an NNRTI
resistance-associated mutation (K101K/E) identified
• No INI resistance-associated mutations were identified
Data pooled across SWORD-1 and -2
*CVW defined as current ‘retest’ HIV-1 RNA ≥200 c/mL, prior ≥50 c/mL
CVW, confirmed virologic withdrawal
Early-switch phase
DTG + RPV
n=513
n (%)
CAR
n=511
n (%)
CVW* 2 (<1) 2 (<1)
GESIDA 2018
Evolution of ART regimens over time
2D or not 2Dthat is the question
Hamlet, Act III, Scene I. Sir William Shakespeare, 1564 - 1616.
GESIDA 2018
Uptake and effectiveness of 2D compared to TT ART
regimens in Europe
Pelchen-Matthews A et al. EuroSida. IAS. Amsterdam, 2018 Poster No. THPEB052
2D ART regimens ART response at 48 wk.
Switching ART in >80% of cases
GESIDA 2018
Pros- Excellent efficacy & safety data
- More long-term data
- No bPI mutations
- bPI can be used in CKD
Cons- DDIs
- No STRs
- “b/PI-side effects”
Pros- Excellent efficacy & safety data
- STRs (DTG+RPV, DTG+3TC soon)
- No DDIs
- No DTG mutations
- DTG + RPV can be used in CKD
Cons- Limited data in acute/recent infection
- Limited data in advanced patients
- “DTG-side effects”
- RPV must be taken with food, avoid
PPIs and separated from antiacids.
2D vs. TT RCTr/PI-based 2DC DTG-based 2DC
Potential 2DC RCTs in naïve patients
• DTG+3TC vs. bDRV+3TC
• BIC+3TC vs. DTG+3TC or bDRV+3TC
• DTG+3TC in Acute-Recent/Advanced Patients
GESIDA 2018
New Modalities of Antiretroviral Treatment
Where we come from: 1 - 2 - 3
Where we are now: TT regimens
New regimens: 2D oral
New regimens: 2D long-acting
Monotherapy
Take home messages
GESIDA 2018
What are the reasons to use long-acting (LA)
antiretrovirals for treating HIV-infection
Adherence to oral
antiretrovirals can be variable
Special populations
- Drug and alcohol abuse
- Psychiatric illness
Antiretroviral stigma
Patients´ preference
Monroe M et al. Bioengineering & Translational Medicine 2018;3:102–123
GESIDA 2018
Requirements Infrequent dosing (~ 2-3 months)
Practical injection volume (≤ 4mL)
Minimal PK tail
High genetic barrier to resistance
Minimal injection associated
adverse events
Stable formulation ideally without
cold chain requirements
LA ARV drugs LA Rilpivirine
LA Cabotegravir
MK-8591 (EFdA)*
GS-CA1 (Capsid inhibitor)**
Broadly Neutralizing
Monoclonal antibodies (PRO140; UB-421; VRC01; VRC01-
LS; 3BNC117; 10-1074)
Main Characteristics of LA ARV drugs
*Nucleoside reverse transcriptase translocation inhibitor” – inhibits reverse transcriptase by two different mechanisms. Implant
Formulations Release Effective Drug Levels for >180 days; ** Capsid inhibitor. It is the most potent antiretroviral agent.
GESIDA 2018
4848Spreen W et al. JAIDS 2014;67:487-92.
Cabotegravir (CAB) LA Single Injection Provides Detectable Drug
in Plasma for 48 Weeks
Time (weeks)
0 4 8 12 16 20 24 28 32 36 40 44 48
Pla
sma C
AB
(
g/m
L)
0.1
1
100mg IM
200mg IM
400mg IM
800mg IM (split)
100mg SC
200mg SC
400mg SC (split)
4*PA-IC90
PA-IC90
Mean Concentration-Time Profile (n=6/cohort)
CAB 5mg/day p.o.
Ctau = 0.6 ug/mL
(0.67 ug/mL)
CAB LA apparent half-life ~40days
versus CAB oral ~40hr half-life
Very very
long PK tail !
GESIDA 2018
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
• CAB is an HIV-1 integrase inhibitor– Oral 30 mg tablet (t½, ~40 hours)
– LA nanosuspension 200 mg/mL (t½, ~20-40 days)
• RPV is an HIV-1 NNRTI– Oral 25 mg tablet (t½, ~50 hours)
– LA nanosuspension 300 mg/mL (t½, ~30-90 days)
• Oral 2-drug CAB + RPV proof of efficacy
through Week 96 in LATTE-1
Parenteral Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-1 RCT
Margolis et al. Lancet ID. 2015; 15:1145-55.
BL, baseline; CAB, cabotegravir; CI, confidence interval; EFV, efavirenz; LA, long-acting; NNRTI, non-nucleoside reverse
transcriptase inhibitor; RPV, rilpivirine; t1/2, half-life.
0
20
40
60
80
100
CAB 10 mg (n=60) CAB 30 mg (n=60)CAB 60 mg (n=61) EFV 600 mg (n=62)
12 1684BL 2 242628 32 36 40 48 60 72 84 96
Pro
po
rtio
n,
% (
95
% C
I)
GESIDA 2018
21st International AIDS Conference; July 18-22, 2016; Durban, South Africa
Induction period
LATTE-2 Study Design (Phase 2)
Week 32
Primary analysis
Dosing regimen
selection
Day 1
Randomization
2:2:1
Week 48
Analysis
Dosing regimen
confirmation
CAB 400 mg IM + RPV 600 mg IM Q4W (n=115)
CAB 600 mg IM + RPV 900 mg IM Q8W (n=115)
Week 96b
CAB loading dose at Day 1
CAB loading doses at Day 1 and Week 4
CAB 30 mg +
ABC/3TC for
20 weeks
CAB 30 mg + ABC/3TC PO QD (n=56)
CAB 30 mg + ABC/3TC PO QD
for 20 weeks
(N=309)
Maintenance perioda
Add RPV
PO QD
4 weeks
Inclusion
criteria
• >18 years old• Naive to antiretroviral therapy• CD4+ >200 cells/mm3
Exclusion
criteria
• Positive for hepatitis B• ALT ≥5 × ULN• Creatinine clearance <50
mL/min
Qualification
for
maintenance
• HIV-1 RNA <50 c/mL between Week -4 and Day 1
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; QD, once daily; Q4W, every 4
weeks; Q8W, every 8 weeks; ULN, upper limit of normal. aSubjects who withdrew after at least 1 IM dose entered the long-term
follow-up period. bSubjects can elect to enter Q4W and Q8W LA Extension Phase beyond Week 96.
286/309 (92,5%)
GESIDA 2018
21st International AIDS Conference; July 18-22, 2016; Durban, South Africa
LATTE 2. HIV-1 RNA <50 c/mL at 48 wk. ITT-ME (Snapshot)
Abstract THAB0206LB.
Oral IM
Virologic outcomes Treatment differences (95% CI)
-6.6 12.4
Q8W IM (CAB 600 + RPV 900 mg)
-7.6 11.6
Q4W IM (CAB 400 + RPV 600 mg)
ITT-e (286 out of 309)
Margolis et al. Lancet ID 2015; 15:1145-55.
GESIDA 2018
9th IAS Conference on HIV Science; July 23-26, 2017; Paris, France
Virologic outcomes Treatment differences (95% CI)
Oral IM
Q8W IM
−8.4% 14.4%
Q4W IM
− 0.6% 20.5%
Eron et al. IAS 2017; Paris, France. MOAX0205LB; * Margolis DA et al. HIV Glasgow, UK, October 28-31, 2018
ITT-ME, intent-to-treat maintenance exposed; LA, long acting; Q4W, every 4 weeks; Q8W, every 8 weeks.
LATTE 2. HIV-1 RNA <50 c/mL at 96 wk. ITT-ME (Snapshot)
90% Q8W vs. 83% Q4W
at W160*GESIDA 2018
21st International AIDS Conference; July 18-22, 2016; Durban, South Africa
01 4 8 12 16 20 24 28 32 36 40 44 48
10
100
1000
Me
an
pla
sm
a R
PV
±S
D, n
g/m
L
Week
Q4W
Q8W
PA-IC90
25 mg PO Cτ
LATTE 2. PK of CAB + RPV Q4W and Q8W.
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
01 4 8 12 16 20 24 28 32 36 40 44 48
0.1
1
10
100
Me
an
pla
sm
a C
AB
±S
D,
μg/m
L
Week
Q4WQ8WPA-IC9010 mg PO Cτ30 mg PO Cτ
Cτ, trough concentration; PA-IC90, protein binding–adjusted 90% inhibitory concentration; SD, standard deviation.
• Both Q4W and Q8W steady state exposures approximate once-daily oral dosing
• Phase 3 FLAIR (NCT02938520), n=570. CAB-LA + RPV-LA Q4 wk. vs. DTG/ABC/3TC
in Naives. Fully recruited.
• Phase 3 ATLAS (NCT02951052), n=570. Switch from any triple ART (2NRTIs + 3rd
drug) to CAB LA + RPV LA Q4 wk. Fully recruited.
• Phase 3 ATLAS 2M, n=1020. Switch from any triple ART to CAB LA +RPV LA Q4 or
Q8 wk. Fully recruited.
GESIDA 2018
Evolution of ART regimens over time
LA or not LAthat is the question
Hamlet, Act III, Scene I. Sir William Shakespeare, 1564 - 1616.
GESIDA 2018
Pros- Innovative approach
- Excellent efficacy data
- Safety (except ISR)
- Useful for non-adherent target
populations
- Also useful for PrEP
Cons- No data in VS patients with
CD4<200/mm3
- Lead-in oral phase duration not
well defined
- Best schedule not defined yet
- Drug toxicity management
- Resistance concern
- Limited PK data in sanctuaries
- Stopping rules not defined (long
PK tail)
- Logistics outside RCT
Long-Acting (LA) ARTGESIDA 2018
New Modalities of Antiretroviral Treatment
Where we come from: 1 - 2 - 3
Where we are now: TT regimens
New regimens: 2D oral
New regimens: 2D long-acting
Monotherapy
Take home messages
GESIDA 2018
Monotherapy
Naïve
- MONARK (LPV/r)*
- IMANI I, II (LPV/r)*
Switching
- OK / OK04 (LPV/r)
- KALMO / IMANI III (LPV/r)
- ACTG5201 (ATV/r)*
- ATARIMO / OREY (ATV/r)*
- MONET / MONOI / MONARCH (DRV/r)
PI/r-Monotherapy
*Hight rates of treatment failures
GESIDA 2018
PI/r monotherapy
• Not recommended in naïve patients
• LPV/r and DRV/r demonstrated the
non-inferiority in switching trials
• Strict adherence is necessary
• VF not associated with PI R mutations
• Most patients resupressed with TT
• EACS Guidelines considered this
option for selected patients
GESIDA 2018
SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL
MOBIDIP/ANRS286 RCT in sub-Saharan Africa
The patients came from a
prospective cohort generated after
the 2LADY study
PI/r* monotherapy (n=133)
Randomization1:1
Basal Week 24 Week 96
- HIV-1 VL <200 c/mL ≥ 6 mo.
- CD4> 100 cels / mm3
- Adherence ≥ 90% last control
- No ART changes in last 3 mo.2 NRTI + 1 boosted PI PI/r* + 3TC (n=132)
PI/r Mono PI/r + 3TC Total
Ciaffi L, et al. Lancet HIV 2017;4:e384-e392
GESIDA 2018
SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL
Ciaffi L, et al. Lancet HIV 2017;4:e384-e392
The monotherapy arm was
stopped by recommendation
of the DSMB
Treatment Failure (ITT análisis)
Efficacy of the PI/r + 3TC arm at W96 was 92%
7/8 VF were genotyped: without R to PIs or NRTI
MOBIDIP/ANRS286 RCT in sub-Saharan Africa
2%
21%
GESIDA 2018
Monotherapy
Naïve
- MONARK (LPV/r)
- IMANI I, II (LPV/r)
Switching
- OK / OK04 (LPV/r)
- KALMO / IMANI III (LPV/r)
- ACTG5201 (ATV/r)
- ATARIMO / OREY (ATV/r)
- MONET / MONOI / MONARCH (DRV/r)
PI/r-Monotherapy DTG-Monotherapy
Naïve
- No studies
Switching
- DOLAM (TT vs. 2D vs. M)
- DOMONO (TT vs. M)
- Several cohort studies
- Recent HIV Infection (TT vs. M)*
*Only study without any case of VF. Braun DL et al. IAS Amsterdam, July 2018.
GESIDA 2018
Study (n)24 weeks
Proportion (95% CI)48 weeks
Proportion (95% CI)
Gubavu et al. (21) 0.00% (0.00-16.1) –
Katlama et al. (28) 10.7% (2.27-28.2) –
Lecompte et al. (8) 0.00% (0.00-36.9) –
Oldenbüttel et al. (31) 3.23% (0.08-16.7) –
Rojas et al. (31) 3.23% (0.08-16.7) –
Rokx et al. (5) 0.00% (0.00-52.2) 20.0% (0.51-71.6)
Wijting et al. (96) 2.08% (0.25-7.32) 8.33% (3.67-15.8)
Borghetti et al. (36) 0.00% (0.00-9.74) –
Gantner et al. (116) 0.86% (0.02-4.71) –
Joly et al. (104) 0.96% (0.02-5.24) 0.96% (0.02-5.24)
Llibre et al. (513) 0.19% (0.00-1.08) 0.39% (0.05-1.40)
Maggiolo et al. (94) 0.00% (0.00-3.85) 0.00% (0.00-3.85)
Reynes et al. (27) 0.00% (0.00-12.8) 0.00% (0.00-12.8)
Riva et al. (61) 0.00% (0.00-5.87) –
SUMMARY 0.8% (0.29-2.19) 1.14% (0.22-5.61)
DTG-
Mono
DTG-
Dual
Virological failure
0% 5% 10% 15% 20% 25%
24 weeks 48 weeks
Meta-analysis DTG+3TC and DTG monotherapyProportion of virologic failures
Buzzi et al. EACS 2017; Milan, Italy. Oral PS1/2.
Mono
Dual
Virological failure
0% 5% 10% 15% 20% 25%
3.18% (1.52-6.52) 8.91% (4.70-16.2)
0.32% (0.10-0.97) 0.41% (0.13-1.25)
GESIDA 2018
Types of
therapy
Subjects
exposed, n
Virological
failureAmplified, n
New
resistancesTypes of resistance
DTG-mono 220 14 12 7
E138K + G140A +
Q148R
E92Q
N155H
S230R
R263K
N155H
Q148H + G140S
DTG-RPV 629 3 2 1 K101K/E
DTG-3TC 261 1 0 - /
DTG-ATZ 61 0 - - /
→ On DTG monotherapy, 50% of virological failures
develop a new resistance to integrase inhibitors
Meta-analysis DTG+3TC and DTG monotherapyResistances
Buzzi et al. EACS 2017; Milan, Italy. Oral PS1/2.
GESIDA 2018
Evolution of ART regimens over time
1984-2018 Future
112/r/c
GESIDA 2018
New Modalities of Antiretroviral Treatment
Where we come from: 1 - 2 - 3
Where we are now: TT regimens
New regimens: 2D oral
New regimens: 2D long-acting
Monotherapy
Take home messages
GESIDA 2018
Take Home Messages Current IAS ART guidelines recommend for initial therapy an integrase strand
transfer inhibitor (InSTI) (bictegravir or dolutegravir) plus 2 nucleoside reverse
transcriptase inhibitors (NRTIs).
Dual-therapy regimens that include boosted darunavir or dolutegravir plus
lamivudine might be considered for initial therapy in selected non-advanced chronic
HIV-infected patients.
Dual-therapy regimens that include a boosted protease inhibitor (lopinavir/darunavir)
plus lamivudine or dolutegravir plus rilpivirine can be considered for switching
therapy in selected virologically suppressed chronic HIV-infected patients.
Monotherapy with PIs or dolutegravir as a maintenance strategy is not
recommended because of higher rates of treatment failure, often with resistant virus
in patients taken dolutegravir monotherapy.
GESIDA 2018
J.R. Arribas
A. Calmy
E. Lazzari
J.M. Llibre
E. Martinez
G. Mora
J. Perez-Molina
Acknowledgements
A. Pharris
Jansen
Gilead
ViiV Healthcare
GESIDA 2018
In Memoriam
Teresa Gallart Gallart (1942-2018)
Servei d‘Inmunologia
Hospital Clínic de Barcelona
GESIDA 2018