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Joel Gallant, MD, MPH
Medical Director of Specialty Services
Southwest CARE Center
Santa Fe, New Mexico
Adjunct Professor of Medicine
Division of Infectious Diseases
Johns Hopkins University School of Medicine
Baltimore, Maryland
Top Advances in ART for 2017
Supported by educational grants from AbbVie; Bristol-Myers Squibb; Gilead
Sciences; Janssen Therapeutics; Merck & Co., Inc; and ViiV Healthcare.
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Slide credit: clinicaloptions.com
Disclosures
Joel Gallant, MD, MPH, has disclosed that he has received
consulting fees from Bristol-Myers Squibb, Gilead Sciences, Merck,
Theratechnologies, and ViiV/GlaxoSmithKline and funds for
research support from AbbVie, Bristol-Myers Squibb, Gilead
Sciences, Janssen, Merck, Sangamo, and ViiV/GlaxoSmithKline.
Initial Regimens: The Growing Dominance of
Integrase Inhibitors
What to Start: DHHS Guidelines, July 2016
Recommended Regimens
PI based  DRV/RTV + (TDF/FTC or TAF/FTC)
INSTI based  DTG/ABC/3TC*
 DTG + (TDF/FTC or TAF/FTC)
 EVG/COBI/TDF/FTC or EVG/c/TAF/FTC
 RAL + (TDF/FTC or TAF/FTC)
Alternative Regimens
NNRTI based  EFV/TDF/FTC or EFV + TAF/FTC
 RPV/TDF/FTC or RPV/TAF/FTC (requires HIV-1 RNA < 100,000
copies/mL and CD4+ cell count > 200 cells/mm3)
PI based  (ATV/COBI or ATV/RTV) + (TDF/FTC or TAF/FTC)
 (DRV/COBI or DRV/RTV) + ABC/3TC*
 DRV/COBI + (TDF/FTC or TAF/FTC)
*Pt must be HLA-B*5701 negative.
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
July 2016. Slide credit: clinicaloptions.com
What to Start: IAS–USA Guidelines, July 2016
Recommended Regimens
 DTG/ABC/3TC*
 DTG + FTC/TAF
 EVG/COBI/FTC/TAF
 RAL + FTC/TAF
Regimens When INSTIs Are Not an Option
 EFV/FTC/TDF
 RPV/FTC/(TAF or TDF)†
 DRV/COBI or DRV/RTV + (FTC/TAF, FTC/TDF, or ABC/3TC*)
Günthard HF, et al. JAMA. 2016;316:191-210. Slide credit: clinicaloptions.com
*Pt must be HLA-B*5701 negative.
†If HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3.
Initial ART With EVG/COBI/FTC/TAF Superior to
EVG/COBI/FTC/TDF at Wk 144
 Efficacy similar across pt
subgroups, trending toward or
significantly better with TAF in
each group
– By baseline HIV-1 RNA, baseline
CD4+ cell count, adherence, age,
sex, race, region
 Virologic failure with resistance by
Wk 144: 1.4% in each arm
Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet. 2015;385:2606-2615. Slide credit: clinicaloptions.com
0
20
60
40
80
100
48 96 144 48 96 144 48 96 144Wk:
Virologic
Success
Virologic
Failure
No Data
92 90
87 85 84
80
4 4 5 4 5 4 4 6
9 11 11
16
Pts(%)
Treatment Difference
Wk 48: 2.0% (95% CI: -0.7% to 4.7%)
Wk 144: 4.2% (95% CI: 0.6% to 7.8%;
P = .02)
EVG/COBI/FTC/TAF (n = 866)
EVG/COBI/FTC/TDF (n = 867)
Initial ART With EVG/COBI/FTC/TAF vs
EVG/COBI/FTC/TDF: Wk 144 Safety Outcomes
 Rate of discontinuation for AEs
higher with TDF vs TAF regimen
– 3.3% vs 1.3% (P = .01)
 Spine and hip BMD loss greater
with TDF vs TAF regimen
– 6 discontinuations for bone AEs in
TDF arm vs 0 in TAF arm
 TC, LDL, and HDL increases
greater with TAF vs TDF regimen,
but no difference in TC:HDL ratio
– Rates of lipid-modifying therapy
initiation similar: 5.5% vs 5.8%
Slide credit: clinicaloptions.com
Renal Events Leading to
Discontinuation, n
EVG/COBI/
FTC/TAF
(n = 866)
EVG/COBI/
FTC/TDF
(n = 867)
Proximal renal tubulopathy 0 4
Cr elevation or eGFR
decrease
0 3
Renal failure 0 2
Nephropathy 0 1
Proteinuria 0 1
Bladder spasm 0 1
Total 0 12
Arribas JR, et al. CROI 2017. Abstract 453.
WAVES: Switch to EVG/COBI/FTC/TAF Maintained
Virologic Suppression in Women at Wk 48
 Open-label extension study
Hodder S, et al. CROI 2017. Abstract 443. Slide credit: clinicaloptions.com
Virologic Outcome Treatment Difference
(95% CI)
HIV-1RNA<50c/mL(%)
100
80
60
40
20
0
Switch to EVG/COBI/
FTC/TAF (n = 159)
Continue ATV + RTV
+ FTC/TAF (n = 53)
Success Failure No Data
n = 150 46 3 2 6 5
94
87
2 4 4
9
0 10 20-20 -10
-1.2
7.5
19.4
Favors
EVG/COBI/
FTC/TAF
Favors
ATV/RTV
+ FTC/TAF
DTG/ABC/3TC
HIV-1RNA<50c/mL(%)
CD4+ Cell CountHIV-1 RNA
Overall ≤ 100K > 100K ≤ 350 > 350
100
80
60
40
20
0
82
71
83
74
80
64
85
72
78
71
203/
248
176/
247
148/
179
134/
181
55/
69
42/
66
111/
130
89/
124
92/
118
87/
123
ATV/RTV + FTC/TDF
n/N = 0 4 8 12 16
3.1
10.5
17.8
Favors
DTG/ABC/3TC
Favors ATV/RTV +
FTC/TDF
Overall Treatment Difference
(95% CI)
20-16 -12 -8 -4
ARIA: DTG/ABC/3TC Superior to ATV/RTV +
FTC/TDF in ART-Naive Women at Wk 48
Orrell C, et al. AIDS 2016. Abstract THAB0205LB. Johnson M, et al. HIV Glasgow 2016. Abstract
P035. Hagins D, et al. IDWeek 2016. Abstract 949. Slide credit: clinicaloptions.com
P = .005
Outcome, % (n)
DTG/ABC/3TC
(n = 248)
ATV/RTV + FTC/TDF
(n = 247)
Virologic nonresponse 6 (16) 14 (35)
No virologic data 12 (29) 15 (36)
Virologic Outcome
Dolutegravir + NRTIs in Treatment-Naive Pts
1. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;70:515-519. 2. Molina JM, et al. Lancet
HIV. 2015;2:e127-e136. 3. Raffi F, et al. Lancet. 2013;381:735-743. 4. Raffi F, et al. Lancet Infect
Dis. 2013;13:927-935. 5. Orrell C, et al. IAS 2016. Abstract THAB0205LB. 6. Fulcher JA, et al.
CROI 2017. Abstract 500LB.
 No resistance selected for in any DTG + 2 NRTI regimen in
SINGLE,[1] FLAMINGO,[2] SPRING-2,[3,4] and ARIA[5]
– 1 case report of possible emergence of INSTI resistance in
treatment-naive pt receiving DTG + FTC/TDF[6]
– Pt with an acute opportunistic infection experienced virologic failure
followed by subsequent resuppression after addition of DRV/RTV
– No baseline integrase resistance data available
Slide credit: clinicaloptions.com
Switching Therapy in Virologically
Suppressed Pts
Switching Therapy in Virologically Suppressed
Pts: When and Why?
 To manage adverse events
 To manage or prevent drug toxicity
 To simplify regimen (number of doses or pills)
 To address food restrictions
 To address drug interactions
 To plan for pregnancy
 To reduce cost
 To address new HBV coinfection
Switch Studies in Virologically Suppressed Pts
Adapted from David Wohl. References in slidenotes.
Trial From To Outcome vs Suppressive ART
GS-123[1] TDF/FTC + RAL EVG/COBI/FTC/TDF Virologic suppression maintained
GS-264[2] TDF/FTC/EFV RPV/FTC/TDF Virologic suppression maintained
Strategy-NNRTI[3] TDF/FTC + NNRTI EVG/COBI/FTC/TDF Noninferior or superior
Strategy-PI[4] TDF/FTC + PI/RTV EVG/COBI/FTC/TDF Noninferior or superior
SPIRIT[5] 2 NRTI + PI/RTV RPV/FTC/TDF Noninferior or superior
SPIRAL[6] 2 NRTI + PI/RTV (experienced pts) RAL + 2 NRTIs Noninferior or superior
SALT[7] ATV/RTV + 2 NRTIs ATV/RTV + 3TC Noninferior or superior
OLE[8] LPV/RTV + 2 NRTIs LPV/RTV + 3TC Noninferior or superior
GS-109[9] TDF-based ART EVG/COBI/FTC/TAF Noninferior or superior
STRIIVING[10] Suppressive ART DTG/ABC/3TC Noninferior or superior
ATLAS-M[11] ATV/RTV + 2 NRTIs ATV/RTV + 3TC Noninferior or superior
GS-119[12] DRV/RTV-containing “salvage” regimen EVG/COBI/FTC/TAF + DRV Noninferior or superior
LATTE[13] CAB or EFV + 2 NRTIs CAB + RPV (PO) Noninferior or superior
GS-1089[14] TDF/FTC + third agent TAF/FTC + third agent Noninferior or superior
LATTE-1[15] CAB + ABC/3TC CAB + RPV (IM) Noninferior or superior
GS-1160[16] EFV/FTC/TDF RPV/FTC/TAF Noninferior or superior
GS-1216[16] RPV/FTC/TDF RPV/FTC/TAF Noninferior or superior
SWORD-1 & 2[17] 3-drug regimen DTG + RPV Noninferior or superior
STRIIVING: Initial vs Delayed Switch to
DTG/ABC/3TC From Suppressive ART
 Pts with HIV-1 RNA < 50
copies/mL on stable ART
≥ 6 mos, no previous virologic
failure, HLA-B*5701 negative
(N = 553)
 Pts randomized to initial vs
delayed switch at Wk 24 and
followed through Wk 48
*ITT-E analysis.
Lake J, et al. AIDS 2016. Abstract THAB0203. Slide credit: clinicaloptions.com
HIV-1RNA<50c/mL(%)
100
80
60
40
20
0
Virologic
Success
Virologic
Nonresponse
No Virologic
Data
85
88
83
1 1 < 1
14
10
17
DTG/ABC/3TC, Day 1 to
Wk 24 (n = 275)*
Continue baseline ART, Day 1
to Wk 24 (n = 278)*
DTG/ABC/3TC, Day 1 to
Wk 48 (n = 275)
TAF vs TDF: Mechanism of Action
Arribas JR, et al. CROI 2017. Abstract 453.
Sax PE, et al. Lancet. 2015;385:2606-2615.
Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58-64. Slide credit: clinicaloptions.com
GI
tract
TDF
300 mg
TAF
25 mg
Plasma
TFV
90% lower
plasma TFV than
with TDF
Lymphocyte
Renal
tubular
cell
Renal
tubular
cell
TFV HIV
Renal Considerations for Recommended Initial Regimens
ABC/3TC  Do not use if CrCl < 50 mL/min
FTC/TDF
 EVG/COBI/FTC/TDF: do not start if CrCl < 70 mL/min; d/c if CrCl < 50 mL/min
 FTC/TDF: dose adjust if CrCl 30-49 mL/min; do not use if CrCl < 30 mL/min
FTC/TAF  No dose adjustment needed if CrCl ≥ 30 mL/min, regardless of coformulation
Class
First-line ART
DHHS Recommended IAS-USA Recommended
INSTI  DTG/ABC/3TC
 DTG + FTC/TDF or FTC/TAF
 EVG/COBI/FTC/TDF
 EVG/COBI/FTC/TAF
 RAL + FTC/TDF or FTC/TAF
 DTG/ABC/3TC
 DTG + FTC/TAF
 EVG/COBI/FTC/TAF
 RAL + FTC/TAF
Boosted PI  DRV + RTV + FTC/TDF or FTC/TAF
What to Start: July 2016
Slide credit: clinicaloptions.com
DHHS Guidelines. July 2016. Günthard HF, et al. JAMA. 2016;316:191-210. ABC/3TC [package
insert]. September 2015. EVG/COBI/FTC/TDF [package insert] January 2017. FTC/TAF [package
insert]. April 2016. FTC/TDF [package insert]. April 2016.
Summary of TAF Switch Studies in Virologically
Suppressed Pts
Trials:
 GS-109: TDF-containing regimens to EVG/COBI/FTC/TAF[1]
 GS -112: switch to EVG/COBI/FTC/TAF in pts with impaired renal function[2]
 GS-119: ART + DRV/RTV to EVG/COBI/FTC/TAF + DRV in ART-experienced pts[3]
 GS-1089: FTC/TDF to FTC/TAF[4]
 GS-1160: EFV/FTC/TDF to RPV/FTC/TAF[5]
 GS-1216: RPV/FTC/TDF to RPV/FTC/TAF[5]
Results:
 Noninferiority, with superiority in GS-109 for switch to EVG/COBI/FTC/TAF from EFV/FTC/TDF or
ATV/RTV + FTC/TDF and superiority in GS-119
 Increase in bone density
 Stability of eGFR (increase in GS-1089 and GS-112) with no tubular toxicity and decrease in overall
and tubular proteinuria
References in slidenotes. Slide credit: clinicaloptions.com
GS-1089: Switch From TDF- to TAF-Containing
ART Noninferior at Wks 48 and 96
 Phase III trial of pts with HIV-1 RNA < 50 c/mL, eGFR ≥ 50 mL/min while receiving
FTC/TDF + third ARV (N = 663)
Pts(%)
Virologic Success Virologic Failure No Virologic Data
Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96
94 93
89 89
0 2 2 1 5 6 9 10
100
80
60
40
20
0
Raffi F, et al. HIV Glasgow 2016. Abstract O125. Slide credit: clinicaloptions.com
0 2 4 6 8
-5.3
-.5
4.4
Favors FTC/TAFFavors FTC/TDF
Overall Treatment Difference (95% CI)
10-6 -4 -2
-2.5
1.3
5.1
Wk 48
Wk 96
FTC/TAF (n = 333)
FTC/TDF (n = 330)
Virologic Outcome
GS-1089: Bone and Renal Parameters for TAF-
vs TDF-Containing ART at Wk 96
Raffi F, et al. HIV Glasgow 2016. Abstract O125. Slide credit: clinicaloptions.com
MeanChangein
HipBMD(%)
P < .001
3
2
1
0
-1
1.9
-0.3
Wk
BL 24 48 72 96
FTC/TAF
FTC/TDF
321
317
309
305
300
303
293
296
288
289
MeanChangein
SpineBMD(%)
P < .001
3
2
1
0
-1
2.2
-0.2
Wk
BL 24 48 72 96
FTC/TAF
FTC/TDF
321
320
310
310
300
306
294
297
287
292
MedianChange(%)
Urine
Albumin:Cr
Urine
Protein:Cr
Urine
β2-M:Cr
Urine
RBP:Cr
MedianChange(mL/min)
eGFR
FTC/TAF FTC/TDF
P ≤ .005
P ≤ .005
P ≤ .005
P ≤ .005
P ≤ .005
GS-119: Immediate vs Delayed Switch to
EVG/COBI/FTC/TAF + DRV for Tx-Experienced Pts
 Multicenter, open-label phase III trial
– Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24 (FDA Snapshot)
– Secondary endpoints: HIV-1 RNA < 50 c/mL at Wk 48, CD4+ cell count change, safety
Tx-experienced pts,
HIV-1 RNA < 50 c/mL for
≥ 4 mos on DRV/RTV-
containing ART, with
history of drug resistance*
and eGFR > 50 mL/min
(N = 135)
Switch to EVG/COBI/FTC/TAF
+ DRV 800 mg QD
(n = 89)
Wk 144Wk 48
Baseline ART
(n = 46)
EVG/COBI/FTC/TAF
+ DRV 800 mg QD
(n = 46)
Wk 24Randomized 2:1
*Resistance to ≥ 2 ARV classes, including ≤ 3 thymidine analogue mutations and/or K65R, but not integrase
inhibitors, unless currently suppressed on RAL, EVG, or DTG (50 mg QD only), and no DRV resistance.
Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200. Slide credit: clinicaloptions.com
GS-119: Baseline Characteristics
Characteristics
EVG/COBI/
FTC/TAF +
DRV (n = 89)
Baseline ART
(n = 46)
Median age, yrs 49 47
Male, % 82 61
Black (or African descent), % 39 57
Median CD4+ cell count,
cells/mm3 519 518
Median eGFRCG, mL/min 99 100
DM/HTN/CVD/hyperlipidemia,% 8/34/7/46 11/37/4/28
Baseline Regimen
Median no. pills per day 5 5
≥ 6 pills per day, % 40 37
At least BID dosing, % 65 65
TDF/ABC/other NRTIs, % 61/11/12 54/11/13
RAL 56 50
Resistance, %
EVG/COBI/
FTC/TAF +
DRV (n = 89)
Baseline ART
(n = 46)
2-class/3-class resistance 70/26 74/20
M184V/I 85 78
K65R 20 30
NNRTI-R/PI-R 89/38 87/28
Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200. Slide credit: clinicaloptions.com
GS-119: Virologic Suppression After Switch to
EVG/COBI/FTC/TAF + DRV
 At Wk 48, virologic efficacy of switch to
EVG/COBI/FTC/TAF + DRV was
noninferior and statistically superior to
continuing baseline regimen (P = .004)[1]
 No emergent resistance in
EVG/COBI/FTC/TAF + DRV arm; 1 pt in
baseline ART arm with viral rebound (Wk
36) developed resistance (M184V +
K65R)[1]
 No impact of genotypic susceptibility score
on the efficacy of the switch regimen[2]
EVG/COBI/FTC/TAF + DRV (n = 89)
Baseline ART (n = 46)
Wk 48
HIV-1 RNA
< 50 c/mL
Virologic
Failure
No Data
94
76
2
11
3
13
Treatment difference: 18.3%
(95% CI: 3.5% to 33.0%; P = .004)
1. Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200.
2. Margot N, et al. HIV Glasgow 2016. Abstract O123. Slide credit: clinicaloptions.com
Trial From To Outcome vs Suppressive ART
GS-123[1] TDF/FTC + RAL EVG/COBI/FTC/TDF Virologic suppression maintained
GS-264[2] TDF/FTC/EFV RPV/FTC/TDF Virologic suppression maintained
Strategy-NNRTI[3] TDF/FTC + NNRTI EVG/COBI/FTC/TDF Noninferior or superior
Strategy-PI[4] TDF/FTC + PI/RTV EVG/COBI/FTC/TDF Noninferior or superior
SPIRIT[5] 2 NRTI + PI/RTV RPV/FTC/TDF Noninferior or superior
SPIRAL[6] 2 NRTI + PI/RTV (experienced pts) 2 NRTI + RAL Noninferior or superior
SALT[7] ATV/r + 2 NRTI ATV/r + 3TC Noninferior or superior
OLE[8] LPV/r + 2 NRTIs LPV/r + 3TC Noninferior or superior
GS-109[9] TDF-based ART EVG/COBI/FTC/TAF Noninferior or superior
STRIIVING[10] Suppressive ART DTG/ABC/3TC Noninferior or superior
ATLAS-M[11] ATV/RTV + 2 NRTIs ATV/RTV + 3TC Noninferior or superior
GS-119[12] DRV/RTV-containing “salvage” regimen EVG/COBI/FTC/TAF + DRV Noninferior or superior
LATTE[13] CAB or EFV + 2 NRTIs CAB + RPV (PO) Noninferior or superior
GS-1089[14] TDF/FTC + third agent TAF/FTC + third agent Noninferior or superior
LATTE-1[15] CAB + ABC/3TC CAB + RPV (IM) Noninferior or superior
GS-1160[16] EFV/FTC/TDF RPV/FTC/TAF Noninferior or superior
GS-1216[16] RPV/FTC/TDF RPV/FTC/TAF Noninferior or superior
SWORD-1 & 2[17] 3-drug regimen DTG/RPV Noninferior or superior
SWITCHMRK[18] 2 NRTI + LPV/RTV (experienced pts) 2 NRTI + RAL ✗
HARNESS[19] 2 NRTI + third agent ATV/RTV + RAL ✗
Switch Studies in Virologically Suppressed Pt
SWITCHMRK 1 and 2: Prior Failure Predicts
Failure
 Parallel, randomized, multicenter, double-blind, active-controlled trials
comparing switch to RAL vs continuing on LPV/RTV-based ARV in pts with
virologic suppression (N = 702)
 Inferior efficacy of RAL appeared driven by more failure among pts with
previous virologic failure
Outcome
SWITCHMRK 1 SWITCHMRK 2
RAL
(n = 174)
LPV/RTV
(n = 174)
RAL
(n = 176)
LPV/RTV
(n = 178)
Pts without previous virologic failure
 HIV-1 RNA < 50 c/mL at Wk 24, % 85.1 85.8 92.5 93.5
 Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3)
Pts with previous virologic failure
 HIV-1 RNA < 50 c/mL at Wk 24, % 72.3 89.7 79.7 93.8
 Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)
Eron JJ, et al. Lancet. 2010;375:396-407. Slide credit: clinicaloptions.com
Investigational Drugs and Strategies
ONCEMRK: RAL 1200 mg QD Noninferior to
400 mg BID at Wk 48 in ART-Naive Pts
 Multinational, double-blind phase
III trial in ART-naive pts with HIV-1
RNA ≥ 1000 c/mL
– Pts randomized to RAL 1200 mg
QD vs RAL 400 mg BID +
FTC/TDF (N = 802)
 Noninferior Wk 48 HIV-1 RNA <
40 copies/mL in pts with BL HIV-1
RNA > 100,000 copies/mL
– RAL QD: 86.7%; RAL BID: 83.8%
(∆ 2.9; 95% CI: -6.5 to 14.1)
 RAL QD associated with overall
safety profile similar to RAL BID
Cahn P, et al. AIDS 2016. Abstract FRAB0103LB. Slide credit: clinicaloptions.com
100
80
60
40
20
0
PtsWithHIV-1RNA<40copies/mL(%)
0 4 8 12 16 20 24 28 32 36 40 44 48
Treatment Wk
RAL 1200 mg QD + FTC/TDF
RAL 400 mg BID + FTC/TDF
88.388.786.5
83.5
78.2
51.9
53.5
76.3
82.1
87.4 87.2 88.9
Bictegravir + FTC/TAF vs DTG + FTC/TAF: Wk 24
and Wk 48 Efficacy (FDA Snapshot)
 Double-blind, active-controlled phase II trial of ART-naive pts with HIV-1 RNA ≥ 1000 c/mL (N = 98)
 No drug resistance detected in either arm through Wk 48
Slide credit: clinicaloptions.comSax PE, et al. CROI 2017. Abstract 41.
Virologic
Failure
Wk 48
Virologic
Success
No Data
100
80
60
40
20
0
97
91
2 6 2 3
Treatment difference: 6.4%
(95% CI: -6.0% to 18.8%)
Virologic
Failure
Wk 24
Virologic
Success
No Data
100
80
60
40
20
0
Pts(%)
97
94
3 6
0 0
Treatment difference: 2.9%
(95% CI: -8.5% to 14.2%)
BIC + FTC/TAF (n = 65)
DTG + FTC/TAF (n = 33)
 Difficult to conclude on safety from small
study, but 4 fully enrolled phase III trials
now evaluating efficacy, safety, tolerability
of coformulated BIC/FTC/TAF
Bictegravir + FTC/TAF vs DTG + FTC/TAF: AEs
and Lab Abnormalities
Slide credit: clinicaloptions.comSax PE, et al. CROI 2017. Abstract 41. Reproduced with permission.
Any Grade AE Occurring
in ≥ 5% in Either Arm, %
BIC + FTC/TAF
(n = 65)
DTG + FTC/TAF
(n = 33)
Diarrhea 12 12
Nausea 8 12
Headache 8 3
URTI 8 0
Fatigue 6 6
Arthralgia 6 6
Chlamydial infection 6 3
Back pain 6 0
Furuncle 5 6
Flatulence 2 6
Gastroenteritis 2 6
Costochondritis 0 6
Hemorrhoids 0 6
Pruritus 0 6
Grade 2-4 Lab Abnormality
≥ 5% in Either Arm, %
BIC + FTC/TAF
(n = 64*)
DTG + FTC/TAF
(n = 32*)
Creatine kinase 13 9
AST 9 3
Hyperglycemia 8 13
ALT 6 0
LDL 6 9
Amylase 5 6
Hematuria 3 6
Glycosuria 2 6
*Pts with ≥ 1 post-BL laboratory assessment, excluding those
not specified for all pts.
Doravirine Is Noninferior to DRV + RTV at Wk 48
(FDA Snapshot)
 Multicenter, randomized, double-blind
phase III trial in ART-naive pts with
HIV-1 RNA ≥ 1000 c/mL (N = 769)
 Efficacy similar in both arms
regardless of baseline HIV-1 RNA or
CD4+ cell count
 No drug resistance detected in pts
with PDVF through Wk 48 in either
arm
– n = 1 pt with noncompliance
discontinued at Wk 24, developed
DOR and FTC resistance
Molina JM, et al. CROI 2017. Abstract 45LB.
Virologic
Nonresponse
Wk 48
HIV-1 RNA
< 50 c/mL
No Data
100
80
60
40
20
0
Pts(%)
84 80
11 13
5 7
Treatment difference: 3.9%
(95% CI: -1.6% to 9.4%)
DOR + 2 NRTIs (n = 383)
DRV + RTV + 2 NRTIs (n = 383)
Slide credit: clinicaloptions.com
Doravirine vs DRV + RTV in Combination With
TDF/FTC or ABC/3TC: Safety
Slide credit: clinicaloptions.comMolina JM, et al. CROI 2017. Abstract 45LB.
AE, %
DOR
(n = 383)
DRV + RTV
(n = 383)
≥ 1 AE 80 78
Treatment-related AE 31 32
Serious AE 5 6
Discontinuation for AE 2 3
AEs of clinical interest
Rash*
Neuropsychiatric†
7
11
8
13
Fasting Lipid Δ From
BL to Wk 48, mg/dL
DOR
(n = 383)
DRV + RTV
(n = 383)
LDL cholesterol* -4.51 9.92
Non-HDL cholesterol* -5.3 13.75
Cholesterol -1.37 17.9
Triglyceride -3.14 21.97
HDL cholesterol 3.94 4.15
*Discontinued due to rash: n = 2 in DOR arm; n = 1 in
DRV + RTV arm.
†No discontinuation for neuropsychiatric conditions.
*P < .0001 for DOR vs DRV + RTV.
TMB-301: Long-Acting Ibalizumab in Pretreated
Pts Infected With Multidrug-Resistant HIV
 Ibalizumab: humanized mAb to conformational epitope on CD4 receptor that blocks
postattachment HIV entry into CD4+ T-cells without altering normal cell function
 Single-arm, open-label phase III trial
– Primary endpoint: ≥ 0.5 log10 HIV-1 RNA decrease at Day 14
 53% with resistance to all drugs from ≥ 3 classes; 68% with INSTI resistance
Lewis S, et al. CROI 2017. Abstract 449LB. Slide credit: clinicaloptions.com
Pts with HIV-1 RNA
> 1000 copies/mL;
on ART ≥ 6 mos, on stable
ART ≥ 8 wks; resistant to
≥ 1 ARV from 3 classes,
sensitive to ≥ 1 ARV for OBR
(N = 40)
Wk 25
Ibalizumab
2000 mg IV Day 7
(Loading Dose)
Continue Failing ART
Days 0-14
Ibalizumab
800 mg IV Day 21, Q2W
(Maintenance Dose)
Switch to OBR
Day 14
Primary
endpoint:
Day 14Control period:
Days 0-7
TMB-301: Efficacy, Safety of Ibalizumab Through
24 Wks
 Primary endpoint: 83% with ≥ 0.5 log10
HIV-1 RNA decrease at Day 14 vs 3%
at end of control period (P < .0001)
– 60% with ≥ 1.0 log10 HIV-1 RNA
decrease
– Mean decrease by Day 14: 1.1 log10
 9 pts reported 17 serious AEs
– 1 drug-related serious AE (IRIS)
resulted in discontinuation
 9 other pts discontinued
– Death (n = 4; liver failure, Kaposi
sarcoma; end-stage AIDS, lymphoma)
– Consent withdrawal (n = 3)
– Lost to follow-up (n = 2)
 No cases of anti-ibalizumab
antibodies
Lewis S, et al. CROI 2017. Abstract 449LB. Slide credit: clinicaloptions.com
Wk 24 Virologic Outcome
Ibalizumab +
OBR
≥ 1.0 log10 HIV-1 RNA decrease, % 55
≥ 2.0 log10 HIV-1 RNA decrease, % 48
HIV-1 RNA < 50 copies/mL, % 43
HIV-1 RNA < 200 copies/mL, % 50
Mean HIV-1 RNA decrease from
baseline, log10
1.6
Simplification With
Dual Therapy and Monotherapy
PADDLE: DTG + 3TC for Treatment-Naive Pts
Cahn P, et al. AIDS 2016. Abstract FRAB0104LB.
Pt #
HIV-1 RNA (copies/mL)
Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 24 Wk 36 Wk 48
1 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
2 8887 10,233 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
3 67,335 151,569 37,604 1565 1178 266 97 53 < 50 < 50 < 50 < 50 < 50 < 50 < 50
4 99,291 148,370 11,797 3303 432 179 178 55 < 50 < 50 < 50 < 50 < 50 < 50 < 50
5 34,362 20,544 4680 1292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
6 16,024 14,499 3754 1634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
7 37,604 18,597 2948 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
8 25,071 24,368 6264 1377
Not
done 268 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
9 14,707 10,832
Not
done 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE
10 10,679 7978 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
11 50,089 273,676160,974 68,129 3880 2247 784 290 288 147 < 50 < 50 < 50 < 50 < 50
12 13,508 64,103 3496 3296 135 351 351 84 67 < 50 < 50 < 50 < 50 < 50 < 50
13 28,093 33,829 37,350 26,343 539 268 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
14 15,348 15,151 3994 791 198 98 < 50 61 64 < 50 < 50 < 50 < 50 < 50 < 50
15 23,185 23,500 15,830 4217 192 69 < 50 < 50 < 50
Not
done < 50 < 50 < 50 < 50 < 50
16 11,377 3910 370 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
17 39,100 25,828 11,879 1970 460 147 52 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
18 60,771 73,069 31,170 2174 692 358 156 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
19 82,803 106,320 35,517 2902 897 352 168 76 < 50 < 50 < 50 < 50 < 50 Virologic failure
20 5190 7368 3433 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
 18/20 pts achieved HIV-1
RNA < 50 c/mL at Wk 48
– 1 pt died by suicide
(deemed unrelated to
study drugs)
– 1 pt experienced PDVF
at Wk 36 (BL HIV-1 RNA
> 100,000 c/mL);
resuppressed HIV-1
RNA without ART
change by d/c visit
(Wk 52)
– 3 other pts with BL HIV-1
RNA > 100,000 c/mL
suppressed at Wk 48
Slide credit: clinicaloptions.com
ANRS 167 LAMIDOL: Switch to DTG + 3TC in
Virologically Suppressed Pts on Triple ART
 Noncomparative, open-label, single-arm multicenter trial
– Primary endpoint: therapeutic success at Wk 56 (ie, after 48 wks of dual
therapy)
– Therapeutic failure: HIV-1 RNA > 50 copies/mL, interruption, LTFU, death
Joly V, et al. CROI 2017. Abstract 458. Slide credit: clinicaloptions.com
DTG 50 mg QD +
2 NRTI†
HIV-infected pts with
HIV-1 RNA ≤ 50 copies/mL
for ≥ 2 yrs on first-line ART;
≤ 2 ART modifications
allowed, except within 6 mos
of study start; CD4+ cell count
> 200 cells/mm3
(N = 110)
Wk 8* Wk 56
*Pts with HIV-1 RNA ≤ 50 copies/mL proceeded to phase II.
†In phase I, third agent in regimen replaced with DTG; baseline NRTI
backbone maintained.
DTG 50 mg QD +
3TC 300 mg QD
(n = 104)
Phase I Phase II
 97% (101/104) pts maintained
therapeutic success through 40
wks of dual therapy (study Wk 48)
– No INSTI resistance in 3 pts with
virologic failure
– 7 pts with serious AEs; only 2
related to dual therapy
Joly V, et al. CROI 2017. Abstract 458.
Wks 0-8: pts on baseline 3-drug ART
switched to DTG + 2 NRTIs
PtsWithHIV-1RNA<50copies/mL(%)
0
20
60
40
80
100
0 8 12 16 40 48Wk:
100
24 32
n/N =
110/
110
104/
104
100 100
104/
104
103/
104
99
103/
104
99
103/
104
99
102/
104
98
101/
104
97
Wks 8-56: pts with HIV-1 RNA < 50 copies/mL
switched to DTG + 3TC
LAMIDOL Interim Analysis: Switch to DTG + 3TC
Effective in Maintaining Viral Suppression
Slide credit: clinicaloptions.com
LATTE-2: Maintenance Therapy With
Cabotegravir IM + RPV IM (ITT-ME Population)
 Multicenter, open-label phase IIb study comparing continuation of oral CAB
vs switching to IM CAB Q4W or Q8W
Treatment Differences (95% CI)
Margolis DA, et al. AIDS 2016. Abstract THAB0206LB. Slide credit: clinicaloptions.com
Virologic Outcomes  2 pts with
resistance
(1 to NNRTI,
1 to INSTI) in
Q8W arm
92
HIV-1RNA<50c/mL(%)
Q8W IM (n = 115)
Q4W IM (n = 115)
Oral CAB (n = 56)
Virologic
Success
Virologic
Nonresponse
No Virologic
Data
91
100
80
60
40
20
0
0 2 4 6 8
-6.6
2.9
12.4
IMOral
14-12 -4 -2
Q8W IM
89
7
< 1 < 1
8
< 1
9
10 12-6-10 -8
0 2 4 6 8
-7.6
2.0
11.6
14-12 -4 -2
Q4W IM
10 12-6-10 -8
SWORD 1 & 2: Switch From Suppressive ART to DTG +
RPV Noninferior to Continued Baseline ART at Wk 48
 Open-label, multicenter phase III
trials of pts with virologic suppression
(N = 1024) randomized to continue
baseline ART vs switch to DTG + RPV
 1 pt with confirmed criteria for virologic
withdrawal at Wk 36 in DTG + RPV
arm had K101K/E
– Documented nonadherence at VF
– Resuppressed with continued
DTG + RPV
– No INSTI resistance
Llibre JM, et al. CROI 2017. Abstract 44LB. Slide credit: clinicaloptions.com
Virologic
Nonresponse
HIV-1 RNA
< 50 c/mL
No Data
100
80
60
40
20
0
Pts(%)
95 95
< 1 1
5 4
Treatment difference: -
0.2%
(95% CI: -3.0% to 2.5%)
DTG + RPV (n = 513)
Baseline ART (n = 511)
Switch From Suppressive ART to DTG + RPV:
Safety Outcomes
 AE rates generally similar between
treatment arms through Wk 52
– Numerically higher rate of drug-
related grade 1/2 AEs with switch:
17% vs 2%
– Numerically higher rate of
withdrawal for AEs with switch:
4% vs < 1%
 No notable change in serum lipid
values from baseline to Wk 48 in
either treatment arm
Llibre JM, et al. CROI 2017. Abstract 44LB. Reproduced with permission. Slide credit: clinicaloptions.com
Bone-specific
alkaline
phosphatase
Osteocalcin Procollagen 1
N-terminal
propeptide
Bone Turnover Marker
DTG + RPV Baseline ART
0
20
60
40
80
Mean(µg/L)
Baseline
Wk 48
15.9
12.9
100 Baseline
Wk 48
16.2 17.1
23.8
19.0
24.0 23.1
53.0
45.6
55.354.7
P < .001
P < .001
P < .001
Emergent INSTI Resistance After Switch to DTG
Monotherapy
 International, multicenter
retrospective study
– Evaluated virologically suppressed
pts switched to DTG 50 mg QD
monotherapy
– Pts with history of VF on INSTI and
INSTI resistance excluded
 11 of 122 pts switched to DTG
monotherapy experienced VF
– Median 5 wks from VF to GRT
– 9 of 11 had genotypic INSTI
resistance at VF
 INSTI resistance pathways varied
Blanco JL, et al. CROI 2017. Abstract 42. Slide credit: clinicaloptions.com
INSTI Resistance at VF
92Q/155H (n = 1)
97A/155H (n = 1)
155H/148R (n = 1)
118R (n = 2)
148K (n = 1)
148H (n = 2)
148R (n = 1)
The Pipeline
Integrase Inhibitors
 Bictegravir (phase III):
QD unboosted INSTI coformulated with
FTC/TAF[1]
 Cabotegravir (phase IIb):
Long-acting injectable for treatment or
PrEP[2]
NNRTIs
 Doravirine (phase III):
Active against some forms of resistant
virus,[3] better tolerated than EFV[4]
 Rilpivirine (phase IIb):
Long-acting injectable version for
treatment or PrEP[2]
Slide credit: clinicaloptions.com
Entry Inhibitors
 Ibalizumab (phase III):
Monoclonal antibody that binds to CD4,
given by IV infusion every 2 wks[5]
 Fostemsavir (phase IIb):
Attachment inhibitor: binds to gp120[6]
NRTIs
 MK-8591 (EFdA) (phase Ib):
Translocation inhibitor, long-acting oral
dosing[7]
Protease Inhibitors
 DRV/COBI/FTC/TAF (phase III):
QD single-tablet regimen[8]
Additional Investigational Agents Reported at
CROI 2017: Phase II
1. Murphy R, et al. CROI 2017. Abstract 452LB.
2. Wang CY, et al. CROI 2017. Abstract 450LB. Slide credit: clinicaloptions.com
Agent
MoA or
Formulation
Phase
Dosing/
Administration
Implications
Elsulfavirine[1]
Prodrug of
new NNRTI
VM1500A
IIb
Combined therapy:
20 mg elsulfavirine
+ FTC/TDF PO
QD
 Less toxic alternative to EFV for initial ART
UB-421[2] Anti-CD4
receptor mAb
II
10 mg/kg QW IV
or
25 mg/kg Q2W IV
 Possible ART alternative for maintenance
therapy in virologically suppressed pts
Take-home Points
 INSTI-based regimens are now the standard of care for initial therapy
 TAF/FTC is the preferred NRTI backbone for all regimens except
DTG/ABC/3TC
 Switching from TDF to TAF increases bone density and eGFR and
decreases proteinuria
 Stay tuned for The Great Debate: 3 drugs vs 2 drugs
 Drug development continues, largely driven by the desire for long-acting
regimens
 DTG resistance can happen but is rare…
 …except with DTG monotherapy. Don’t do it!
Slide credit: clinicaloptions.com
clinicaloptions.com/hiv
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Топ достижений лечения ВИЧ в 2017 г / Top Advances in ART for 2017

  • 1. Joel Gallant, MD, MPH Medical Director of Specialty Services Southwest CARE Center Santa Fe, New Mexico Adjunct Professor of Medicine Division of Infectious Diseases Johns Hopkins University School of Medicine Baltimore, Maryland Top Advances in ART for 2017 Supported by educational grants from AbbVie; Bristol-Myers Squibb; Gilead Sciences; Janssen Therapeutics; Merck & Co., Inc; and ViiV Healthcare.
  • 2. About These Slides  Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients  When using our slides, please retain the source attribution:  These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details Slide credit: clinicaloptions.com
  • 3. Disclosures Joel Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Merck, Theratechnologies, and ViiV/GlaxoSmithKline and funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Sangamo, and ViiV/GlaxoSmithKline.
  • 4. Initial Regimens: The Growing Dominance of Integrase Inhibitors
  • 5. What to Start: DHHS Guidelines, July 2016 Recommended Regimens PI based  DRV/RTV + (TDF/FTC or TAF/FTC) INSTI based  DTG/ABC/3TC*  DTG + (TDF/FTC or TAF/FTC)  EVG/COBI/TDF/FTC or EVG/c/TAF/FTC  RAL + (TDF/FTC or TAF/FTC) Alternative Regimens NNRTI based  EFV/TDF/FTC or EFV + TAF/FTC  RPV/TDF/FTC or RPV/TAF/FTC (requires HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3) PI based  (ATV/COBI or ATV/RTV) + (TDF/FTC or TAF/FTC)  (DRV/COBI or DRV/RTV) + ABC/3TC*  DRV/COBI + (TDF/FTC or TAF/FTC) *Pt must be HLA-B*5701 negative. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. July 2016. Slide credit: clinicaloptions.com
  • 6. What to Start: IAS–USA Guidelines, July 2016 Recommended Regimens  DTG/ABC/3TC*  DTG + FTC/TAF  EVG/COBI/FTC/TAF  RAL + FTC/TAF Regimens When INSTIs Are Not an Option  EFV/FTC/TDF  RPV/FTC/(TAF or TDF)†  DRV/COBI or DRV/RTV + (FTC/TAF, FTC/TDF, or ABC/3TC*) Günthard HF, et al. JAMA. 2016;316:191-210. Slide credit: clinicaloptions.com *Pt must be HLA-B*5701 negative. †If HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3.
  • 7. Initial ART With EVG/COBI/FTC/TAF Superior to EVG/COBI/FTC/TDF at Wk 144  Efficacy similar across pt subgroups, trending toward or significantly better with TAF in each group – By baseline HIV-1 RNA, baseline CD4+ cell count, adherence, age, sex, race, region  Virologic failure with resistance by Wk 144: 1.4% in each arm Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet. 2015;385:2606-2615. Slide credit: clinicaloptions.com 0 20 60 40 80 100 48 96 144 48 96 144 48 96 144Wk: Virologic Success Virologic Failure No Data 92 90 87 85 84 80 4 4 5 4 5 4 4 6 9 11 11 16 Pts(%) Treatment Difference Wk 48: 2.0% (95% CI: -0.7% to 4.7%) Wk 144: 4.2% (95% CI: 0.6% to 7.8%; P = .02) EVG/COBI/FTC/TAF (n = 866) EVG/COBI/FTC/TDF (n = 867)
  • 8. Initial ART With EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF: Wk 144 Safety Outcomes  Rate of discontinuation for AEs higher with TDF vs TAF regimen – 3.3% vs 1.3% (P = .01)  Spine and hip BMD loss greater with TDF vs TAF regimen – 6 discontinuations for bone AEs in TDF arm vs 0 in TAF arm  TC, LDL, and HDL increases greater with TAF vs TDF regimen, but no difference in TC:HDL ratio – Rates of lipid-modifying therapy initiation similar: 5.5% vs 5.8% Slide credit: clinicaloptions.com Renal Events Leading to Discontinuation, n EVG/COBI/ FTC/TAF (n = 866) EVG/COBI/ FTC/TDF (n = 867) Proximal renal tubulopathy 0 4 Cr elevation or eGFR decrease 0 3 Renal failure 0 2 Nephropathy 0 1 Proteinuria 0 1 Bladder spasm 0 1 Total 0 12 Arribas JR, et al. CROI 2017. Abstract 453.
  • 9. WAVES: Switch to EVG/COBI/FTC/TAF Maintained Virologic Suppression in Women at Wk 48  Open-label extension study Hodder S, et al. CROI 2017. Abstract 443. Slide credit: clinicaloptions.com Virologic Outcome Treatment Difference (95% CI) HIV-1RNA<50c/mL(%) 100 80 60 40 20 0 Switch to EVG/COBI/ FTC/TAF (n = 159) Continue ATV + RTV + FTC/TAF (n = 53) Success Failure No Data n = 150 46 3 2 6 5 94 87 2 4 4 9 0 10 20-20 -10 -1.2 7.5 19.4 Favors EVG/COBI/ FTC/TAF Favors ATV/RTV + FTC/TAF
  • 10. DTG/ABC/3TC HIV-1RNA<50c/mL(%) CD4+ Cell CountHIV-1 RNA Overall ≤ 100K > 100K ≤ 350 > 350 100 80 60 40 20 0 82 71 83 74 80 64 85 72 78 71 203/ 248 176/ 247 148/ 179 134/ 181 55/ 69 42/ 66 111/ 130 89/ 124 92/ 118 87/ 123 ATV/RTV + FTC/TDF n/N = 0 4 8 12 16 3.1 10.5 17.8 Favors DTG/ABC/3TC Favors ATV/RTV + FTC/TDF Overall Treatment Difference (95% CI) 20-16 -12 -8 -4 ARIA: DTG/ABC/3TC Superior to ATV/RTV + FTC/TDF in ART-Naive Women at Wk 48 Orrell C, et al. AIDS 2016. Abstract THAB0205LB. Johnson M, et al. HIV Glasgow 2016. Abstract P035. Hagins D, et al. IDWeek 2016. Abstract 949. Slide credit: clinicaloptions.com P = .005 Outcome, % (n) DTG/ABC/3TC (n = 248) ATV/RTV + FTC/TDF (n = 247) Virologic nonresponse 6 (16) 14 (35) No virologic data 12 (29) 15 (36) Virologic Outcome
  • 11. Dolutegravir + NRTIs in Treatment-Naive Pts 1. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;70:515-519. 2. Molina JM, et al. Lancet HIV. 2015;2:e127-e136. 3. Raffi F, et al. Lancet. 2013;381:735-743. 4. Raffi F, et al. Lancet Infect Dis. 2013;13:927-935. 5. Orrell C, et al. IAS 2016. Abstract THAB0205LB. 6. Fulcher JA, et al. CROI 2017. Abstract 500LB.  No resistance selected for in any DTG + 2 NRTI regimen in SINGLE,[1] FLAMINGO,[2] SPRING-2,[3,4] and ARIA[5] – 1 case report of possible emergence of INSTI resistance in treatment-naive pt receiving DTG + FTC/TDF[6] – Pt with an acute opportunistic infection experienced virologic failure followed by subsequent resuppression after addition of DRV/RTV – No baseline integrase resistance data available Slide credit: clinicaloptions.com
  • 12. Switching Therapy in Virologically Suppressed Pts
  • 13. Switching Therapy in Virologically Suppressed Pts: When and Why?  To manage adverse events  To manage or prevent drug toxicity  To simplify regimen (number of doses or pills)  To address food restrictions  To address drug interactions  To plan for pregnancy  To reduce cost  To address new HBV coinfection
  • 14. Switch Studies in Virologically Suppressed Pts Adapted from David Wohl. References in slidenotes. Trial From To Outcome vs Suppressive ART GS-123[1] TDF/FTC + RAL EVG/COBI/FTC/TDF Virologic suppression maintained GS-264[2] TDF/FTC/EFV RPV/FTC/TDF Virologic suppression maintained Strategy-NNRTI[3] TDF/FTC + NNRTI EVG/COBI/FTC/TDF Noninferior or superior Strategy-PI[4] TDF/FTC + PI/RTV EVG/COBI/FTC/TDF Noninferior or superior SPIRIT[5] 2 NRTI + PI/RTV RPV/FTC/TDF Noninferior or superior SPIRAL[6] 2 NRTI + PI/RTV (experienced pts) RAL + 2 NRTIs Noninferior or superior SALT[7] ATV/RTV + 2 NRTIs ATV/RTV + 3TC Noninferior or superior OLE[8] LPV/RTV + 2 NRTIs LPV/RTV + 3TC Noninferior or superior GS-109[9] TDF-based ART EVG/COBI/FTC/TAF Noninferior or superior STRIIVING[10] Suppressive ART DTG/ABC/3TC Noninferior or superior ATLAS-M[11] ATV/RTV + 2 NRTIs ATV/RTV + 3TC Noninferior or superior GS-119[12] DRV/RTV-containing “salvage” regimen EVG/COBI/FTC/TAF + DRV Noninferior or superior LATTE[13] CAB or EFV + 2 NRTIs CAB + RPV (PO) Noninferior or superior GS-1089[14] TDF/FTC + third agent TAF/FTC + third agent Noninferior or superior LATTE-1[15] CAB + ABC/3TC CAB + RPV (IM) Noninferior or superior GS-1160[16] EFV/FTC/TDF RPV/FTC/TAF Noninferior or superior GS-1216[16] RPV/FTC/TDF RPV/FTC/TAF Noninferior or superior SWORD-1 & 2[17] 3-drug regimen DTG + RPV Noninferior or superior
  • 15. STRIIVING: Initial vs Delayed Switch to DTG/ABC/3TC From Suppressive ART  Pts with HIV-1 RNA < 50 copies/mL on stable ART ≥ 6 mos, no previous virologic failure, HLA-B*5701 negative (N = 553)  Pts randomized to initial vs delayed switch at Wk 24 and followed through Wk 48 *ITT-E analysis. Lake J, et al. AIDS 2016. Abstract THAB0203. Slide credit: clinicaloptions.com HIV-1RNA<50c/mL(%) 100 80 60 40 20 0 Virologic Success Virologic Nonresponse No Virologic Data 85 88 83 1 1 < 1 14 10 17 DTG/ABC/3TC, Day 1 to Wk 24 (n = 275)* Continue baseline ART, Day 1 to Wk 24 (n = 278)* DTG/ABC/3TC, Day 1 to Wk 48 (n = 275)
  • 16. TAF vs TDF: Mechanism of Action Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet. 2015;385:2606-2615. Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58-64. Slide credit: clinicaloptions.com GI tract TDF 300 mg TAF 25 mg Plasma TFV 90% lower plasma TFV than with TDF Lymphocyte Renal tubular cell Renal tubular cell TFV HIV
  • 17. Renal Considerations for Recommended Initial Regimens ABC/3TC  Do not use if CrCl < 50 mL/min FTC/TDF  EVG/COBI/FTC/TDF: do not start if CrCl < 70 mL/min; d/c if CrCl < 50 mL/min  FTC/TDF: dose adjust if CrCl 30-49 mL/min; do not use if CrCl < 30 mL/min FTC/TAF  No dose adjustment needed if CrCl ≥ 30 mL/min, regardless of coformulation Class First-line ART DHHS Recommended IAS-USA Recommended INSTI  DTG/ABC/3TC  DTG + FTC/TDF or FTC/TAF  EVG/COBI/FTC/TDF  EVG/COBI/FTC/TAF  RAL + FTC/TDF or FTC/TAF  DTG/ABC/3TC  DTG + FTC/TAF  EVG/COBI/FTC/TAF  RAL + FTC/TAF Boosted PI  DRV + RTV + FTC/TDF or FTC/TAF What to Start: July 2016 Slide credit: clinicaloptions.com DHHS Guidelines. July 2016. Günthard HF, et al. JAMA. 2016;316:191-210. ABC/3TC [package insert]. September 2015. EVG/COBI/FTC/TDF [package insert] January 2017. FTC/TAF [package insert]. April 2016. FTC/TDF [package insert]. April 2016.
  • 18. Summary of TAF Switch Studies in Virologically Suppressed Pts Trials:  GS-109: TDF-containing regimens to EVG/COBI/FTC/TAF[1]  GS -112: switch to EVG/COBI/FTC/TAF in pts with impaired renal function[2]  GS-119: ART + DRV/RTV to EVG/COBI/FTC/TAF + DRV in ART-experienced pts[3]  GS-1089: FTC/TDF to FTC/TAF[4]  GS-1160: EFV/FTC/TDF to RPV/FTC/TAF[5]  GS-1216: RPV/FTC/TDF to RPV/FTC/TAF[5] Results:  Noninferiority, with superiority in GS-109 for switch to EVG/COBI/FTC/TAF from EFV/FTC/TDF or ATV/RTV + FTC/TDF and superiority in GS-119  Increase in bone density  Stability of eGFR (increase in GS-1089 and GS-112) with no tubular toxicity and decrease in overall and tubular proteinuria References in slidenotes. Slide credit: clinicaloptions.com
  • 19. GS-1089: Switch From TDF- to TAF-Containing ART Noninferior at Wks 48 and 96  Phase III trial of pts with HIV-1 RNA < 50 c/mL, eGFR ≥ 50 mL/min while receiving FTC/TDF + third ARV (N = 663) Pts(%) Virologic Success Virologic Failure No Virologic Data Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96 94 93 89 89 0 2 2 1 5 6 9 10 100 80 60 40 20 0 Raffi F, et al. HIV Glasgow 2016. Abstract O125. Slide credit: clinicaloptions.com 0 2 4 6 8 -5.3 -.5 4.4 Favors FTC/TAFFavors FTC/TDF Overall Treatment Difference (95% CI) 10-6 -4 -2 -2.5 1.3 5.1 Wk 48 Wk 96 FTC/TAF (n = 333) FTC/TDF (n = 330) Virologic Outcome
  • 20. GS-1089: Bone and Renal Parameters for TAF- vs TDF-Containing ART at Wk 96 Raffi F, et al. HIV Glasgow 2016. Abstract O125. Slide credit: clinicaloptions.com MeanChangein HipBMD(%) P < .001 3 2 1 0 -1 1.9 -0.3 Wk BL 24 48 72 96 FTC/TAF FTC/TDF 321 317 309 305 300 303 293 296 288 289 MeanChangein SpineBMD(%) P < .001 3 2 1 0 -1 2.2 -0.2 Wk BL 24 48 72 96 FTC/TAF FTC/TDF 321 320 310 310 300 306 294 297 287 292 MedianChange(%) Urine Albumin:Cr Urine Protein:Cr Urine β2-M:Cr Urine RBP:Cr MedianChange(mL/min) eGFR FTC/TAF FTC/TDF P ≤ .005 P ≤ .005 P ≤ .005 P ≤ .005 P ≤ .005
  • 21. GS-119: Immediate vs Delayed Switch to EVG/COBI/FTC/TAF + DRV for Tx-Experienced Pts  Multicenter, open-label phase III trial – Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24 (FDA Snapshot) – Secondary endpoints: HIV-1 RNA < 50 c/mL at Wk 48, CD4+ cell count change, safety Tx-experienced pts, HIV-1 RNA < 50 c/mL for ≥ 4 mos on DRV/RTV- containing ART, with history of drug resistance* and eGFR > 50 mL/min (N = 135) Switch to EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 89) Wk 144Wk 48 Baseline ART (n = 46) EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 46) Wk 24Randomized 2:1 *Resistance to ≥ 2 ARV classes, including ≤ 3 thymidine analogue mutations and/or K65R, but not integrase inhibitors, unless currently suppressed on RAL, EVG, or DTG (50 mg QD only), and no DRV resistance. Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200. Slide credit: clinicaloptions.com
  • 22. GS-119: Baseline Characteristics Characteristics EVG/COBI/ FTC/TAF + DRV (n = 89) Baseline ART (n = 46) Median age, yrs 49 47 Male, % 82 61 Black (or African descent), % 39 57 Median CD4+ cell count, cells/mm3 519 518 Median eGFRCG, mL/min 99 100 DM/HTN/CVD/hyperlipidemia,% 8/34/7/46 11/37/4/28 Baseline Regimen Median no. pills per day 5 5 ≥ 6 pills per day, % 40 37 At least BID dosing, % 65 65 TDF/ABC/other NRTIs, % 61/11/12 54/11/13 RAL 56 50 Resistance, % EVG/COBI/ FTC/TAF + DRV (n = 89) Baseline ART (n = 46) 2-class/3-class resistance 70/26 74/20 M184V/I 85 78 K65R 20 30 NNRTI-R/PI-R 89/38 87/28 Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200. Slide credit: clinicaloptions.com
  • 23. GS-119: Virologic Suppression After Switch to EVG/COBI/FTC/TAF + DRV  At Wk 48, virologic efficacy of switch to EVG/COBI/FTC/TAF + DRV was noninferior and statistically superior to continuing baseline regimen (P = .004)[1]  No emergent resistance in EVG/COBI/FTC/TAF + DRV arm; 1 pt in baseline ART arm with viral rebound (Wk 36) developed resistance (M184V + K65R)[1]  No impact of genotypic susceptibility score on the efficacy of the switch regimen[2] EVG/COBI/FTC/TAF + DRV (n = 89) Baseline ART (n = 46) Wk 48 HIV-1 RNA < 50 c/mL Virologic Failure No Data 94 76 2 11 3 13 Treatment difference: 18.3% (95% CI: 3.5% to 33.0%; P = .004) 1. Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200. 2. Margot N, et al. HIV Glasgow 2016. Abstract O123. Slide credit: clinicaloptions.com
  • 24. Trial From To Outcome vs Suppressive ART GS-123[1] TDF/FTC + RAL EVG/COBI/FTC/TDF Virologic suppression maintained GS-264[2] TDF/FTC/EFV RPV/FTC/TDF Virologic suppression maintained Strategy-NNRTI[3] TDF/FTC + NNRTI EVG/COBI/FTC/TDF Noninferior or superior Strategy-PI[4] TDF/FTC + PI/RTV EVG/COBI/FTC/TDF Noninferior or superior SPIRIT[5] 2 NRTI + PI/RTV RPV/FTC/TDF Noninferior or superior SPIRAL[6] 2 NRTI + PI/RTV (experienced pts) 2 NRTI + RAL Noninferior or superior SALT[7] ATV/r + 2 NRTI ATV/r + 3TC Noninferior or superior OLE[8] LPV/r + 2 NRTIs LPV/r + 3TC Noninferior or superior GS-109[9] TDF-based ART EVG/COBI/FTC/TAF Noninferior or superior STRIIVING[10] Suppressive ART DTG/ABC/3TC Noninferior or superior ATLAS-M[11] ATV/RTV + 2 NRTIs ATV/RTV + 3TC Noninferior or superior GS-119[12] DRV/RTV-containing “salvage” regimen EVG/COBI/FTC/TAF + DRV Noninferior or superior LATTE[13] CAB or EFV + 2 NRTIs CAB + RPV (PO) Noninferior or superior GS-1089[14] TDF/FTC + third agent TAF/FTC + third agent Noninferior or superior LATTE-1[15] CAB + ABC/3TC CAB + RPV (IM) Noninferior or superior GS-1160[16] EFV/FTC/TDF RPV/FTC/TAF Noninferior or superior GS-1216[16] RPV/FTC/TDF RPV/FTC/TAF Noninferior or superior SWORD-1 & 2[17] 3-drug regimen DTG/RPV Noninferior or superior SWITCHMRK[18] 2 NRTI + LPV/RTV (experienced pts) 2 NRTI + RAL ✗ HARNESS[19] 2 NRTI + third agent ATV/RTV + RAL ✗ Switch Studies in Virologically Suppressed Pt
  • 25. SWITCHMRK 1 and 2: Prior Failure Predicts Failure  Parallel, randomized, multicenter, double-blind, active-controlled trials comparing switch to RAL vs continuing on LPV/RTV-based ARV in pts with virologic suppression (N = 702)  Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure Outcome SWITCHMRK 1 SWITCHMRK 2 RAL (n = 174) LPV/RTV (n = 174) RAL (n = 176) LPV/RTV (n = 178) Pts without previous virologic failure  HIV-1 RNA < 50 c/mL at Wk 24, % 85.1 85.8 92.5 93.5  Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3) Pts with previous virologic failure  HIV-1 RNA < 50 c/mL at Wk 24, % 72.3 89.7 79.7 93.8  Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6) Eron JJ, et al. Lancet. 2010;375:396-407. Slide credit: clinicaloptions.com
  • 27. ONCEMRK: RAL 1200 mg QD Noninferior to 400 mg BID at Wk 48 in ART-Naive Pts  Multinational, double-blind phase III trial in ART-naive pts with HIV-1 RNA ≥ 1000 c/mL – Pts randomized to RAL 1200 mg QD vs RAL 400 mg BID + FTC/TDF (N = 802)  Noninferior Wk 48 HIV-1 RNA < 40 copies/mL in pts with BL HIV-1 RNA > 100,000 copies/mL – RAL QD: 86.7%; RAL BID: 83.8% (∆ 2.9; 95% CI: -6.5 to 14.1)  RAL QD associated with overall safety profile similar to RAL BID Cahn P, et al. AIDS 2016. Abstract FRAB0103LB. Slide credit: clinicaloptions.com 100 80 60 40 20 0 PtsWithHIV-1RNA<40copies/mL(%) 0 4 8 12 16 20 24 28 32 36 40 44 48 Treatment Wk RAL 1200 mg QD + FTC/TDF RAL 400 mg BID + FTC/TDF 88.388.786.5 83.5 78.2 51.9 53.5 76.3 82.1 87.4 87.2 88.9
  • 28. Bictegravir + FTC/TAF vs DTG + FTC/TAF: Wk 24 and Wk 48 Efficacy (FDA Snapshot)  Double-blind, active-controlled phase II trial of ART-naive pts with HIV-1 RNA ≥ 1000 c/mL (N = 98)  No drug resistance detected in either arm through Wk 48 Slide credit: clinicaloptions.comSax PE, et al. CROI 2017. Abstract 41. Virologic Failure Wk 48 Virologic Success No Data 100 80 60 40 20 0 97 91 2 6 2 3 Treatment difference: 6.4% (95% CI: -6.0% to 18.8%) Virologic Failure Wk 24 Virologic Success No Data 100 80 60 40 20 0 Pts(%) 97 94 3 6 0 0 Treatment difference: 2.9% (95% CI: -8.5% to 14.2%) BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33)
  • 29.  Difficult to conclude on safety from small study, but 4 fully enrolled phase III trials now evaluating efficacy, safety, tolerability of coformulated BIC/FTC/TAF Bictegravir + FTC/TAF vs DTG + FTC/TAF: AEs and Lab Abnormalities Slide credit: clinicaloptions.comSax PE, et al. CROI 2017. Abstract 41. Reproduced with permission. Any Grade AE Occurring in ≥ 5% in Either Arm, % BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33) Diarrhea 12 12 Nausea 8 12 Headache 8 3 URTI 8 0 Fatigue 6 6 Arthralgia 6 6 Chlamydial infection 6 3 Back pain 6 0 Furuncle 5 6 Flatulence 2 6 Gastroenteritis 2 6 Costochondritis 0 6 Hemorrhoids 0 6 Pruritus 0 6 Grade 2-4 Lab Abnormality ≥ 5% in Either Arm, % BIC + FTC/TAF (n = 64*) DTG + FTC/TAF (n = 32*) Creatine kinase 13 9 AST 9 3 Hyperglycemia 8 13 ALT 6 0 LDL 6 9 Amylase 5 6 Hematuria 3 6 Glycosuria 2 6 *Pts with ≥ 1 post-BL laboratory assessment, excluding those not specified for all pts.
  • 30. Doravirine Is Noninferior to DRV + RTV at Wk 48 (FDA Snapshot)  Multicenter, randomized, double-blind phase III trial in ART-naive pts with HIV-1 RNA ≥ 1000 c/mL (N = 769)  Efficacy similar in both arms regardless of baseline HIV-1 RNA or CD4+ cell count  No drug resistance detected in pts with PDVF through Wk 48 in either arm – n = 1 pt with noncompliance discontinued at Wk 24, developed DOR and FTC resistance Molina JM, et al. CROI 2017. Abstract 45LB. Virologic Nonresponse Wk 48 HIV-1 RNA < 50 c/mL No Data 100 80 60 40 20 0 Pts(%) 84 80 11 13 5 7 Treatment difference: 3.9% (95% CI: -1.6% to 9.4%) DOR + 2 NRTIs (n = 383) DRV + RTV + 2 NRTIs (n = 383) Slide credit: clinicaloptions.com
  • 31. Doravirine vs DRV + RTV in Combination With TDF/FTC or ABC/3TC: Safety Slide credit: clinicaloptions.comMolina JM, et al. CROI 2017. Abstract 45LB. AE, % DOR (n = 383) DRV + RTV (n = 383) ≥ 1 AE 80 78 Treatment-related AE 31 32 Serious AE 5 6 Discontinuation for AE 2 3 AEs of clinical interest Rash* Neuropsychiatric† 7 11 8 13 Fasting Lipid Δ From BL to Wk 48, mg/dL DOR (n = 383) DRV + RTV (n = 383) LDL cholesterol* -4.51 9.92 Non-HDL cholesterol* -5.3 13.75 Cholesterol -1.37 17.9 Triglyceride -3.14 21.97 HDL cholesterol 3.94 4.15 *Discontinued due to rash: n = 2 in DOR arm; n = 1 in DRV + RTV arm. †No discontinuation for neuropsychiatric conditions. *P < .0001 for DOR vs DRV + RTV.
  • 32. TMB-301: Long-Acting Ibalizumab in Pretreated Pts Infected With Multidrug-Resistant HIV  Ibalizumab: humanized mAb to conformational epitope on CD4 receptor that blocks postattachment HIV entry into CD4+ T-cells without altering normal cell function  Single-arm, open-label phase III trial – Primary endpoint: ≥ 0.5 log10 HIV-1 RNA decrease at Day 14  53% with resistance to all drugs from ≥ 3 classes; 68% with INSTI resistance Lewis S, et al. CROI 2017. Abstract 449LB. Slide credit: clinicaloptions.com Pts with HIV-1 RNA > 1000 copies/mL; on ART ≥ 6 mos, on stable ART ≥ 8 wks; resistant to ≥ 1 ARV from 3 classes, sensitive to ≥ 1 ARV for OBR (N = 40) Wk 25 Ibalizumab 2000 mg IV Day 7 (Loading Dose) Continue Failing ART Days 0-14 Ibalizumab 800 mg IV Day 21, Q2W (Maintenance Dose) Switch to OBR Day 14 Primary endpoint: Day 14Control period: Days 0-7
  • 33. TMB-301: Efficacy, Safety of Ibalizumab Through 24 Wks  Primary endpoint: 83% with ≥ 0.5 log10 HIV-1 RNA decrease at Day 14 vs 3% at end of control period (P < .0001) – 60% with ≥ 1.0 log10 HIV-1 RNA decrease – Mean decrease by Day 14: 1.1 log10  9 pts reported 17 serious AEs – 1 drug-related serious AE (IRIS) resulted in discontinuation  9 other pts discontinued – Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma) – Consent withdrawal (n = 3) – Lost to follow-up (n = 2)  No cases of anti-ibalizumab antibodies Lewis S, et al. CROI 2017. Abstract 449LB. Slide credit: clinicaloptions.com Wk 24 Virologic Outcome Ibalizumab + OBR ≥ 1.0 log10 HIV-1 RNA decrease, % 55 ≥ 2.0 log10 HIV-1 RNA decrease, % 48 HIV-1 RNA < 50 copies/mL, % 43 HIV-1 RNA < 200 copies/mL, % 50 Mean HIV-1 RNA decrease from baseline, log10 1.6
  • 35. PADDLE: DTG + 3TC for Treatment-Naive Pts Cahn P, et al. AIDS 2016. Abstract FRAB0104LB. Pt # HIV-1 RNA (copies/mL) Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 24 Wk 36 Wk 48 1 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 2 8887 10,233 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 3 67,335 151,569 37,604 1565 1178 266 97 53 < 50 < 50 < 50 < 50 < 50 < 50 < 50 4 99,291 148,370 11,797 3303 432 179 178 55 < 50 < 50 < 50 < 50 < 50 < 50 < 50 5 34,362 20,544 4680 1292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 6 16,024 14,499 3754 1634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 7 37,604 18,597 2948 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 8 25,071 24,368 6264 1377 Not done 268 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 9 14,707 10,832 Not done 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE 10 10,679 7978 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 11 50,089 273,676160,974 68,129 3880 2247 784 290 288 147 < 50 < 50 < 50 < 50 < 50 12 13,508 64,103 3496 3296 135 351 351 84 67 < 50 < 50 < 50 < 50 < 50 < 50 13 28,093 33,829 37,350 26,343 539 268 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 14 15,348 15,151 3994 791 198 98 < 50 61 64 < 50 < 50 < 50 < 50 < 50 < 50 15 23,185 23,500 15,830 4217 192 69 < 50 < 50 < 50 Not done < 50 < 50 < 50 < 50 < 50 16 11,377 3910 370 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 17 39,100 25,828 11,879 1970 460 147 52 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 18 60,771 73,069 31,170 2174 692 358 156 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 19 82,803 106,320 35,517 2902 897 352 168 76 < 50 < 50 < 50 < 50 < 50 Virologic failure 20 5190 7368 3433 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50  18/20 pts achieved HIV-1 RNA < 50 c/mL at Wk 48 – 1 pt died by suicide (deemed unrelated to study drugs) – 1 pt experienced PDVF at Wk 36 (BL HIV-1 RNA > 100,000 c/mL); resuppressed HIV-1 RNA without ART change by d/c visit (Wk 52) – 3 other pts with BL HIV-1 RNA > 100,000 c/mL suppressed at Wk 48 Slide credit: clinicaloptions.com
  • 36. ANRS 167 LAMIDOL: Switch to DTG + 3TC in Virologically Suppressed Pts on Triple ART  Noncomparative, open-label, single-arm multicenter trial – Primary endpoint: therapeutic success at Wk 56 (ie, after 48 wks of dual therapy) – Therapeutic failure: HIV-1 RNA > 50 copies/mL, interruption, LTFU, death Joly V, et al. CROI 2017. Abstract 458. Slide credit: clinicaloptions.com DTG 50 mg QD + 2 NRTI† HIV-infected pts with HIV-1 RNA ≤ 50 copies/mL for ≥ 2 yrs on first-line ART; ≤ 2 ART modifications allowed, except within 6 mos of study start; CD4+ cell count > 200 cells/mm3 (N = 110) Wk 8* Wk 56 *Pts with HIV-1 RNA ≤ 50 copies/mL proceeded to phase II. †In phase I, third agent in regimen replaced with DTG; baseline NRTI backbone maintained. DTG 50 mg QD + 3TC 300 mg QD (n = 104) Phase I Phase II
  • 37.  97% (101/104) pts maintained therapeutic success through 40 wks of dual therapy (study Wk 48) – No INSTI resistance in 3 pts with virologic failure – 7 pts with serious AEs; only 2 related to dual therapy Joly V, et al. CROI 2017. Abstract 458. Wks 0-8: pts on baseline 3-drug ART switched to DTG + 2 NRTIs PtsWithHIV-1RNA<50copies/mL(%) 0 20 60 40 80 100 0 8 12 16 40 48Wk: 100 24 32 n/N = 110/ 110 104/ 104 100 100 104/ 104 103/ 104 99 103/ 104 99 103/ 104 99 102/ 104 98 101/ 104 97 Wks 8-56: pts with HIV-1 RNA < 50 copies/mL switched to DTG + 3TC LAMIDOL Interim Analysis: Switch to DTG + 3TC Effective in Maintaining Viral Suppression Slide credit: clinicaloptions.com
  • 38. LATTE-2: Maintenance Therapy With Cabotegravir IM + RPV IM (ITT-ME Population)  Multicenter, open-label phase IIb study comparing continuation of oral CAB vs switching to IM CAB Q4W or Q8W Treatment Differences (95% CI) Margolis DA, et al. AIDS 2016. Abstract THAB0206LB. Slide credit: clinicaloptions.com Virologic Outcomes  2 pts with resistance (1 to NNRTI, 1 to INSTI) in Q8W arm 92 HIV-1RNA<50c/mL(%) Q8W IM (n = 115) Q4W IM (n = 115) Oral CAB (n = 56) Virologic Success Virologic Nonresponse No Virologic Data 91 100 80 60 40 20 0 0 2 4 6 8 -6.6 2.9 12.4 IMOral 14-12 -4 -2 Q8W IM 89 7 < 1 < 1 8 < 1 9 10 12-6-10 -8 0 2 4 6 8 -7.6 2.0 11.6 14-12 -4 -2 Q4W IM 10 12-6-10 -8
  • 39. SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV Noninferior to Continued Baseline ART at Wk 48  Open-label, multicenter phase III trials of pts with virologic suppression (N = 1024) randomized to continue baseline ART vs switch to DTG + RPV  1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K101K/E – Documented nonadherence at VF – Resuppressed with continued DTG + RPV – No INSTI resistance Llibre JM, et al. CROI 2017. Abstract 44LB. Slide credit: clinicaloptions.com Virologic Nonresponse HIV-1 RNA < 50 c/mL No Data 100 80 60 40 20 0 Pts(%) 95 95 < 1 1 5 4 Treatment difference: - 0.2% (95% CI: -3.0% to 2.5%) DTG + RPV (n = 513) Baseline ART (n = 511)
  • 40. Switch From Suppressive ART to DTG + RPV: Safety Outcomes  AE rates generally similar between treatment arms through Wk 52 – Numerically higher rate of drug- related grade 1/2 AEs with switch: 17% vs 2% – Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1%  No notable change in serum lipid values from baseline to Wk 48 in either treatment arm Llibre JM, et al. CROI 2017. Abstract 44LB. Reproduced with permission. Slide credit: clinicaloptions.com Bone-specific alkaline phosphatase Osteocalcin Procollagen 1 N-terminal propeptide Bone Turnover Marker DTG + RPV Baseline ART 0 20 60 40 80 Mean(µg/L) Baseline Wk 48 15.9 12.9 100 Baseline Wk 48 16.2 17.1 23.8 19.0 24.0 23.1 53.0 45.6 55.354.7 P < .001 P < .001 P < .001
  • 41. Emergent INSTI Resistance After Switch to DTG Monotherapy  International, multicenter retrospective study – Evaluated virologically suppressed pts switched to DTG 50 mg QD monotherapy – Pts with history of VF on INSTI and INSTI resistance excluded  11 of 122 pts switched to DTG monotherapy experienced VF – Median 5 wks from VF to GRT – 9 of 11 had genotypic INSTI resistance at VF  INSTI resistance pathways varied Blanco JL, et al. CROI 2017. Abstract 42. Slide credit: clinicaloptions.com INSTI Resistance at VF 92Q/155H (n = 1) 97A/155H (n = 1) 155H/148R (n = 1) 118R (n = 2) 148K (n = 1) 148H (n = 2) 148R (n = 1)
  • 42. The Pipeline Integrase Inhibitors  Bictegravir (phase III): QD unboosted INSTI coformulated with FTC/TAF[1]  Cabotegravir (phase IIb): Long-acting injectable for treatment or PrEP[2] NNRTIs  Doravirine (phase III): Active against some forms of resistant virus,[3] better tolerated than EFV[4]  Rilpivirine (phase IIb): Long-acting injectable version for treatment or PrEP[2] Slide credit: clinicaloptions.com Entry Inhibitors  Ibalizumab (phase III): Monoclonal antibody that binds to CD4, given by IV infusion every 2 wks[5]  Fostemsavir (phase IIb): Attachment inhibitor: binds to gp120[6] NRTIs  MK-8591 (EFdA) (phase Ib): Translocation inhibitor, long-acting oral dosing[7] Protease Inhibitors  DRV/COBI/FTC/TAF (phase III): QD single-tablet regimen[8]
  • 43. Additional Investigational Agents Reported at CROI 2017: Phase II 1. Murphy R, et al. CROI 2017. Abstract 452LB. 2. Wang CY, et al. CROI 2017. Abstract 450LB. Slide credit: clinicaloptions.com Agent MoA or Formulation Phase Dosing/ Administration Implications Elsulfavirine[1] Prodrug of new NNRTI VM1500A IIb Combined therapy: 20 mg elsulfavirine + FTC/TDF PO QD  Less toxic alternative to EFV for initial ART UB-421[2] Anti-CD4 receptor mAb II 10 mg/kg QW IV or 25 mg/kg Q2W IV  Possible ART alternative for maintenance therapy in virologically suppressed pts
  • 44. Take-home Points  INSTI-based regimens are now the standard of care for initial therapy  TAF/FTC is the preferred NRTI backbone for all regimens except DTG/ABC/3TC  Switching from TDF to TAF increases bone density and eGFR and decreases proteinuria  Stay tuned for The Great Debate: 3 drugs vs 2 drugs  Drug development continues, largely driven by the desire for long-acting regimens  DTG resistance can happen but is rare…  …except with DTG monotherapy. Don’t do it! Slide credit: clinicaloptions.com
  • 45. clinicaloptions.com/hiv Go Online for More CCO Coverage of HIV! Multimedia modules featuring video of expert faculty discussions of controversies and challenging cases Downloadable slidesets for your own study or presentations