Top Advances in ART for 2017
In this downloadable slideset, Joel E. Gallant, MD, MPH, provides a comprehensive update on ART management.
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Date posted: 3/29/2017
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
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.
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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.
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
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
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
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
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