Слайдсет о новом в лечении ВИЧ.Key Slides on What’s Hot in HIV Treatment.2020

Key Slides on What’s Hot in HIV
Treatment
Supported by an educational grant from Merck Sharp & Dohme Corp.

Program Director
Monica Gandhi, MD, MPH
Professor of Medicine
Division of HIV, Infectious Diseases, and Global Medicine
University of California, San Francisco
Medical Director
Ward 86 HIV Clinic
San Francisco General Hospital
San Francisco, California

Faculty
Linda-Gail Bekker,
FCP(SA), PhD
Chief Operating Officer
Desmond Tutu HIV Foundation
Deputy Director
Desmond Tutu HIV Centre
Immediate Past President
International AIDS Society
Faculty of Health Sciences
University of Cape Town
Cape Town, South Africa
Pedro Cahn, MD, PhD
Senior Consultant, Infectious
Diseases
Hospital Juan Fernández
Director, Fundación Huesped
Professor of Infectious Diseases
Buenos Aires University Medical
School
Buenos Aires, Argentina
Laura Waters, FRCP, MD
Consultant Physician, HIV/GU
Medicine
Mortimer Market Centre

Faculty Disclosures
Linda-Gail Bekker, MBChB, DTM&H, DCH, FCP(SA),
PhD, has no relevant conflicts of interest to report.
Pedro Cahn, MD, PhD, has disclosed that he has received
funds for research support and consulting fees from Merck
and ViiV Healthcare and fees for non-CME/CE services from
Gilead Sciences, Merck, and ViiV Healthcare
Monica Gandhi, MD, MPH, has no relevant conflicts of
interest to report.
Laura Waters, FRCP, MD, has disclosed that she has
received consulting fees from Cipla, Gilead Sciences,
Janssen, MSD, Mylan, and ViiV Healthcare.

Outline
 Navigating Current ART Options
 Optimizing ART in Women of Childbearing Potential and
Pregnancy
 Evolving Data on ART-Associated AEs
 Update on ART Strategies Under Investigation

Navigating Current ART Options

Key First-line ART Trials: Virologic Success
at Wk 48
1. Cahn. Lancet. 2019;393:143. 2. Gallant. Lancet. 2017;390:2063. 3. Sax. Lancet. 2017;390:2073. 4. Sax. Lancet.
2015;385:2606.
5. Eron. AIDS. 2018;32:1431. 6. Clotet. Lancet. 2014;383:2222. 7. DeJesus. Lancet. 2012;379:2429. 8. Cahn. Lancet HIV.
2017;4:e486.
9. Eron. Lancet Infect Dis. 2011;11:907. 10. Walmsley. NEJM. 2013;369:1807. 11. Raffi. Lancet. 2013;381:735. 12. Sax.
Lancet. 2012;379:2439.
13. Squires. Lancet HIV. 2016;3:e410. 14. Lennox. Lancet. 2009;374:796. 15. Cohen. AIDS. 2014;28:989. 16. Cohen.
Lancet. 2011;378:229.
17. Orkin. Clin Infect Dis. 2019;68:535. 18. Molina. Lancet HIV. 2018;5:e211. 19. Ortiz. AIDS. 2008;22:1389. 20. Stephan.
HIV Med. 2013;14:284.
21. Molina. Lancet. 2011;378:238. 22. Orrell. Lancet HIV. 2017;4:e536. Slide credit: clinicaloptions.com
Trials not head-to-head with differences in baseline
characteristics.
*Regimens colored by non-NRTI component: PIs,
INSTIs, NNRTIs.
Trial Regimen* n
VL <
50 c/
mL,
%
SPRING-2[11] RAL BID + 2
NRTIs
41
1
85.4
DRIVE-AHEAD[17] DOR/3TC/
TDF
36
4
84.3
GS-102[12]
EFV/FTC/TDF
35
2
84.1
DRIVE-
FORWARD[18]
DOR + 2
NRTIs
38
3
83.8
ARTEMIS[19,20] DRV/r + FTC/
TDF
34
3
83.7
ECHO[21] RPV +
FTC/TDF
34
6
82.9
ECHO[21]
EFV +
FTC/TDF
34
4
82.8
ARIA[22] DTG/ABC/
3TC
24
8
81.9
DRIVE-AHEAD[17]
EFV/FTC/TDF
36
4
80.8
DRIVE- DRV/r + 2 38
79.9
Trial Regimen* n
VL <
50 c/
mL, %
GEMINI[1]
DTG +
FTC/TDF
71
7
93.3
GS-1489[2] DTG/ABC/
3TC
31
5
93.0
GS-1490[3] DTG +
FTC/TAF
32
5
92.9
GS-1489[2]
BIC/FTC/TAF
31
4
92.4
GS-104/111[4]
EVG/c/FTC/
TAF
86
6
92.4
GEMINI[1]
DTG + 3TC
71
6
91.5
AMBER[5] DRV/c/FTC/
TAF
36
2
91.4
GS-104/111[4]
EVG/c/FTC/
TDF
86
7
90.4
FLAMINGO[6] DTG + 2
NRTIs
24
2
89.7
GS-103[7] EVG/c/FTC/
TDF
35
3
89.5
Trial Regimen* n
VL <
50 c/
mL, %
ONCEMRK[8]
RAL QD +
FTC/TDF
53
1
88.9
QDMRK[9] RAL BID +
FTC/TDF
38
6
88.9
AMBER[5] DRV/c + FTC/
TDF
36
3
88.4
SINGLE[10] DTG +
ABC/3TC
41
4
87.9
SPRING-2[11]
DTG + 2
NRTIs
41
1
87.8
GS-102[12] EVG/c/FTC/
TDF
34
8
87.6
WAVES[13] EVG/c/FTC/
TDF
28
9
87.2
GS-103[7]
ATV/r +
FTC/TDF
35
5
86.8
STARTMRK[14] RAL BID +
FTC/TDF
28
1
86.1
STaR[15]
RPV/FTC/TDF
39
4
85.8

DHHS[1]
IAS-USA[2]
EACS[3]
WHO[4]
Recommended Initial
Regimens for Most
PWH
 BIC/FTC/TAF
 DTG/3TC
 DTG/ABC/3TC
 DTG + XTC + (TAF
or TDF)
 RAL + XTC + (TAF
or TDF)
Generally
Recommended
Initial Regimens
 BIC/FTC/TAF
 DTG/ABC/3TC
 DTG + FTC/TAF
Recommended
Regimens (Preferred)
 BIC/FTC/TAF
 DTG/ABC/3TC
 DTG + FTC/TAF or
XTC/TDF
 RAL + FTC/TAF or XTC/
TDF
Recommended
Regimens
 DOR + FTC/TAF or
XTC/TDF
 DRV + (COBI or RTV)
+ (FTC/TAF or
XTC/TDF)
 DTG + 3TC
 RPV + FTC/TAF or
Preferred First-
line Regimen
 DTG +
XTC/TDF
International Guidance on First-line ART
Slide credit: clinicaloptions.com
1. DHHS Guidelines. December 2019. 2. Saag. JAMA.
2018;320:379. 3. EACS Guidelines. November 2019. 4.
WHO Policy Brief. July 2019.

900mgBID
-1.99
25mgQD
-1.29
200mgQD
-1.52
200mgQD
-1.41
(200or400)/100mgBID
-1.85
600/100mgBID-1.5
500mgQD
-1.58
300mgBID
-1.19
300mgBID
-0.85
300mgBID
-1.55
300mgQD
-1.5
25mgQD
-1.46
200mgQD
-1.7
600mgBID
-2.16
50mgQD
-2.46
50/100mgQD
-1.99
30mgQD
-2.34
50mgQD
-2.06
300mgBID
-1.6
100mgBID
-1.96
Why INSTIs?
Antiviral Activity After 7-14 Days of
Monotherapy
HIV-1RNADecline(log10c/
mL)*
ETR
[1]
RPV
[2]
LPV/r
†[5]
D
RV/r
[6]
ATV
[7]
3TC
[8]
ZD
V
[9]
ABC
‡[10]
TAF
[12]
TD
F
†[11]
FTC
[13]
RAL
[14]
D
TG
[15]
EVG
/r
[16]
CAB
[17]
BIC
[18]
T-20
[20]
D
O
R
[4]
NNRTIs PIs NRTIs INSTIs EIs
N
VP
[3]
*Mean reported for most ARVs; median reported for RPV, DRV/r, ABC, TAF, and T-20. †
Wk 3. ‡
Wk 4.
M
VC
[19]
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0
1. Gruzdev. AIDS. 2003;17:2487. 2. Goebel. AIDS. 2006;20:1721. 3. de Jong. J Infect Dis. 1997;175:966. 4. Schürmann. AIDS. 2016;30:57. 5. Murphy. AIDS.
2001;15:F1.
6. Arastéh. AIDS. 2005;19:943. 7. Sanne. JAIDS. 2003;32:18. 8. Eron. NEJM. 1995;333:1662. 9. Ruane. Pharmacotherapy. 2004;24:307. 10. Staszewski. AIDS.
1998;12:F197.
11. Louie. AIDS. 2003;17:1151. 12. Ruane. JAIDS. 2013;63:449. 13. Rousseau. J Infect Dis. 2003;188:1652. 14. Markowitz. JAIDS. 2006;43:509. 15. Min. AIDS.
2011;25:1737.
16. DeJesus. JAIDS. 2006;43:1. 17. Spreen. HIV Clin Trials. 2013;14:192. 18. Gallant. JAIDS. 2017;75:61. 19. Fätkenheuer. Nat Med. 2005;11:1170. 20. Kilby. Nat
Med. 1998;4:1302.

INSTI Efficacy Across ART-Naive Trials
1. Lennox. Lancet. 2009;374:796. 2. Rockstroh. JAIDS. 2013;63:77. 3. Lennox. Ann Intern Med. 2014;161:461. 4. Cahn. Lancet HIV. 2017;4:e486. 5.
Cahn. JAIDS. 2018;78:589.
6. Sax. Lancet. 2012;379:2439. 7. Zolopa. JAIDS. 2013;63:96. 8. Wohl. JAIDS. 2014;65:e118. 9. DeJesus. Lancet. 2012;379:2429. 10. Rockstroh. JAIDS.
2013;62:483.
11. Clumeck. JAIDS. 2014;65:e121. 12. Squires. Lancet HIV. 2016;3:e410. 13. Raffi. Lancet. 2013;381:735. 14. Raffi. Lancet Infect Dis. 2013;13:927. 15.
Walmsley. NEJM. 2013;369:1807.
16. Walmsley. JAIDS. 2015;70:515. 17. Clotet. Lancet. 2014;383:2222. 18. Molina. Lancet HIV. 2015;2:e127. 19. Orrell. Lancet HIV. 2017;4:e536. 20.
Cahn. Lancet. 2019;393:143.
21. Cahn. JAIDS. 2020;83:310. 22. Gallant. Lancet. 2017;390:2063. 23. Wohl. Lancet HIV. 2019;6:e355. 24. Sax. Lancet. 2017;390:2073. 25.
Stellbrink. Lancet HIV. 2019;6:e364.
 STARTMRK: BID dose
noninferior to EFV at Wk
48, superior at Wk 240[1,2]
 ACTG A5257: BID dose
equivalent to ATV/r and
DRV/r at Wk 96[3]
 ONCEMRK: QD dose
noninferior to BID dose at
Wk 48 and Wk 96[4,5]
 GS-102: Noninferior to EFV
at
Wk 48, Wk 96, and Wk 144[6-
8]
 GS-103: Noninferior to ATV/
r at
Wk 48, Wk 96, and Wk 144[9-
11]
 WAVES: Superior to ATV/r in
women at Wk 48[12]
 SPRING-2: Noninferior to
RAL BID at Wk 48 and Wk
96[13,14]
 SINGLE: Superior to EFV at
Wk 48, Wk 96, and Wk
144[15,16]
 FLAMINGO: Superior to
DRV/r at Wk 48 and Wk
96[17,18]
 ARIA: Superior to ATV/r in
women at Wk 48[19]
 GEMINI: 2-DR noninferior to
3-DR at Wk 48 and Wk
96[20,21]
 GS-1489/1490: Noninferior
to DTG at Wk 48 and Wk
96[22-25]
RALEVG/c
DTGBI
C

60
GS-1489 and GS-1490: BIC/FTC/TAF
Noninferior to
DTG/ABC/3TC and DTG + FTC/TAF in ART-
Naive Adults
1. Gallant. Lancet. 2017;390:2063. 2. Wohl. Lancet HIV. 2019;6:e355. 3. Sax. Lancet. 2017;390:2073. 4. Stellbrink.
Lancet HIV. 2019;6:e364.
2.5
Outcome by
Analysis,[2]
%
BIC/
FTC/
TAF
DTG/
ABC/
3TC
Per protocol 99.6 98.9
Missing =
failure
87.9 90.8
Missing =
excluded
98.9 99.3
GS-1489[1,2]
GS-1490[3,4]
HIV-1 RNA < 50 c/mL at Wk 96
Outcome by
Analysis,[4]
%
BIC/
FTC/
TAF
DTG +
FTC/
TAF
Per protocol 100 98.2
Missing =
failure
86.3 88.0
Missing =
excluded
100 98.3
Patients(%)
HIV-1 RNA < 50
c/mL
HIV-1 RNA ≥ 50 c/
mL
No Virological
Data
DTG + FTC/TAF (n =
325)
BIC/FTC/TAF (n =
320)
Tx difference: -
2.3%
(95% CI: -7.9% to
3.2%)
Wk
96
Wk
48
100
80
60
40
20
0
89 93
84 86
4 1 4 3 6 6
12 11
Patients(%)
HIV-1 RNA < 50
c/mL
HIV-1 RNA ≥ 50 c/
mL
No Virological
Data
DTG/ABC/3TC (n =
315)
BIC/FTC/TAF (n =
314)
Tx difference: -
1.9%
(95% CI: -6.9% to
3.1%)
Wk
96
Wk
48
100
80
40
20
0
92.
4
93.
0
87.
9
89.
8
1.0 0.62.2 6.74.4
11.
5
7.9

GEMINI: DTG + 3TC Noninferior to
DTG + FTC/TDF in ART-Naive Adults
 No emergent resistance among patients meeting criteria for CVW; lower
rate of drug-related AEs and more favorable renal/bone changes with
DTG + 3TC vs DTG + FTC/TDF
Wk 96
Responders
by Analysis,
% (n)
DTG + 3TC
(n = 716)
DTG + FTC/
TDF
(n = 717)
Difference,
% (95% CI)
Snapshot 86.0 (616) 89.5 (642)
-3.4 (-6.7 to
0.0007)*
TRDF†
96.6 (692) 96.4 (691) 0.2 (-1.8 to 2.2)
*Adjusted for baseline HIV-1 RNA, baseline CD4+ cell count, and study. †
Accounts for
CVW, withdrawal for lack of efficacy or treatment-related AE, and participants
meeting protocol-defined stopping criteria.
HIV-1RNA<50
copies/mLby
Snapshot,%(95%
CI)
100
80
60
40
20
0
0 4 8 12 16 24 36 48 60 72 84 96
Wk
87.0
93.2 91.5 87.2 86.0
89.589.4
93.393.4
84.4
Cahn. IAS 2019. Abstr WEAB0404LB. Cahn. JAIDS. 2020;83:310.

AMBER: DRV/COBI/FTC/TAF vs DRV/COBI
+ FTC/TDF
in ART-Naive Adults
4.4% 5.5%
4.1% 9.4%
DRV/COBI/FTC/TAF (n
= 362)
Wk 48
3.3% 4.4%
8.3% 11.8%
DRV/COBI + FTC/TDF
(n = 363)
Wk 48Wk 96 Wk 96
HIV-1 RNA ≥ 50
c/mL
No virologic data
HIV-1RNA<50c/mL
(%)
91.4 88.485.1 83.7
 Virologic efficacy of
DRV/COBI/FTC/TAF noninferior
to DRV/COBI + FTC/TDF at Wk
48, durable through Wk 96
 Patients receiving DRV/COBI +
FTC/TDF switched to DRV/COBI/
FTC/TAF at Wk 48
 Resistance analysis of 9/15
patients with PDVF in
DRV/COBI/FTC/TAF arm vs 8/19 in
control arm through Wk 96
‒ 1 patient with M184V/I in each
arm
‒ No evidence of emergent DRV,
primary PI, or TFV RAMs
FDA Snapshot Analysis (ITT)
0
20
40
60
80
100
Orkin. AIDS. 2020;34:707.

DRIVE-FORWARD/AHEAD: DOR + 2 NRTIs
Noninferior to (DRV + RTV) or EFV + 2
NRTIs in ART-Naive Adults
 Favorable lipid profile, significantly lower rates of neuropsychiatric AEs
(eg, dizziness, sleep disorders/disturbances, altered sensorium) with
DOR/3TC/TDF vs EFV/FTC/TDF[1]
1. Orkin. IDWeek 2018. Abstr LB1. 2. Molina. Lancet HIV. 2018;5:e211. 3. Molina. Lancet HIV. 2020;7:e16. 4. Orkin.
Clin Infect Dis. 2019;68:535.
DOR/3TC/TDF (n =
364)
EFV/FTC/TDF (n =
364)
DRIVE-AHEAD
DOR + 2 NRTIs (n = 383)
DRV + RTV + 2 NRTIs (n =
383)
DRIVE-FORWARD
3.9% (-1.6% to 9.4%)
Wk 96[3]
Wk 48[2]
100
80
60
40
20
0
HIV-1RNA<50c/
mL(%)
83.8 79.9
73.1
66.0
Wk 96[1]
Wk 48[4]
100
80
60
40
20
0
HIV-1RNA<50c/
mL(%)
84.3 80.8 77.5 73.6
7.1% (0.5% to 13.7%) 3.5% (-2.0% to 9.0%)3.8% (-2.4% to 10.0%)
Tx
difference,
% (95% CI):

Patient Case 1: Background
 64-yr-old MSM, former rugby
player diagnosed with HIV 8 yrs
ago
‒ BL HIV-1 RNA: 187,000 copies/mL
‒ BL CD4+ cell count: 118
cells/mm3
 Virologically suppressed on
EFV/FTC/TDF for 7 yrs (first
regimen)
 Type 1 diabetes; frequent
consumer of pain killers and
sleeping pills; occasional use of
marijuana, alcohol, and cocaine
 Presents with depression and
Parameter at
Current
Presentation
Value
CD4+ cell count,
cells/mm3 469*
HIV-1 RNA, copies/mL Undetectable
HIV-1 genotype Wildtype†
HLA-B*5701 Positive
BMI 23
Glucose, mg/dL 185
CrCl, mL/min 99
HBV Immune
HCV antibody Negative
*Other CBC parameters normal. †
Assessed at
baseline.

Switching From Suppressive ART to an
STR:
Noninferior Efficacy Across Phase III
Studies
1. Daar. Lancet HIV. 2018;5:e347. 2. Molina. Lancet HIV. 2018;5:e357. 3. Sax. IAS 2019. Abstr MOAB0105. 4. Kityo. CROI
2018. Abstr 500. 5. Johnson. JAIDS. 2019;81:463. 6. Orkin. Lancet HIV. 2017;4:e195. 7. DeJesus. Lancet HIV. 2017;4:e205.
8. Trottier. Antivir Ther. 2017;22:295. 9. Mills. Lancet
Infect Dis. 2016;16:43. 10. Orkin. Lancet HIV. 2018;5:e23 11. van Wyk. Clin Infect Dis. 2020;[Epub]. 12. Llibre. Lancet.
2018;391:839. Slide credit: clinicaloptions.com
Key Studies* Switch to Switch From
380-1878,[1]
380-1844,[2]
380-
4030,[3]
and 380-1961[4] BIC/FTC/TAF
Boosted PI + 2 NRTIs,
DTG/ABC/3TC, DTG + FTC/(TAF or
TDF), or EVG/COBI/FTC/(TAF or
TDF)
DRIVE-SHIFT[5]
DOR/3TC/TDF
Boosted PI, EVG/COBI, or NNRTI +
2 NRTIs
GS-1216[6]
and GS-1160[7]
RPV/FTC/TAF RPV/FTC/TDF or EFV/FTC/TDF
STRIIVING[8]
DTG/ABC/3TC Third agent + 2 NRTIs
GS-109[9]
EVG/COBI/FTC/TAF TDF-based regimen
EMERALD[10]
DRV/COBI/FTC/TAF Boosted PI + FTC/TDF
TANGO[11]
DTG/3TC 3-drug or 4-drug TAF-based ART
SWORD-1/2[12]
DTG + RPV Third agent + 2 NRTIs
*Listed studies not head to head.

TANGO: Switch to DTG/3TC in
Virologically Suppressed Adults
Receiving Stable TAF-Based ART
 Multicenter, randomized,
open-label phase III
noninferiority study
 Primary endpoint: HIV-1 RNA ≥
50 copies/mL at Wk 48 by FDA
Snapshot (noninferiority
margin: 4%)
Adults with HIV-1
RNA
< 50 c/mL for > 6
mos on stable TAF-
based ART;
no previous VF,
current HBV, or HCV
requiring therapy;
no major NRTI or
INSTI
RAMs
(N = 741)
Switch to DTG/3TC
(n = 369)
Continue
TAF-Based ART
(n = 372)
Wk
196
Switch
to DTG/3TC
Wk
148
Primary
Endpoint
Wk 48
van Wyk. Clin Infect Dis. 2020;[Epub]. NCT03446573.
Permitte
d to
continue
DTG/3TC
Patients(%)
100
80
40
60
20
0
HIV-1
RNA
≥ 50 c/
mL
HIV-1
RNA
< 50 c/
mL
No
Virologi
c Data
93.
2
93.
0
6.
5
6.
5
Switch to DTG/3TC
(n = 369)
Continue TAF-based ART
(n = 372)
FDA Snapshot at Wk 48
(ITT-E)
0.3 0.
5
TAF-Based
ART
DTG/3TC
-1.2 0.7
-0.3
-8 -6 -4 -2 0 2 4 6 8
Adjusted Treatment Difference
(95% CI)*
Primary
Endpoint
(HIV-1 RNA ≥ 50
c/mL)
DTG/3TC
noninferior to
continued
TAF-based ART
4% NI
margin
*Per Cochran-Mantel-Haenszel stratified analysis adjusted for BL
third agent class.

SWORD-1 and -2: Switch to DTG + RPV
vs Continuation of Baseline ART in
Virologically Suppressed Adults
 Parallel, randomized, open-label, multicenter phase III
noninferiority studies[1,2]
 Primary endpoint: HIV-1 RNA < 50 copies/mL maintained in 95% of
patients in each arm at Wk 48; adjusted treatment difference: -
0.2% (95% CI: -3.0 to 2.5)[2]
Switch to DTG + RPV
(n = 513)
Continue Baseline ART
(n = 511)
Switch to DTG + RPV
Continue DTG + RPV
Early Switch Phase
1. Aboud. Lancet. 2019;6:E576. 2. Llibre. Lancet. 2018;391:839. Slide credit: clinicaloptions.com
Adults on stable ART
(INSTI, NNRTI, or PI +
2 NRTIs) with HIV-1 RNA
< 50 copies/mL for ≥ 6
mos at screening; no
previous VF or current
HBV infection; no
resistance to DTG or RPV
(N = 1024)
Late Switch
Phase
Wk 148Wk 52
Current Analysis
Wk 100
DTG dosed 50 mg PO QD; RPV dosed 25
mg PO QD.
Primary Endpoint
Wk 48
*70% to 73% of patients receiving TDF at baseline.
Virologic Response
With DTG + RPV by
FDA Snapshot
89
%
93%
(HIV-1 RNA < 50
copies/mL
at Wk 100)[1]

DRIVE-SHIFT: Efficacy of Switch to
DOR/3TC/TDF at
Wks 24 and 48 vs Continued BL ART
 Multicenter, randomized, open-label phase III noninferiority trial of
immediate switch to DOR/3TC/TDF vs maintaining BL ART and
switching at Wk 24 in patients with no earlier VF or resistance to study
drugs, and eGFR ≥ 50 mL/min
 No treatment-emergent resistance in patients receiving DOR/3TC/TDF (N
= 670)
Johnson. JAIDS. 2019;81:463. Slide credit: clinicaloptions.com
Efficacy Analysis by FDA Snapshot, % Immediate
Switch to
DOR/3TC/TDF
(n = 447)
Continued BL
ART
(n = 223)
Difference Between
Arms, % (95% CI)
Wk 48 DOR/3TC/TDF vs Wk 24 BL ART (Primary Endpoint)
 HIV-1 RNA < 50 copies/mL
 HIV-1 RNA ≥ 50 copies/mL
 No virologic data
90.8
1.6
7.6
94.6
1.8
3.6
3.8 (-7.9 to 0.3)
0.2 (-2.5 to 2.1)
--
Wk 24 DOR/3TC/TDF vs Wk 24 BL ART
 HIV-1 RNA < 50 copies/mL
 HIV-1 RNA ≥ 50 copies/mL
 No virologic data
93.7
1.8
4.5
94.6
1.8
3.6
-0.9 (-4.7 to 3.0)
0 (-2.3 to 2.3)
--

EMERALD: Virologic Outcomes in
DRV/COBI/FTC/TAF Immediate Switch
Arm Through Wk 96 (ITT)
 Randomized, open-label phase III
trial of immediate switch to DRV/
COBI/FTC/TAF vs maintaining
boosted PI + FTC/TDF with Wk
48 switch to DRV/COBI/FTC/ TAF in
virologically suppressed patients
with no prior VF on DRV; no DRV
RAMs (N = 1141)
 Primary endpoint: virologic
rebound at Wk 48 with switch to
DRV/COBI/FTC/TAF vs continue
boosted PI + FTC/TDF: 2.5% vs
2.1% (difference: 0.4%; 95% CI: -
1.5% to 2.2%; noninferiority P
< .0001)
Slide credit: clinicaloptions.comEron. Antiviral Res. 2019;170:104543.
Cumulative
PDVR
BL to Wk
48
(n = 763)
BL to Wk
96
(n = 763)
VL ≥ 50 c/mL, n
(%)
 Rebounders
resuppressed,
n/N
19 (2.5)
12/19
24 (3.1)
14/24
VL ≥ 200 c/mL, n
(%)
 Rebounders
3 (0.4) 4 (0.5)
FDA Snapshot Results
of Patients on
DRV/COBI/FTC/TAF, n
(%)
Wk 48
(n =
763)
Wk 96
(n =
763)
VL ≤ 50 c/mL
724
(95)
692
(91)
VL < 200 c/mL
725
(95)
696
(91)

Questions to Consider for Case 1
 What are you considering
when determining which STR
to recommend for this patient?
 Which of these regimens
would you recommend?
‒ BIC/TAF/FTC
‒ DOR/3TC/TDF
‒ DTG/3TC
‒ DTG/RPV
‒ DRV/COBI/FTC/TAF
‒ DTG/3TC/ABC
 What would be the pros/cons
of a
2-drug regimen in this case?
 64-yr-old MSM virologically suppressed
on EFV/FTC/TDF presents with
depression and thoughts of self-harm
 Current CD4+ cell count 469 cells/mm3
 Type 1 diabetes; normal renal function;
frequent consumer of pain killers and
sleeping pills; occasional use of
marijuana, alcohol, and cocaine

Patient Case 1: Update
 The patient started DTG/3TC
 Remains virologically suppressed with undetectable HIV-1
RNA
 His depression is improving
 He continues to take NSAIDs and sleeping pills

WHO: Recommended Regimens for First-
line ART in Adults and Adolescents
WHO Policy Brief on First-line and Second-line ART. July 2019. Slide credit: clinicaloptions.com
Preferred
DTG + 3TC (or FTC) + TDF*
†
Except in settings with pretreatment HIV
drug resistance to EFV/nevirapine
exceeding 10%.
Alternative
EFV 400 mg + 3TC + TDF†
*Offer effective contraception to women and
adolescent girls of childbearing
age/potential. DTG can be prescribed in this
group if the patient wishes to become
pregnant or is not using consistent/effective
contraception provided the patient has been
fully informed of the potential increased risk
of NTDs (with use at conception and until
end of first trimester).

“Real-World” Low- and Middle-Income
Country Studies of DTG- vs EFV-Based
ART
 Multicenter, randomized, open-label phase III trials[1-3]
DTG 50 mg + 3TC/TDF QD
(n = 310)
EFV 400 mg + 3TC/TDF QD
(n = 303)
ART-naive patients (≥
12 yrs) with HIV-1 RNA
≥ 500 c/mL
(N = 1053)
ADVANCE: South
Africa[5]
Wk
96
DTG 50 mg + FTC/TAF QD
(n = 351)
DTG 50 mg + FTC/TDF QD
(n = 351)
EFV 600 mg/FTC/TDF QD
(n = 351)
1. Hill. IAS 2019. Abstr MOAX0102LB. 2. NCT02777229. 3. NCT03122262.
4. NAMSAL ANRS 12313 Study Group. NEJM. 2019:381:816. 5. Venter. NEJM. 2019:381:803.
ART-naive adults
with HIV-1 RNA >
1000 c/mL
(N = 613)
NAMSAL:
Cameroon[4]
Primary Endpoint (Both
Trials)
HIV-1 RNA < 50 c/mL at Wk
48 by FDA Snapshot in ITT
population (noninferiority
margin: -10%)

Global Status of DTG-Based ART Use
 By mid 2019, 123 LMICs (90%) included/planned to include
DTG in HIV policy
Slide credit: clinicaloptions.comhttps://www.who.int/hiv/pub/arv/treat-all-uptake/en/
DTG introduced in national guidelines, but procurement not yet initiated
DTG introduced in national guidelines and procurement initiated
DTG introduction in national guidelines planned for late 2019
Data not reported
Fast-track countries
Not applicable
High-income countries
EFV/XTC/TDF first-line ARVs only

0.
1
00
Unintended Pregnancies in Women
Receiving ART
 Women with HIV
experiencing unintended
pregnancy have worse
ART outcomes on
average
 Independent of mental
health,
sociodemographics,
intimate partner
violence, poverty,
stigma, social support
 Causal mechanism Slide credit: clinicaloptions.comMyer. IAS 2019. Abstr WESY0105. Brittain. AIDS. 2019;33:885.
Unplann
ed
Ambivalent Planne
d
120 1 2 3 4 5 6 7 8 9 10 11
0.
5
0.
4
0.
3
0.
2
PredictedProbabilityof
ElevatedVL
LMUPScorePercentage
30
20
10

Drug–Drug Interactions Between ART and
Contraception
WHO. Interim guidelines. December 2018. Annex J: Table of drug interactions with ARV drugs. https://www.hiv-
druginteractions.org/checker
Contraceptive
NRT
Is ATV LPV
DR
V RTV
DO
R EFV ETR NVP RPV BIC DTG RAL
EVG/
c
Desogestrel (COC)
Desogestrel (POP)
Drospirenone (COC)
Estradiol
Ethinylestradiol
Etonogestrel (implant)
Etonogestrel (ring)
Gestodene
Levonorgesterel (COC)
Levonorgesterel (IUD)
Levonorgesterel (POP or
implant)
Medroxyprogesterone (IM
Depot)
Medroxyprogesterone (oral)
Norelgestromin (patch)
Norethisterone (COC)
Norethisterone (IM Depot)
Norethisterone (POP)
Norgestimate or norgestrel
Weak potential
interaction
No interaction
expected
Potential
interaction
that may
require
monitoring,
dose/timing
alterationInteraction
likely, should
not be
coadministere
d

12
10
6
4
2
0
8
Hormonal Contraception With
Concomitant EFV
 Progestin concentrations from
subdermal implants 50% to 70%
lower with concomitant EFV-
based ART vs no ART[1]
 Contraception failure and higher
pregnancy rates among women
using implants + EFV vs implants
+ non-EFV ART or no ART in
several clinical studies[2-5]
 However, in one study,
pregnancy rates were lower with
implant vs oral or injectable
contraception among woman
receiving EFV[1,5]
‒ Suggests adherence benefits
afforded by implants may
1. Patel. J Int AIDS Soc. 2017;20:21396. 2. Leticee. Contraception. 2012;85:425. 3. Perry. AIDS.
2014;28:791. 4. Pyra. AIDS. 2015;29:2353. 5. Patel. Lancet HIV. 2015;2:e474. 6. Carten. Infect
Dis Obstet Gynecol. 2012;2012:137192.
Levonorgestrel PO
Levonorgestrel + EFV PO
Hrs
MeanPlasmaLNG,
ng/mL(SD)
Plan B Levonorgestrel PK
in Healthy Volunteers (N =
21)[6]
0 2 4 6 8 10 12 14

Tsepamo: NTD Prevalence by ARV Agent
and Timing, August 2014 to March 2019
At Conception
DTG
During
Pregnanc
y
HIV
NegativeDTG Non-DTG EFV
Total NTDs per exposures, n/
N
5/1683 15/14,792 3/7959 1/3840 70/89,372
 Prevalence difference, %
0.20 0.26 0.27 0.22
DeliveriesWith
NeuralTubeDefect
(%)
0.30
0.10 0.08
0.5
1.0
0 0.04 0.03
“99.8% of the
women for
whom folate
was prescribed
started taking
folate during,
not before,
pregnancy”
Zash. NEJM. 2019;381:827.

International Guidance on DTG Use at
Conception
https://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-
option-in-all-populations
1. DHHS Guidelines. December 2019. 2. EACS Guidelines. November 2019. Slide credit: clinicaloptions.com
EACS[2]
: DTG not recommended in women who wish to conceive or
who become pregnant while on ART; initiate after 8 wks of pregnancy
DHHS: Starting DTG in
Persons
of Childbearing Potential[1]
 Perform a pregnancy test and
discuss benefits/risks of DTG
at conception
 Recommended: if using
effective contraception
 Alternative: if trying to
conceive;
if sexually active, not planning
to conceive, not using
contraception

DolPHIN-2: Kinetics of Virologic
Suppression in Women Initiating ART
During the Third Trimester
Slide credit: clinicaloptions.comKintu. Lancet HIV. 2020;7:e332.
Time to HIV-1 RNA <
1000 c/mL
HIV-1 RNA < 50 c/mL at delivery: 74.2% in DTG arm vs 42.7% in EFV arm (RR: 1.65; 95%
CI: 1.31-2.06; P < .0001).
HIV-1 RNA < 1000 c/mL at delivery: 93.3% in DTG arm vs 82.1% in EFV arm (RR: 1.10;
95% CI: 0.99-1.23; P = .089).
Median time on ART at delivery: 55 days (IQR: 33-77).
Days Since
Randomization
ProportionWith
Outcome
1.0
0.8
0.6
0.4
0.2
0
0 15 30 45 60 75
DTG-based ART (n
= 125) EFV-based
ART ( n = 125)
HR: 1.50 (95% CI: 1.14-
1.96; log-rank P
= .0007)
Time to HIV-1 RNA < 50
c/mL
Days Since
Randomization
ProportionWith
Outcome
1.0
0.8
0.6
0.4
0.2
0
0 15 30 45 60 75
HR: 2.67 (95% CI: 1.88-
3.79; log-rank P
< .0001)

ADVANCE: BMI Category Over Time in
Women Initiating DTG- or EFV-Based ART
*Obese at baseline excluded.
Slide credit: clinicaloptions.comVenter. IAS 2019. Abstr WEAB0405LB.
Obes
eOverweig
htNormal
Underweig
ht
DTG +
FTC/TAF
DTG +
FTC/TDF
EFV/FTC/TDF
Participants(%)*
80
60
40
20
0
10
0
Wk
BMI
Class
0 48 96
181 158 73
n
=
80
60
40
20
0
10
0
0 48 96
165 144 60
n
=
80
60
40
20
0
10
0
0 48 96
162 129 50
n
=

Caniglia. IAS 2019. Abstr LBPEB14. Slide credit: clinicaloptions.com
Tsepamo: Weight Gain in Pregnant
Women
 Women initiating DTG between conception and 17 wks gestation
gained more weight vs EFV; neither ARV group gained as much
weight as HIV negative womenWeekly Weight Gain* Weight Gain From (18 ± 2) to (36 ± 2) Wks’ Gesta
MeanDifference,kg/wk
(95%CI)
*Adjusted for age, CD4+ cell count, employment, education, parity, gravidity, marital status, site, smoking, alcohol, pre-pregnancy weight,
weight at ART initiation or first ANC, gestational age at ART initiation or first ANC.
EFV (n = 1127)DTG (n = 929)HIV negative (n = 16,406)
Overall
BL
Weight
< 50 kg
BL
Weight
> 80 kg
Primigra
vid
Non-
primigra
vid
MeanDifference,kg
(95%CI)
EFV (n = 757)DTG (n = 621)HIV negative (n = 11,280)
0.25
0.2
0.15
0.1
0.05
0
-0.05
-0.1
-0.15
-0.2
Overall
BL
Weight
< 50 kg
BL
Weight
> 80 kg
Primigra
vid
Non-
primigra
vid
3.5
2.5
1.5
0.5
-0.5
-1.5
-2.5
-3.5

Long-Acting Injectable ART: Perspectives
From Women
 Multi-site study of women with HIV at 6 WIHS locations in the US (N
= 59)[1]
‒ At baseline: median age, 53 yrs; 96% women of color; no prior
participation in
long-acting injectable ART clinical trials
‒ Performed in-depth interviews probing interest in and perceived
barriers to
long-acting injectable ART
 Most interviewees enthusiastically endorsed this new ART
paradigm[1]
‒ Primary cited reasons for approval: convenience and privacy,
avoidance of daily HIV reminder, belief that shots are more powerful
than pills
 Remaining challenges: medical mistrust, concerns about
efficacy and safety, pills may still be needed for comorbidities,
1. Philbin. JAIDS. 2020;[Epub]. 2. Swindells. NEJM. 2020;382:1112. 3. Orkin. NEJM. 2020;382:1124. Slide credit: clinicaloptions.com

 Edinah is a 24-yr-old
student and nurse
diagnosed with HIV in
2017 when she presented
with herpes zoster
 She switched from EFV to
DTG + 3TC/TDF in January
2020 due to difficulties
concentrating
 She and her partner are
keen to try for a baby
 Her partner is HIV
Parameter at
Current
Presentation
Value
CD4+ cell count,
cells/mm3 865*
HIV-1 RNA, copies/mL Undetectable
HLA-B*5701 Negative
BMI 20
Assessed at
baseline.

Weighing Current Benefits-Risks of DTG
 Advantages
‒ Rapid decline in viral load
‒ QD dosing
‒ Available as STR
‒ High barrier to resistance
‒ Few drug or food
interactions
‒ DTG preferred guideline
option during pregnancy
 Disadvantages/Risks
‒ DTG increases metformin
levels
‒ Increased NTD risk with
DTG periconception
exposure in large
Botswana study
[Updated data will be
presented from this
cohort at AIDS 2020
on Thursday]
‒ Higher weight gain vs PIs/
NNRTIs (clinical relevance
Slide credit: clinicaloptions.comDHHS Guidelines. December 2019.

Addressing DTG Use and the Risk of NTDs
1. Watts. Curr HIV/AIDS Rep. 2007;4:135. Slide credit: clinicaloptions.com
Women of childbearing
potential should be
included with full
consent in trials and
phase IV monitoring
> 2000
preconception
exposures needed
to rule out 3-fold
increase in rare
event (eg, NTD)[1]Pregnancy
registries key to
capture NTDs
Folate
supplementati
on
recommended
Community
involvement in
policy decisions
key

 Should her partner go on PrEP?
 How would you counsel her on the pros and cons of
continuing DTG?
 Would you recommend she switch to an alternative ART
regimen for the first trimester and then change back?
 24-yr-old woman virologically suppressed on DTG + 3TC/TDF
 Partner is HIV negative
 They would like to try to conceive

Individualizing ART Based on Evolving
Safety and Tolerability Data

Spotlight on Common Early ART-
Associated AEs
Vella. AIDS. 2012;26:1231. Reust. Am Fam Physician. 2011;83:1443.
NRTIs PIs
 Anemia
 Lactic acidosis
 Lipoatrophy
 Pancreatitis
 Portal
hypertension
 Diarrhea
 Jaundice
 Renal stones
NNRTIs
 Insomnia
 Rash
First FDA
approval: 1987
First FDA
approval: 1995
First FDA
approval: 1996

EACS: Recommended[1]
INSTI + 2 NRTIs (Preferred)
 BIC/FTC/TAF
 DTG/ABC/3TC
 DTG + FTC/TAF or XTC/TDF
 RAL + FTC/TAF or XTC/TDF
INSTI + 1 NRTI
 DTG + 3TC
NNRTI + 2 NRTIs
 DOR + FTC/(TAF or TDF),
DOR/3TC/TDF
 RPV + 3TC/TDF, RPV/FTC/(TAF or TDF)
Boosted PI + 2 NRTIs
 DRV/COBI/FTC/TAF, DRV/COBI +
XTC/TDF
 DRV + RTV + FTC/TAF or XTC/TDF
International Guidelines for First-line ART
Slide credit: clinicaloptions.com1. EACS Guidelines. November 2019. 2. DHHS Guidelines. December 2019.
DHHS: Recommended for Most
PWH[2]
INSTI + 2 NRTIs
 BIC/FTC/TAF
 DTG/ABC/3TC
 DTG + XTC + (TAF or TDF)
 RAL + XTC + (TAF or TDF)
INSTI + 1 NRTI
 DTG/3TC

Then vs Now: AEs Across First-line RCTs
1. Soriano. Antivir Ther. 2011;16:339. 2. Sax. Lancet. 2017;390:2073.
Wk 48 Outcome,
%
ARTEN[1]
GS-1490[2]
NVP +
FTC/TDF
(n = 376)
ATV/RTV +
FTC/TDF
(n = 193)
BIC/FTC/
TAF
(n = 320)
DTG +
FTC/TAF
(n = 325)
Drug-related AEs 34.6 48.7 18 26
Discontinuation for
AEs
13.6 3.6 2 < 1

1. Hoffmann. HIV Med. 2017;18:56. 2. Institute of Medicine. 2006. Sleep Disorders and Sleep Deprivation:
An Unmet Public Health Problem. Washington, DC: The National Academies Press.
https://doi.org/10.17226/11617. 3. Capetti. HIV Med. 2018;19:e62. Slide credit: clinicaloptions.com
Managing DTG-Associated
Neuropsychiatric AEs
 Retrospective cohort analysis of patients initiating or
switching to
INSTI-based ART in 2 German outpatient clinics, 2007-2016 (N
= 1704)[1]
‒ Discontinuation within 24 mos due to neuropsychiatric AEs (eg,
insomnia,
sleep disturbances) higher for DTG (6.7%) vs EVG (1.5%) or RAL
(2.3%)
‒ Increased risk of DTG discontinuation among women, those >
60 yrs of age or using concomitant ABC
 Chronic sleep loss associated with increased risk of HTN,
diabetes, obesity, depression, MI, and stroke[2]
 Shifting DTG dose to morning eliminated

Have We Progressed Past “Classic” ART-
Associated AEs?
 Contemporary strategies
to mitigate ART-associated
AEs
‒ Avoid drugs that may
increase CV risk (eg,
boosted PIs, ABC)
‒ Switch or drop TDF to
improve renal/bone
outcomes
‒ Reduce ARV exposure
(ie, use 2 drugs vs 3
drugs) Slide credit: clinicaloptions.comSolomon. Curr Opin HIV AIDS. 2015;10:219. Masters. Expert Rev Clin Pharmacol. 2019;12:1129.

 34-yr-old MSM newly
diagnosed with HIV-1
 Last negative test was July
2019
 No seroconversion symptoms
 HBV immune
 No major comorbidities
 Takes multivitamin/mineral
supplement and a proton
pump inhibitor as needed
 “I don’t want a treatment that
will make me gain weight!”
Parameter at
Current
Presentation
Value
CD4+ cell count,
cells/mm3 154*
HIV-1 RNA, copies/mL 367,000
HLA-B*5701 Negative
BMI 24
Assessed at
baseline.

Trials not head-to-head with differences in baseline demographics (eg, sex, race, age,
weight).1. Wohl. Lancet HIV. 2019;6:e355. 2. Stellbrink. Lancet HIV. 2019;6:e364. 3. Cahn. JAIDS. 2020;83:310. 4. Hill. IAS
2019. Abstr MOAX0102LB.
0
2.
4
DTG/
ABC/
3TC
3.6
BIC/
FTC/
TAF
3.
5
BIC/
FTC/
TAF
3.9
DTG +
FTC/T
AFGS-1489[1]
GS-1490[2]
4
6
8
10
WeightΔFromBLto
Wk96(kg)
2
Mean Weight GainMedian Weight Gain
2.
1
3.1
8
5
2
GEMINI[3]
ADVANCE[4]
DTG +
3TC
DTG +
FTC/T
DF
DTG +
FTC/T
AF
DTG +
FTC/T
DF
EFV/
FTC/
TDF
n = 314 315 320 325 716 717 351 351 351
Weight Change Across First-line RCTs

*
*
Multivariate Analysis of Weight Gain
Following ART Initiation in RCTs
 Pooled analysis of weight gain across 8 randomized
phase III clinical trials of first-line ART initiation occurring
in 2003-2015 (N = 5680)
*Color-coded to match respective comparators, denoting P ≤ .05 vs NNRTI (first panel), EVG/COBI (second
panel), or ZDV (last panel).
TAF
ABC
TDF
ZDV
BIC
DTG
EVG/COBI
INSTI
PI
NNRTI
1
0
4
3
LSMeanWeightΔ,kg(95%CI)
Wks
1
2
2
4
3
6
4
8
6
0
7
2
8
4
9
6
2 *
*
* *
* *
**
Wks
1
2
2
4
3
6
4
8
6
0
7
2
8
4
9
6
6
0
5
4
3
2
1
Wks
1
2
2
4
3
6
4
8
6
0
7
2
8
4
9
6
6
0
5
4
3
2
1
*
*
*
*
*
*
*
*
*
* *
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Sax. Clin Infect Dis. 2019;[Epub].

DOR in Treatment-Naive Patients:
Change in Body Weight From Baseline
 No difference in proportion of patients with ≥ 10% weight
gain or who switched BMI class at Wk 96 between DOR
arm and EFV armOrkin. EACS 2019. Abstr PS3/2. Slide credit: clinicaloptions.com
MeanΔinBody
Weight
FromBL,kg(95%
CI)
Wk 48 Wk 96
4
3
2
1
0
1.7 1.4 0.6
2.4
1.8 1.6
MedianΔinBody
Weight
FromBL,kg(IQR)
Wk 48 Wk 96
6
3
2
1
0
1.0 0.6 0 1.5 0.7 1.0
5
4
-3
-2
-1
Combined
DOR
DRV +
RTV
Combined
EFV

ADVANCE: Emergent MetS and Risk of
Diabetes
51
Hill. CROI 2020. Abstr 81.
MetS, n/N
(%)
DTG +
FTC/T
AF
DTG +
FTC/T
DF
EFV/
FTC/
TDF
BL
16/351
(5)
21/351
(6)
14/351
(4)
Emergent
at Wk 96
20/259
(8)*
15/258
(6)
8/242
(3)
Estimated
10-Yr Risk
of
Diabetes,
%
DTG
+
FTC/T
AF
DTG
+
FTC/T
DF
EFV/
FTC/
TDF
BL 0.30 0.40 0.30
Median Δ
from BL to
Wk 48
+0.70†
+0.40 +0.60‡
Median Δ
from BL to
Wk 96
+0.90†
+0.50 +0.70‡
†
Significantly higher vs DTG + FTC/TDF at Wk
48
(P = .008) and Wk 96 (P = .004).
‡
Significantly higher vs DTG + FTC/TDF at Wk
48
(P = .047) and Wk 96 (P = .005).
*Significantly higher vs EFV/FTC/TDF (P
= .031).

Cardiovascular Safety of Switch From
TDF to TAF
 Retrospective observational study of virologically suppressed PWH
switching TDF to TAF after ≥ 1 yr of stable ART (N = 110)
‒ Mean age: 50 yrs
‒ 73% male, 65% overweight or obese, 58% black, 49% receiving
INSTIs
 Median weight increase of + 3.0 lbs post-switch (P < .01)
 In regression analysis comparing values from 1 yr before and after
ART modification, switch to TAF associated with significant
increases in:
‒ BMI: 0.45 (95% CI: 0.14-0.76)
‒ ASCVD risk score: 13% (95% CI: 4% to 23%)
Slide credit: clinicaloptions.comSchafer. Open Forum Infect Dis. 2019;[Epub].

Retrospective Cohort Study of Cardiac
Events Among PWH Receiving TAF
Appelman. CROI 2020. Abstr 655.
Cardiac
Event, n
TAF
(n =
1537)
TDF
(n =
1170)
No TFV
(n =
278)
MI 8 23 4
Angina
pectoris
13 15 5
Cardiomyopa
thy
6 3 1
Arrhythmia 16 17 1
Total 43 58 11
nadjusted Kaplan-Meier Cardiac Event-Free Survival
TAF
TDF
No TFV
Risk of
Cardiac
Event
Adjusted
HR
(95% CI)
P Value
TAF vs no
TFV
3.86 (1.51-
9.82)
.005
TAF vs TDF
1.94 (1.05-
3.57)
.034
CumulativeSurvival
1.0
0.8
0.6
0.4
0
0.2
300 10 20
Yrs After Start Date
1.0
0
0.9
5
0.9
0
0.8
5 300 10 20

 What potential safety/tolerability concerns do you
consider in this case when recommending a first-line
regimen?
‒ XTC/TDF + 3rd
Agent
‒ XTC/TAF + 3rd
Agent
‒ 2-drug therapy (DTG/3TC or DTG/RPV)
 Would you start ART same-day if he expressed interest?
How would that influence your ART recommendation? 34-yr-old MSM newly diagnosed with HIV
 HIV-1 RNA is 367,000 copies/mL
 No Major comorbidities; takes multivitamin/mineral supplement and a proton pump inhibitor
as needed
 “I don’t want a treatment that will make me gain weight!” Slide credit: clinicaloptions.com

Data on Weight Gain and ART From AIDS
2020
Study Population Reported Outcome
OPERA
Longitudin
al Cohort[1]
Prospective data collected from
adults virologically suppressed on
3DR with TDF who switched to TAF (N
= 6919)
Weight gain of +2.64/yr with switch from
TDF to TAF (other ARVs maintained) and
weight gain of +2.55 to +4.47 kg/yr
(depending on INSTI) with switch from TDF
to TAF and non-INSTI to INSTI in 9 mos post-
switch; Weight gain plateaued ~9 mos post-
switch
DRIVE-
SHIFT[2]
Adults virologically suppressed on 2
NRTIs + bPI who switched to
DOR/3TC/TDF (N = 656)
Mean weight gain of +1.38 kg in the
immediate switch group and +1.23 kg in the
delayed switch group at Wk 144; > 70%
participants experienced < 5% weight gain
AFRICOS[3]
Adults with HIV infection starting or
switching ART at 12 PEPFAR
supported clinics in Uganda, Kenya,
Tanzania, and Nigeria (N = 2927)
1.85 times the rate of developing high BMI
with DTG/3TC/TDF vs other ART; no significant
difference in hyperglycemia incidence with
DTG/3TC/TDF vs other ART
TANGO[4]
Adults virologically suppressed on
TAF-based regimen who switched to
DTG/3TC (n = 369) or continued TAF-
based ART (n = 370)
Weight gain of +0.81 kg with switch to DTG/
3TC vs +0.76 kg with continued TAF-based
ART at Wk 48; Significant improvement in
lipids with switch to DTG/3TC; Lower insulin
resistance with DTG/3TC vs TAF-based ART
1. Mallon. AIDS 2020. Abstr OAB0604. 2. Kumar. AIDS 2020. Abstr OAB0605. 3. Ake. AIDS 2020.
Abstr OAB0602. 4. Van Wyk. AIDS 2020. Abstr OAB0606. Slide credit: clinicaloptions.com

Additional Questions to Consider for
Case 3
 Do concerns about weight gain impact your ART
recommendations for switch?
 Do you switch patients who are gaining weight to
potentially mitigate weight gain?

Anticipated Roles of Emerging and
Investigational Novel ART Strategies

FLAIR: Long-Acting CAB + RPV Q4W
Noninferior
to Daily Oral DTG/ABC/3TC in ART-Naive
Adults Multicenter, randomized, open-label phase III noninferiority trial
CAB LA 400 mg IM +
RPV LA 600 mg IM Q4W
(n = 278)
Continue DTG/ABC/3TC PO QD‡
(n = 283)
ART-naive adults with
HIV-1 RNA ≥ 1000
copies/mL,
HBsAg negative,
no NNRTI RAMs*
(N = 629)
*K103N permitted. †
Patients with HIV-1 RNA < 50 copies/mL from Wk 16 to Wk 20 continued to maintenance phase.
‡
Alternative, non-ABC NRTIs permitted for intolerance or HLA-B*5701 positivity. §
Loading dose: CAB LA 600 mg IM +
RPV LA 900 mg IM; regular dosing begun at Wk 8.
CAB 30 mg +
RPV 25 mg PO QD
(n = 283)
Wk 4§
DTG/ABC/3TC
PO QD‡
Induction
Phase†
Maintenance Phase
Wk 96
Wk 20
Orkin. NEJM. 2020;382:1124. Orkin. CROI 2020. Abstr 482.
 HIV-1 RNA ≥ 50 c/mL: 2.1% vs 2.5% at Wk 48, 3.2% vs 3.2% at
Wk 96
 HIV-1 RNA < 50 c/mL: 93.6% vs 93.3% at Wk 48, 86.6% vs
89.4% at Wk 96
Wk 48Day 0

FLAIR: Plasma Trough Concentrations by
Visit
 Plasma concentrations with IM CAB and RPV Q4W similar to
effective PO regimens
Orkin. NEJM. 2020;382:1124. Slide credit: clinicaloptions.com
4 488 12 16 20 24 28 32 36 40 44
Visit (Wk)
0.1
1
10
PlasmaCAB(μg/mL)*
CAB (n =
278)PA-IC90 (0.166 µg/
mL)
4 488 12 16 20 24 28 32 36 40 44
Visit (Wk)
10
10
0
PlasmaRPV(ng/mL)*
RPV (n = 278)
PA-IC90 (12 ng/mL)
*Median (5th, 95th percentile) concentration–time data.

ATLAS-2M: Switch to Long-Acting CAB +
RPV Q8W
vs Q4W in Virologically Suppressed
Adults
Overton. CROI 2020. Abstr 34. NCT03299049.
 Multicenter, randomized, open-label phase III noninferiority trial
CAB LA 600 mg + RPV LA 900 mg IM Q8W
(n = 522)
CAB LA 400 mg + RPV LA 600 mg IM Q4W
(n = 523)
2 populations: adults
from ATLAS receiving
either CAB LA + RPV LA
Q4W* or SoC ART and
patients receiving SoC
ART outside of ATLAS†
(N = 1045)*Participants transitioning from ATLAS must have been on CAB LA + RPV LA Q4W or a current ART regimen through at least Wk 52
and had HIV-1 RNA < 50 c/mL at screening. †
SoC participants not transitioning from ATLAS study on uninterrupted current
regimen (initial or second combined ART) for ≥ 6 mos prior to screening and documented evidence of ≥ 2 plasma HIV-1 RNA < 50
c/mL in 12 mos prior to screening (one 6-12 mos and one within 6 mos prior to screening). Participants excluded if history of VF or
if prior genotype results show any major INSTI or NNRTI mutations (except K103N).
Option
to
continu
e CAB
LA +
RPV LA
Q4W or
Q8W
after
Wk 100
Oral CAB
30 mg +
RPV 25
mg QD
(except ATLAS
participants
on LA tx)
Primary
Endpoint
Wk 48
Wk 4 Wk 96Wk 100
 Primary endpoint: HIV-1 RNA ≥ 50 copies/mL at Wk 48 by FDA snapshot
in ITT-E
 Secondary endpoints: HIV-1 RNA < 50 copies/mL at Wk 48 by FDA
snapshot in ITT-E,
safety and tolerability, VF, resistance, and treatment preference
Stratified by
prior CAB +
RPV exposure

ATLAS-2M: Virologic Outcomes at Wk 48
(ITT-E)
Slide credit: clinicaloptions.comOverton. CROI 2020. Abstr 34.
Q4WQ8W
Difference (%)
-
0.6
2.2
0.8
4% NI
margin
Difference (%)
-
2.1
3.7
0.8
Q8WQ4W
-10% NI
margin
Primary
endpoint
(HIV-1 RNA ≥ 50
c/mL):
CAB LA + RPV LA
Q8W noninferior to
Q4W
Key secondary
endpoint (HIV-1
RNA < 50 c/mL):
CAB LA + RPV LA
Q8W noninferior to
Q4W
CAB LA + RPV LA Q8W
(n = 522)
CAB LA + RPV LA Q4W
(n = 523)
Adjusted Treatment Difference (95%
CI)*
Virologic Outcomes
*Based on Cochran-Mantel-Haenszel analysis adjusting for prior CAB +
RPV exposure.
100
80
60
40
20
0
Participants(%)
Virologic
Nonrespons
e (≥ 50
c/mL)
Virologic
Success
(< 50 c/mL)
No Virologic
Data
1
5.5
94.3 93.5
-10 -8 -6 -4 -2 0 2 4 6 8 10
-10 -8 -6 -4 -2 0 2 4 6 8 10
1.7 4.0

0 1 3 6 9 12 10 3 6 9 12
10
LATTE-2/ATLAS: Pharmacokinetics After
Long-Acting CAB + RPV Discontinuation
 After d/c, LA CAB + RPV may be detectable in plasma for ≥ 1 yr
 No DDIs expected between residual LA CAB + RPV after d/c and
newly begun ARVs, even CYP3A/UGT1A1 inducers or inhibitors
Ford. CROI 2020. Abstr 466. Slide credit: clinicaloptions.com
Mos After Last Injection Mos After Last Injection
CAB PA-IC90 (0.166 μg/mL)
Q4W (n = 29)
Q8W (n = 5)
RPV PA-IC90 (12 ng/mL)
Q4W (n = 24)
Q8W (n = 5)
PlasmaCAB(μg/mL)
PlasmaRPV(ng/mL)
0.1
1
0.025
(LLOQ)
10
100
1
(LLOQ)

P011: ISL + DOR vs DOR/3TC/TDF in
Treatment-Naive Adults
 International, randomized, double-blind phase IIb trial of ISL + DOR vs
DOR/3TC/TDF in treatment-naive adults with HIV-1 RNA ≥ 1000 copies/mL
and CD4+ count ≥ 200 cells/mm3
Orkin. AIDS 2020. Abstr OAB0302. Reproduced with permission.
*Participants initially received ISL + DOR + 3TC and switched to ISL + DOR during the Wk 24-48 period of the
study. Slide credit: clinicaloptions.com
DESIGN: please resize graph and legend on
previous slide to fit below bullet on this slide
HIV-1 RNA < 50 copies/
mL
HIV-1 RNA ≥ 50 copies/
mL
No Virologic Data in
Window
Patients,%
26/2
9
27/3
0
24/3
1
26/3
1
2/29 2/30 4/31n/N
=
89.7
6.9 3.4
90
6.7 3.3
77.4
12.9 9.7
83.9
6.5 9.7
0
20
40
60
80
100
2/31 1/29 1/30 3/31 3/31
ISL (0.25 mg) + DOR*
QD
QD
QD
DOR/3TC/TDF QD
FDA Snapshot Analysis at Wk 48

P011: Protocol Defined Virologic Failure
at Wk 48
 HIV-1 RNA levels at second assessment were < 80 copies/mL in all patients
with PDVF; no patient met criteria for resistance testing (HIV-1 RNA > 400
copies/mL)
 No evidence that PDVF was associated with drug pharmacokinetics
Orkin. AIDS 2020. Abstr OAB0302. Slide credit: clinicaloptions.com
Outcome at Wk 48
ISL 0.25
mg +
DOR QD
(n = 29)
ISL 0.75
mg + DOR
QD
(n = 30)
ISL 2.25
mg + DOR
QD
(n = 31)
DOR/3TC/T
DF QD
(n = 31)
PDVF, n (%)
 Nonresponse
 Rebound with HIV-1 RNA > 50
c/mL
 Rebound with HIV-1 RNA >
200 c/mL
0 (0)
2 (6.9)
0 (0)
0 (0)
2 (6.7)
0 (0)
1 (3.2)
0 (0)
0 (0)
0 (0)
1 (3.2)
0 (0)
HIV-1 RNA ≥ 50 c/mL not
classified as PDVF, n (%)
 Early d/c
 Reason for early d/c
0 (0)
--
0 (0)
--
3 (9.7)
2 LTFU; 1
withdrawal
1 (3.2)
1 protocol
violation

Supporting Candidates for Long-Acting
ART
 Strategies to ensure adherence and/or adequate ARV
concentrations to prevent a prolonged pharmacokinetic tail should
be implemented[1]
 Bimodal population wanting or needing long-acting ART often
invoked
1. Ford. CROI 2020. Abstr 466. 2. NCT03635788. Slide credit: clinicaloptions.com
Highly Adherent Poorly Adherent
LATITUDE (ACTG A5359)
[2]
 Shot clinics (in and out)
in clinical programs
 Pharmacies administer
shots
 Constant supply of oral
CAB/RPV at home for
 Incentives
 Mobile vans
Strategies to Monitor and Circumvent Barriers to Long-
Acting ART

Questions to Consider on Long-Acting
ART
 Which patient populations do you think will benefit most
from
long-acting ART?
 What challenges do you foresee in implementing long-
acting ART?
 What strategies can be implemented to circumvent
barriers to
long-acting ART?
 How can we ensure oral coverage after discontinuation of
long-acting ART?

Why New ARV Development Remains
Critical
 Deidentified samples
from a commercial
testing database of US
patients with HIV, July
2012 to June 2018 (N =
84,611)
‒ 33% with reduced
susceptibility to ≥ 1
ARV
 Decline in multiclass
resistance temporally
consistent with
availability of newer,
highly efficacious drugs
with favorable cross-
Henegar. CROI 2020. Abstr 521. Slide credit: clinicaloptions.com
Multiclass Resistance Among Resistant Sample
2012 2018
1-Class 2-Class 3-Class 4-Class
ProportionofResistantSamples(%)
60
100
20
40
0
80
52.2
71.4
33.5
21.9
11.3
5.5 3.1 1.1

S
Lenacapavir (GS-6207): Novel Capsid
Inhibitor
 Inhibits key assembly
steps during HIV-1
replication; affects
stability and transport of
capsid complexes[1]
 Picomolar potency;
increased antiviral activity
(as measured by EC50) vs
current ARVs[2]
 In vitro activity against
wide array of HIV-1
isolates, including those1. Sager. CROI 2019. Abstr 141. 2. Yant. CROI 2019. Abstr 480. Slide credit: clinicaloptions.com
Cl
H3C
O
F
N
S
F
O
F
F
HN
F
O
CH3
CH3
CH3
FF
H
H
F F
F
O
ON
N
N
N
N
H

Lenacapavir: Randomized Phase I Study
of Single Ascending SQ Doses in Healthy
Volunteers
 Systemic exposure observed for ≥ 6 mos; plasma
concentrations above the paEC95 evident at Wk 12 with
doses ≥ 100 mg
 No deaths,
serious AEs, or
grade 4 lab
abnormalities
 All AEs were mild
to moderate
‒ Transient grade
1 ISRs common
paEC95 3.87 ng/mL
MeanPlasma
Lenacapavir,ng/mL
(SD)
Wks
450 mg (n = 8)
300 mg (n = 8)
100 mg (n = 8)
30 mg (n = 8)
Longitudinal
Exposure100
1
10
0.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Sager. CROI 2019. Abstr 141.

 At BL: median age, 33 yrs; 10% women; 54% white; 31% black; median
HIV-1 RNA,
4.5 log10 c/mL; median CD4+ cell count, 463 cells/mm3
; 82% ART naive
Lenacapavir: Randomized Phase Ib Dose-
Ranging SQ Study in PWH
Slide credit: clinicaloptions.comDaar. CROI 2020. Abstr 469.
 Maximal mean Δ in
HIV-1 RNA from BL at
Day 10: -1.4 to -
2.3 log10 c/mL
 Maximal antiviral
activity predicted at
mean concentrations
≥ 4.4 ng/mL
 Most common AEs:
mild to moderate
ISRs (28% erythema,
49% pain)
MeanΔinHIV-1RNA,
log10c/mL(95%CI)
Day
750 mg (n = 5)
450 mg (n = 6)
150 mg (n = 6)
50 mg (n = 6)
20 mg (n = 6)
Placebo (n = 10)
Antiviral Activity
-2.0
-3.0
-2.5
-3.5
1 2 3 4 5 6 7 8 9 10
0
-1.0
-0.5
-1.5

Lenacapavir PK Study: PK Profile
Begley. AIDS 2020. Abstr PEB0265. Slide credit: clinicaloptions.com
*IQ = plasma concentration/protein-adjusted EC95 (macrophages, 1.16 ng/mL; CD4+ cells, 2.32 ng/mL, MT-4
cells, 3.87 ng/mL)
LEN 900 mg (3 x 1 mL; n
= 8)
LEN 300 mg (1 x 1 mL;
n = 8)
LEN 900 mg (2 x 1.5 mL;
n = 8)
Mean LEN Single-Dose Plasma Concentration-Time
Profiles6 mos (26
wk)
24 ng/mL;
mean IQ ≥
6*
Wks Post-SC Dose
560 4 8 12 16 20 24 28 32 36 40 44 48 52
100
10
1
0.1
MeanLEN,ng/mL
(SD)
 Per antiviral activity, mean lenacapavir target plasma
concentration is 24 ng/mL, corresponding to mean inhibitory
quotient ≥ 6 (range: 6.2-20.3)

Islatravir (MK-8591): Novel NRTTI
 Inhibits viral replication via multiple
mechanisms (eg, translocation
inhibition, delayed chain termination)
 Long intracellular half-life allows for
low-dose options
Grobler. CROI 2019. Abstr 481. Molina. IAS 2019. Abstr WEAB0402LB. Slide credit: clinicaloptions.com
 Compared with available NRTIs, MK-8591-TP IC50 for HIV-1
> 4-fold lower, increased potency against most resistant
strains
OH
NH2
F
OH
N
N
N N
O

Islatravir: Randomized Phase IIb Dose-
Ranging Study of Oral ISL + DOR vs
DOR/3TC/TDF in ART-Naive PWH
Molina. IAS 2019. Abstr WEAB0402LB. Slide credit: clinicaloptions.com
Primary Endpoint: Virologic Outcomes Through Wk 48
(FDA Snapshot)
HIV-1 RNA ≥ 50
copies/mL
HIV-1 RNA < 50
copies/mL
No Virologic
Data in Window
ISL 0.25 mg + DOR QD*
(n = 29)
(n = 30)
(n = 31)
DOR/3TC/TDF QD (n =
31)
*Participants initially received ISL + DOR + 3TC
through Wk 24.
60
20
40
0
80 77.4
89.7 90
83.9
6.9 6.7
12.9
6.5
100
Participants(%)
3.4 3.3
9.7 9.7

McComsey. CROI 2020. Abstr 686.
Islatravir: Phase IIb Exploratory
Metabolic Endpoints at Wk 48
 Minimal effects of ISL + DOR on body composition and metabolic
parameters; peripheral and trunk fat, glucose, and lipid changes
similar vs DOR/3TC/TDF
ISL 0.25
mg +
DOR QD
(n = 27)
ISL 0.75
mg +
DOR QD
(n = 28)
Combine
d
ISL
Groups
(n = 80)
DOR/
3TC/ TDF
QD
(n = 26)
MeanΔinWeight,%(95%CI)
Weight Change
For spine BMD: *n = 26, †
n = 24, ‡
n =
77.
ISL 0.25 mg + DOR QD
(n = 27)
(n = 27)*
(n = 25)†
Combined ISL Groups (n
= 79)‡
8
6
10
2
0
4
-2
5.4
4.8
1.1
3.8
3.0
MeanΔinBMD,%(95%CI)
0
1
2
-2
-3
-4
-1
-5
-0.2
-1.1
-2.0
-1.1
-3.5
-0.8
-2.0
-1.3
-1.3
-2.2
Hip BMD Loss Spine BMD Loss
ISL 2.25
mg +
DOR QD
(n = 25)

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