Expert-authored slides on evolving ART concepts, including simplification to 2-drug therapy, ART safety during pregnancy, weight gain, and long-acting injectable ART. File Size: 580 KB Released: October 20, 2020

1. Key Slides on ART for HIV: Evolving Concepts and
Innovative Strategies
This program is supported by educational grants from Merck Sharp & Dohme Corp.
and ViiV Healthcare

2. About These Slides
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Slide credit: clinicaloptions.com

3. Chair
W. David Hardy, MD
Scientific and Medical Consultant
Adjunct Professor of Medicine
Division of Infectious Diseases
Johns Hopkins University School of Medicine
Baltimore, Maryland
W. David Hardy, MD, has disclosed that he has received consulting fees from
Enochian Biosciences, Gilead Sciences, Merck, and ViiV/GlaxoSmithKline.

4. Faculty
Michelle S. Cespedes, MD, MS
Associate Professor of Medicine
Division of Infectious Disease
Department of Medicine
Icahn School of Medicine at Mount Sinai
Attending Physician
Mount Sinai Medical Center
New York, New York
Michelle S. Cespedes, MD, MS, has disclosed that she has received consulting
fees from Gilead Sciences and ViiV Healthcare.

5. Overview
 Simplifying ART to 2-drug regimens
 Safety of dolutegravir in pregnancy
 ARV-associated weight gain
 Future ART innovations

6. Simplification to 2-Drug ART

7. Case 1: ART Simplification
 A 32-yr-old African American woman with perinatally acquired HIV infection visits
your office for the first time following relocating from Atlanta to request an ART
regimen with as few pills as possible
 CD4+ cell count: 326 cells/mm3; HIV-1 RNA: 45 copies/mL
 History of cervical dysplasia yrs ago, serial cervical PAPs with normal cytology,
HPV cotesting negative for hrHPV, no other significant PMH
 ARV history (the patient cannot recall the yrs she started some meds)
‒ ? ZDV
‒ ? ABC/3TC/ZDV
‒ 2003 LPV/RTV + ZDV/3TC
‒ 2006 EFV/TDF/FTC (stopped meds for ~ 1.5 yrs due to lost insurance and fell out of care)
‒ 2014 ATV/RTV + TDF/FTC (reinitiated ARV for PMTC)
‒ 2018 DRV/COBI + TDF/FTC

8. Case 1: Additional Information
 The patient reports having stopped ART
before but has been consistent since the birth
of her son 5 yrs ago
 States that her former doctor switched her
meds from time to time “when a better
treatment option was available”
 Works as a teacher’s aide, lives with her sister
and her son, good family and social support—
all are aware of her HIV status
 Never smoked, occasional alcohol use, no
previous or current illicit drug use
Laboratory Parameter Result
WBC, x 109/L 6.2
Hemoglobin, g/dL 12
Platelets, x 109/L 289
Na/K, mmol/L 138/3.9
Creatinine, mg/dL 0.89
Albumin, g/dL 3.9
AST/ALT, u/L 26/22
Hepatitis A virus Immune
Hepatitis B virus Immune
Hepatitis C virus Ab negative
HLA-B*5701 Negative
Historical genotype (> 15 yrs ago) M184V
Archive genotype No predicted resistance

9. Outcomes of Switch to BIC/FTC/TAF in Patients With
Virologic Suppression and Preexisting M184V
 Retrospective study of stably suppressed patients
switched to BIC/FTC/TAF in Newark and Patterson,
NJ (N = 54)
‒ All patients undetectable (HIV-1 RNA < 50 c/mL) at
time of switch
 15 patients had M184V plus other clinically
significant NRTI and/or INSTI mutations
 Resistance testing: Proviral archive DNA genotype
(53%); traditional genotype (47%)
 Demographics: 67% Black race, mean age 57 yrs
 All patients maintained HIV-1 RNA < 200 c/mL,
suggesting durable viral suppression with
BIC/FTC/TAF even if mutations beyond M184V are
present; study limited by small sample size
Mutation Category
(N = 15)
Baseline
Mutations,
n (%)
HIV-1 RNA < 50 c/mL
at Latest Visit on
BIC/FTC/TAF, n/N (%)
HIV-1 RNA < 200 c/mL
at Latest Visit on
BIC/FTC/TAF, n/N (%)
Mean Duration of
BIC/FTC/TAF, Mos
(Range)
M184V + TAMs 13 (86) 12/13 (92) 13/13 (100) 11 (6-17)
M184V + other NRTI mutation 1 (7) 1/1 (100) 1/1 (100) 19
M184V + INSTI mutation 1 (7) 1/1 (100) 1/1 (100) 21
Natali. AIDS 2020. Abstr PEB0252. Slide credit: clinicaloptions.com

10. Comorbidity, n (%)
Treatment Experienced
Suppressed
(n = 671)
Not Suppressed
(n = 197)
Any 587 (87.5) 159 (80.7)
Autoimmune disease 29 (4.3) 8 (4.1)
Cardiovascular disease 89 (13.3) 20 (10.2)
Invasive cancer 80 (11.9) 15 (7.6)
Endocrine disorder 422 (62.9) 94 (47.7)
Mental health disorder 232 (34.6) 58 (29.4)
Liver disease 115 (17.1) 40 (20.3)
Bone disorder 52 (7.7) 17 (8.6)
Peripheral neuropathy 83 (12.4) 27 (13.7)
Renal disease 198 (29.5) 51 (25.9)
Hypertension 290 (43.2) 77 (39.1)
Substance use 92 (13.7) 31 (15.7)
Real-World Experience With DTG/RPV in the
United States
 Retrospective analysis of clinical characteristics and
outcomes in PWH switching to DTG/RPV between
Jan 2018 and Dec 2018 in OPERA study (N = 880)
 BL characteristics: 68% had CD4+ cell count
> 500 cells/mm3, 63% initiated ART after 2013
 88% remained on drug at 12 mos, virologic failure
occurred in 1.5%; of 42 patients who discontinued,
41% were virologically suppressed
Pierone. IDWeek 2019. Abstr 2483. Slide credit: clinicaloptions.com
Region (South)
Age (50+)
Risk Factor (MSM)
Race (Black)
Ethnicity (Hispanic)
Sex (Female)
0 10 20 30 40 50 60 70 80 90 100
Baseline Demographics of Patients Initiating DTG/RPV (N = 880)
DTG/RPV initiators
OPERA population
63%
57%
54%
38%
35%
60%
35%
44%
28%
25%
18%
17%

11. GEMINI-1 and -2: Virologic Response Through Wk 96
With DTG + 3TC for Treatment-Naive Patients
 Parallel, randomized, double-blind phase III noninferiority studies (N = 1433)
 HIV-1 RNA < 50 c/mL at Wk 96:
‒ All patients: DTG + 3TC 86.0% vs DTG + FTC/TDF 89.5%
‒ Patients with BL CD4+ cell count < 200 cells/mm3: 68% vs 87%
‒ 3 patients with CVW, 2 patients with HIV-1 RNA ≥ 50 copies/mL in window,
2 patients discontinued due to nontreatment-related AEs, 1 patient
discontinued due to treatment-related AEs, 2 patients with protocol violation,
3 patients LTFU, 4 patients withdrew consent, 1 change in ART due to
incarceration
Cahn. JAIDS. 2020;83:310. Slide credit: clinicaloptions.com

12. Key Secondary Endpoint
(HIV-1 RNA < 50 c/mL)
DTG/3TC noninferior to
continued TAF-based ART
TANGO: Switch to DTG/3TC vs Continuing TAF-Based
3-Drug or 4-Drug Regimen
Slide credit: clinicaloptions.com
0.5
Patients(%)
100
80
40
60
20
0
HIV-1 RNA
≥ 50 c/mL
HIV-1 RNA
< 50 c/mL
No Virologic
Data
0.3
93.2 93.0
6.5 6.5
Switch to DTG/3TC
(n = 369)
Continue TAF-based ART
(n = 372)
Virologic Outcomes by FDA Snapshot (ITT-E) at Wk 48 Adjusted Treatment Difference (95% CI)*
Primary Endpoint
(HIV-1 RNA ≥ 50 c/mL)
DTG/3TC noninferior to
continued TAF-based ART
*Adjusted for baseline third agent class.
Difference (%)
-3.4
0.2
-8 -6 -4 -2 0 2 4 6 8
3.9
-8% NI
margin
TAF-Based ARTDTG/3TC
TAF-Based ART DTG/3TC
-1.2 0.7
-0.3
-8 -6 -4 -2 0 2 4 6 8
4% NI
margin
van Wyk. IAS 2019. Abstr WEAB0403LB.
 No CVW in DTG/3TC arm, CVW in 1 (< 1%) patient in
TAF-based ART arm; no resistance detected at failure
 All 7 patients (4 in DTG/3TC group, 3 in TAF-based ART
group) with proviral M184V/I mutation at baseline
maintained HIV-1 RNA < 50 c/mL at Wk 48
 International, randomized, open-label phase III noninferiority study in adults with HIV-1 RNA < 50 c/mL for
> 6 mos on TAF-based ART

13. DOLULAM 4-Yr Follow-up: DTG/3TC in Heavily
Treatment Experienced PWH
 French prospective study of switching stably
suppressed (HIV-1 RNA < 50 c/mL for > 12 mos,
with no INSTI resistance) PWH to DTG/3TC (N = 27)
 Demographics: 74% male, 100% white, median age
59 yrs, 56% had pretreatment HIV-1 RNA
> 100,000 c/mL, median duration of ARV 215 mos
(range: 22-329)
 Regimen immediately prior to switch: 48% TDF,
81% PI/RTV, 26% RAL; median duration of current
ART: 51 mos (range: 13-108)
 10 (37%) patients had a history of genotypic test
with M184V mutation prior to switch
 Median weight change from BL to 4 yrs: 0 kg
(range: -6 to +7)
 Results suggest that in stable HTE patients with or
without history of M184V, DTG/3TC dual therapy
is an effective and durable maintenance strategy
 Limitations: small sample size
Reynes. IAS 2020. Abstr PEB0241. Slide credit: clinicaloptions.com
Patient Disposition After 4 Yrs, n N = 17
Virologic failure (HIV-1 RNA > 200 c/mL) 0
Treatment-related discontinuation
 Due to AE*
 Patient decision
 Persistent low-level viremia
(HIV-1 RNA 50-200 c/mL)
4
2
1
1
LTFU/severe biological AE 0/0
*Fatigue (n = 2), intestinal discomfort (n = 1).

14. Resistance Emergence on Long-Acting CAB + RPV
 ATLAS/FLAIR: 1.2% of patients with confirmed
virologic failure across both studies[1,2]
‒ 6 LA CAB + RPV subjects developed resistance
‒ CAB and RPV concentration at failure below
population means, but within range for the
majority who maintained suppression
 LATTE-2 6-yr results: 181 randomized to LA,
110 completed study at Wk 312[3]
‒ Among patients who began CAB + RPV at Wk
24, 66% maintained HIV-1 RNA < 50 c/mL, 9%
had HIV-1 RNA ≥ 50 c/mL, 25% had no
virologic data by Snapshot at Wk 312
‒ PDVF in 8 patients, of whom 3 developed
treatment-emergent major INSTI resistance
mutations, 2 of which were after Wk 144
Study
HIV-1
Sub-
type
Wk of
Failure
NNRTI RAMs INSTI RAMs
BL Failure BL Failure
ATLAS[1]
A/A1 8 E138E/A E138A L74I L74I
AG 12
V108V/I,
E138K
V108I,
E138K
None None
A/A1 20 None E138E/K L74I L74I, N155H
FLAIR[2]
A1 20 None E138E/A/K/T L74I L74I, Q148R
A1 28 None K101E L74I L74I, G140R
A1 48 None E138K L74I L74I, Q148R
1. Swindells. NEJM. 2020;382:1112. 2. Orkin. NEJM. 2020;382:1124. 3. Margolis. IDWeek 2019. Abstr 2840. Slide credit: clinicaloptions.com

15. ATLAS and FLAIR: Switch to Long-Acting CAB + RPV vs
Continued 3-Drug ART in Virologically Suppressed Patients
Teichner. IDWeek 2019. Abstr 884.
Virologic Snapshot Outcomes at Wk 48 (ITT-E)
1.7
ProportionofParticipants(%)
100
80
40
60
20
0
Virologic
Nonresponse
≥ 50 c/mL
Virologic
Success
< 50 c/mL
No Virologic
Data
1.9
93.1 94.4
5.1 3.9
LA CAB + RPV
(n = 591)
CAR
(n = 591)
Virologic Outcomes
Adjusted Treatment Difference (95% CI)*
Primary Endpoint:
LA noninferior to CAR
(HIV-1 RNA ≥ 50 c/mL)
at Wk 48
Difference (%)
-4.1
-1.4
1.4
-10% NI
margin
CARLA CAB + RPV
CAR LA CAB + RPV
-1.4 1.7
0.2
-8 -6 -4 -2 0 2 4 6 8
4% NI
margin
10-10
Key Secondary Endpoint:
LA noninferior to CAR
(HIV-1 RNA ≥ 50 c/mL) at
Wk 48
-8 -6 -4 -2 0 2 4 6 8 10-10
Slide credit: clinicaloptions.com

16. ATLAS and FLAIR: Favorable Adherence and Tolerability
at Wk 48
 High rates of adherence to injection visits through Wk 48 in patients receiving CAB LA +
RPV LA
‒ 98% of injection visits occurred within the allowed ± 7-day dosing window
 Oral bridging with CAB and RPV was an effective strategy for maintaining virologic
suppression to cover missed injection visits
‒ 7 patients received oral bridging covering 8 planned missed injection visits; all maintained virologic
suppression < 50 c/mL
 25% (3663/14,682) of injections associated with local ISRs
‒ Pain was most common ISR: 84% (3087/3663)
‒ 99% of ISRs were grade 1/2 with median duration 3 days, < 1% associated with discontinuation
Orkin. NEJM. 2020;382:1124. Teichner. IDWeek 2019. Abstr 884. Slide credit: clinicaloptions.com

17. ATLAS-2M: Switch to CAB LA + RPV LA Every 2 Mos vs
Switch to CAB LA + RPV LA Monthly Injections
 Multicenter, randomized, open-label phase III noninferiority study of CAB LA + RPV LA every 8 wks
vs every 4 wks in virologically suppressed patients with no prior virologic failure (N = 1045)
Slide credit: clinicaloptions.comOverton. CROI 2020. Abstr 34. Reproduced with permission.
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
*Based on Cochran-Mantel-Haenszel analysis adjusting for prior CAB + RPV exposure.
Q4WQ8W
Difference (%)
-0.6 2.2
0.8
4% NI
margin
Difference (%)
-2.1 3.7
0.8
Q8WQ4W
-10% NI
margin
CAB LA + RPV LA Q8W
(n = 522)
CAB LA + RPV LA Q4W
(n = 523)
Adjusted Treatment Difference (95% CI)*Virologic Outcomes
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

18. ATLAS-2M: Confirmed Virologic Failures
 CVF in CAB LA + RPV LA Q8W arm: n = 8
‒ 5 had preexisting major RPV RAMs (E138A,
Y188L, Y181Y/C, H221H/Y, E138E/A,
Y188Y/F/H/L)
‒ 1 had preexisting major INSTI RAM (G140G/R)
‒ 5 had L74I polymorphism (3 subtype A/A1,
1 subtype C, 1 complex subtype)
 Fully active oral ART resulted in viral
resuppression in 9/10 patients with CVF
‒ 1 patient noncompliant on PI-based ART
 In all patients with CVF (n = 10), virus
maintained phenotypic sensitivity to DTG
Slide credit: clinicaloptions.comOverton. CROI 2020. Abstr 34.
Characteristic
CAB LA + RPV LA
Q8W
(n = 522)
CAB LA + RPV LA
Q4W
(n = 523)
CVF, n (%) 8 (1.5) 2 (0.4)
CVF with RPV
RAMs,* n/N
6/8 1/2
Treatment-
emergent RPV
RAMs
K101E, E138E/K,
E138A, Y188L
K101E, M230L
CVF with INSTI
RAMs,* n/N
5/8 2/2
Treatment-
emergent INSTI
RAMs
Q148R, N155H† E138E/K,Q148R,
N155N/H
*Post hoc BL PBMC HIV-1 DNA testing. †Or a mixture.

19. Women of Childbearing Potential

20. Case 1
 Prior to initiating her new regimen, a pregnancy test is administered, and it is
negative
 Upon asking about her fertility desires, you learn that:
‒ She identifies as a woman and describes her sexual orientation as bisexual
‒ She is not currently in a relationship; her last long-term relationship was with a man and ended
6 mos ago
‒ She uses condoms for birth control
‒ Not planning to get pregnant anytime soon but would not be opposed to having another child
before she “gets too old”
 32-yr-old African American woman; wants to take as few pills as possible
 CD4+ cell count: 326 cells/mm3; HIV-1 RNA: 45 c/mL
 HLA-B*5701 negative, no predicted RAMs, history of M184V

21. Tsepamo Birth Outcomes Surveillance Study in
Botswana: Background
 In May 2018, unplanned analysis of Tsepamo birth outcomes surveillance study
found increase in NTD incidence among Botswanan women who conceived on DTG[1]
‒ DTG vs non-DTG ART: 0.94% (95% CI: 0.37-2.4) vs 0.12% (95% CI: 0.07-0.21)
‒ Prevalence difference: 0.82% (95% CI: 0.24-2.3)
 Analysis of data through April 2019 found NTD prevalence among women who
received DTG at conception lower than previous analysis, but still higher than other
exposure groups[2]
‒ DTG vs non-DTG ART: 0.30% (95% CI: 0.13-0.69) vs 0.10% (95% CI: 0.06-0.17)
‒ Prevalence difference: 0.20% (95% CI: 0.01-0.59)
 Current analysis reports data from Tsepamo through April 2020[3]
1. Zash. NEJM. 2018; 379:979. 2. Zash. IAS 2019. Abstr MOAX0105LB. 3. Zash. AIDS 2020. Abstr OAXLB01. Slide credit: clinicaloptions.com

22. Tsepamo Update: Prevalence of NTDs by ARV Exposure
Zash. AIDS 2020. Abstr OAXLB01. Slide credit: clinicaloptions.com
Parameter
Conception Pregnancy
HIV Negative
(n = 119,630)DTG
(n = 3591)
Non-DTG
(n = 19,361)
EFV
(n = 10,958)
DTG
(n = 4581)
Total NTDs per exposures, n/N 7/3591 21/19,361 8/10,958 2/4581 87/119,630
NTD prevalence, % (95% CI)
 April 2019
 April 2020
0.30
(0.13-0.69)
0.19
(0.09-0.40)
0.10
(0.06-0.17)
0.11
(0.07-0.17)
0.04
(0.01-0.11)
0.07
(0.03-0.17)
0.03
(0.00-0.15)
0.04
(0.01-0.16)
0.08
(0.06-0.10)
0.07
(0.06-0.09)
Prevalence diff. with DTG
conception, Apr 2020, % (95% CI)
Ref
0.09
(-0.03 to 0.30)
0.12
(0 to 0.32)
0.15
(0 to 0.36)
0.12
(0.01 to 32.0)
NTDs per exposure between April
2019 and April 2020, n/N
2/1908* 6/4569 5/2999 1/741 17/30,258
*Includes 1 lumbosacral myelomeningocele (spina bifida) and 1 encephalocele.

23. Pregnancy Outcomes With Raltegravir Exposure
 Pooled analysis of 2550 prospective pregnancy outcomes following RAL exposure (51% first trimester
exposure, including 34% RAL use at periconception)
 No association between RAL and adverse outcomes; spontaneous abortions, stillbirths, major anomalies
comparable to gen population
 Data supports treatment guideline use of RAL in women of childbearing potential and during pregnancy
‒ No neural tube defects among the 765 peri-conception exposures
Prospective Outcomes,
Birth Outcome N
(Pregnancy Exposure n)
Earliest Trimester of Exposure
Periconception,
328 (325)
Other First,
173 (169)
Second/Third,
450 (442)
Unknown,
25 (25)
Total,
976 (961)
Live births 290 (288) 143 (139) 440 (433) 19 (19) 892 (879)
Major congenital abnormality
 NTD
5 (5)
0
4 (4)
0
23 (21)
0
1 (1)
0
33 (31)
0
Spontaneous abortions 20 (19) 13 (13) 2 (2) 1 (1) 36 (35)
Stillbirth or fetal death 2 (2) 3 (3) 6 (5) 0 11 (10)
Elective terminations 15 (15) 13 (13) 2 (2) 5 (5) 35 (35)
Ectopic pregnancies 1 (1) 1 (1) 0 0 2 (2)
Shamsuddin. IDWeek 2019. Abstr 886. Slide credit: clinicaloptions.com

24. Periconception INSTI Use and NTDs
 DHHS on DTG in United States: “ . . . because of mandatory food folate
fortification, the overall risk of NTDs in the United States is low in the
general population, and there are currently insufficient DTG
periconception exposures reported to the Antiretroviral Pregnancy
Registry to be able to determine whether there is an increase in the risk
of NTDs in the United States.”
 BIC: Insufficient data
 RAL: Data from APR, drug manufacturer, and multinational cohort
study
DHHS Guidelines. December 2019. Slide credit: clinicaloptions.com

25. Current Guidance on DTG Use in Treatment-Naive
Women of Childbearing Potential
 DTG can be prescribed for adult
women and adolescent girls of
childbearing age or potential who
wish to become pregnant or who are
not otherwise using or accessing
consistent and effective contraception
if they have been fully informed of
the potential increase in the risk of
neural tube defects (at conception
and until the end of the first
trimester)
 DTG a “preferred” ARV for pregnant
women, irrespective of trimester
‒ Based on higher rate of virologic
suppression, faster rate of HIV-1 RNA
decline, and higher genetic barrier of
DTG vs other ARVs
 DTG an “alternative” ARV for women
trying to conceive
‒ Rationale: More time to reach
virologic suppression using
DTG-sparing ART in these cases
1. WHO ARV Policy Update. July 2019. 2. DHHS Perinatal Guidelines. April 2020. Slide credit: clinicaloptions.com
WHO Guidance[1] DHHS Guidance[2]

26. Panel Discussion

27. ARV-Associated Weight Gain

28. Case 2
 60-yr-old white man with HIV infection well controlled on DTG/ABC/3TC
‒ CD4+ cell count: 532 cells/mm3
 Receiving lisinopril for HTN
 Presents with 2 mos intermittent malaise, generalized weakness, now with several
wks of diarrhea, 2 wks of poor PO intake
 BMI: 24 kg/m2
 Nonsmoker, denies alcohol use, distant cocaine use “in the 80s,” denies recent
illicit drug use
 He had been reluctant to present to clinic during COVID-19 lockdowns but has
tested negative for SARS-CoV-2 at a walk-in clinic twice in the past 2 mos
 In clinic, he is normotensive and afebrile but slightly slow to respond to questions
and states that he does not feel like himself

29.  Additional workup during hospitalization
significant for:
‒ ANA positive, +dsDNA, pattern c/w SLE
 Reports sister died from lupus in her 30s
 Understands that he may need to change his
HIV regimen because of his kidney function
 States that he is very concerned about
weight gain since he saw his sister gain
weight after she was diagnosed with lupus
Case 2
 Patient is sent to the ED from clinic;
evaluation in ED notable for:
‒ WBC: 4 x 109/L, hemoglobin: 10.1 g/dL (BL 12
g/dL), platelets: 117 x 109/L
‒ Creatinine: 6 mg/dL (BL 0.9 mg/dL), K: 7
mmol/L with EKG changes, BUN: 72 mg/dL
 Noncontrast head CT: negative; CT abd/pel:
negative, no evidence of obstruction
 Urine sediment with RBC
 Required emergent HD x 1 session
 Creatinine stabilized to 1.8 mg/dL;
GFR: 40 mL/min (CKD stage 3B:
GFR 30-44 mL/min)

30. ADVANCE: Mean Weight Change by Sex
 Greater weight increase with DTG vs EFV, with TAF vs TDF; plateau in weight gain after
Wk 48 observed in men but not in women
‒ Same patterns observed for percentage change in weight and change in BMI category over time
Slide credit: clinicaloptions.com
Men Women
0 4 12 24 36 48 60 72 84 96
0
2
10
4
6
8
MeanWeightChange(kg)
Wk
12
DTG + FTC/TAF
DTG + FTC/TDF
EFV/FTC/TDF
+6 kg
+3 kg
+1 kg
0 4 12 24 36 48 60 72 84 96
0
2
10
4
6
8
MeanWeightChange(kg) Wk
12
+9 kg
+5 kg
+3 kg
McCann. EACS 2019. Abstr PS3/3. Venter. NEJM. 2019;381:803.

31. 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)
Slide credit: clinicaloptions.comSax. Clin Infect Dis. 2019;[Epub].
Female
Male
0.5
0
2.5
LSMWeightΔ,kg(95%CI)
Wks
12 24 36 48 60 72 84 96
1.0
*
4.5
3.5
3.0
1.5
2.0
Black
Nonblack
0.5
0
2.5
LSMWeightChange(kg)
Wks
12 24 36 48 60 72 84 96
1.0
4.0
3.5
3.0
1.5
2.0
5.0
Black female
Black male
Nonblack female
Nonblack male
1
0
6
5
LSMWeightChange(kg)
Wks
12 24 36 48 60 72 84 108
2
3
4
96
*
*
*
*
* *
*
*
* *
*
*†
*Color-coded to match respective comparators, denoting P < .05 vs male (first panel), nonblack (second panel), or nonblack females
(last panel). †P < .05 vs black males.
*†
*† *†
*† *†
4.0 4.5

32. INSTIs and TAF Associated With Greater Weight Gain vs
Other ARVs
OR (95% CI)
P Value
.82
.44
.31
.003
.034
.003
.73
.026
.035
.002
ABC vs ZDV
TDF vs ZDV
TDF vs ABC
TAF vs TDF
TAF vs ZDV
TAF vs ABC
ATV/RTV vs EFV
EVG/COBI vs EFV
RPV vs EFV
BIC or DTG vs EFV
4-2 -1 0 1 2 3
Decreased Risk Increased Risk
Sax. Clin Infect Dis. 2019;[Epub].
Risk of Weight Gain ≥ 10%[1]
Slide credit: clinicaloptions.com

33. Normal/Underweight
(< 25.0 kg/m2)
Overweight
(25.0-29.9 kg/m2)
Obese
(≥ 30 kg/m2)
BMI Changes Over Time by HIV Status and Baseline BMI
 Kaiser Permanente EMR database (N = 138,222) of PWH ≥ 21 yrs of age who initiated ART
between 2006 and 2016 with available baseline BMI; uninfected controls matched 1:10 by
age, sex, race/ethnicity, clinic, yr
Slide credit: clinicaloptions.comSilverberg. AIDS 2020. Abtstr OQB0603.
Yrs From Baseline
BMI(kg/m2)
28
26
24
22
20
120 2 4 6 8 10
Uninfected (n = 32,038)
PWH (n = 3852)
0.31 kg/m2/yr
(P < .001)
0.20 kg/m2/yr
(reference)
25.1
22.0 24.2
21.6
32
30
28
26
24
120 2 4 6 8 10
Uninfected (n = 49,602)
PWH (n = 2927)
0.18 kg/m2/yr
(P < .001)
0.09 kg/m2/yr
(reference)
28.3
26.3
27.4
26.2
38
36
34
32
30
120 2 4 6 8 10
Uninfected (n = 48,326)
PWH (n = 1477)
0.07 kg/m2/yr
(P = .09)
-0.02 kg/m2/yr
(reference)
33.5
33.5
33.2
32.6

34. OPERA: Weight Change With Switch From TDF to TAF
While Maintaining Other ARVs by Class of Anchor Agent
Mallon. AIDS 2020. Abstr OAB0604. Reproduced with permission. Slide credit: clinicaloptions.com
Mos From Switch
Weight(kg)
INSTI NNRTI Boosted PI
92
90
88
86
84
82
80
78
0
-60-54-48-42-36-30-24-18-12-6 0 6 1218243036 4248
92
90
88
86
84
82
80
78
0
-60-54-48-42-36-30-24-18-12-6 0 6 1218243036 4248
92
90
88
86
84
82
80
78
0
-60-54-48-42-36-30-24-18-12-6 0 6 1218243036 4248
Estimated Weight Δ by Time From TDF
to TAF Switch, kg/yr (95% CI)
INSTI
(n = 3281)
NNRTI
(n = 1452)
Boosted PI
(n = 746)
-60 to 0 mos 0.42 (0.26 to 0.59) 0.66 (0.51 to 0.81) 0.31 (-0.02 to 0.64)
0 to 9 mos 2.64 (2.26 to 3.01) 2.25 (1.78 to 2.71) 1.98 (1.13 to 2.83)
9+ mos 0.29 (0.08 to 0.51) 0.20 (-0.14 to 0.54) -0.11 (-0.57 to -0.35)

35. BMI and ASCVD Changes With Switch From TDF to TAF
 Retrospective observational study, 6-12 mos after suppressed patients switched from TDF to TAF
without switching any other ART regimen components (N = 110)
 Switch from TDF to TAF led to 0.45 BMI increase (95% CI: 0.14-0.76; P < .01) and 13% increase in
ASCVD 10-yr risk score (95% CI: 4-23; P < .01)
‒ Shifted 50.7% of patients to ASCVD scores indicating use of a statin
Outcome Variable Preswitch (TDF) Postswitch (TAF) Change (Post–Pre) P Value
Median weight, lbs (IQR) 185.4 (55.8) 190.5 (60.5) 3.0 (9.2) < .01
Median BMI, kg/m2
(IQR) 28.0 (10.8) 28.2 (10.0) 0.5 (1.4) < .01
Median total cholesterol, (IQR) 173.8 (44.0) 195.0 (42.0) 12.5 (32.3) < .01
Median LDL cholesterol, (IQR) 98.6 (40.2) 112.1 (46.6) 8.2 (21.0) < .01
Median HDL cholesterol, (IQR) 51.0 (19.0) 55.8 (24.0) 3.0 (12.0) < .01
Median total to HDL cholesterol ratio, (IQR) 3.5 (1.6) 3.5 (1.7) 0.1 (0.6) .25
Median triglyceride levels, (IQR) 103.5 (68.0) 109.5 (93.0) 4.0 (64.0) .28
Median atherosclerotic CVD risk score, (IQR) 6.9 (8.1) 8.1 (10.9) 0.4 (1.9) < .01
Slide credit: clinicaloptions.comSchafer. Open Forum Infect Dis. 2019;[Epub].

36. TAF vs TDF: Analysis in Black and Latinx Participants
 Pooled data from Hispanic/Latinx and Black
adults who initiated/switched to TAF vs TDF in
7 randomized trials (N = 5825)
‒ 1138 Hispanic/Latinx and 1324 Black
participants
 Demographics
‒ Treatment naive (n = 1733): 15% female, 25%
Black, 19% Hispanic/Latino, median age 34 yrs
‒ Switch (n = 4092): 13% female, 22% Black,
20% Hispanic/Latino, median age 45 yrs
 Those on TAF had significantly improved bone
and renal parameters, with similar rates of
virologic suppression at Wk 96
 Efficacy and biomarkers were similar to the
overall study population
 Significant increase in weight in those on TAF
regimens
‒ Difference ~ 2 kg at Wk 96
Slide credit: clinicaloptions.comDeJesus. IDWeek 2019. Abstr 318.
Median
Change at
Wk 96, kg
Treatment Naive Suppressed
TAF TDF
P
Value
TAF TDF
P
Value
All pts 3.2 1.4 < .001 2.5 0.5 < .001
Hispanic/
Latinx pts
3.1 1.2 .01 2.3 0.5 < .001
Black pts 3.7 3.2 .55 2.7 0.4 < .001

37. Future ART Innovations

38. Slide credit: clinicaloptions.com
Agent MoA Phase Innovation
Elsulfavirine[1] NNRTI I Long acting
Lenacapavir (GS-6207)[2] Capsid inhibitor I
Long acting, fewer than 3
drugs
Islatravir (MK-8591)[3] NRTTI II
Long acting, fewer than 3
drugs
Leronlimab (PRO 140)[4] Anti-CCR5 mAb IIb/III
Long acting, fewer than 3
drugs
CAB + RPV[5,6] INSTI + NRTI III
Long acting, fewer than 3
drugs
1. NCT03730311. 2. Sager. CROI 2019. Abstr 141. 3. Grobler. CROI 2019. Abstr 0481.
4. Dhody. CROI 2019. Abstr 486. 5. Swindells. NEJM. 2020;382:1112. 6. Orkin. NEJM. 2020;382:1124
Novel ART Strategies Under Investigation

39. Matthews, IAS 2019, #4843 Slide credit: clinicaloptions.comMatthews. IAS 2019. Abstr 4843.
Islatravir (MK-8591, ISL): Novel Nucleoside Reverse
Transcriptase Translocation Inhibitor
 First-in-class NRTTI
‒ High potency; half-life up to 128
hrs, once per yr dosing feasible
 HIV prevention
‒ Islatravir implant inserted into
upper arm for 12 wks, then
removed
‒ PK modeling indicated ISL-TP
levels remain > level needed for
HIV prevention for > 12 mos
ISLPlasmaConcentrations
(µM)
ISL-TPConcentrations
(pmol/106Cells)
Projected CWk52 ISL-TP:
~ 0.076 pmol/106 cells
0.000
0.005
0.010
0.015
0.020
0 10 20 30 40 50
Wks
0.00
0.02
0.04
0.06
0.08
Projected ISL-TP
PrEP PK threshold: 0.05 pmol/106 cells
Mean observed plasma data
Model fit
O
N
N
N N
F
NH3
OH
HOTranslocation Inhibition
Due to the 4’-ethynyl group
vRNA
vDNA
*Prevents nucleotide binding and
incorporation to the DNA chain, resulting
in immediate chain termination
vRNA
vDNA
*Prevents nucleotide incorporation even
in the event of translocation
*ISL is no longer susceptible to resistance-
conferring mutations, once out of the
active site
Delayed Chain Termination
Due to the 4’-ethynyl and 3’-hydroxyl groups

40. P011: ISL + DOR Following ISL, DOR, 3TC Induction in
Treatment-Naive Patients
 Analysis of patients discontinuing international, randomized, double-blind phase IIb trial with PDVF
 PDVF defined as: Viral rebound (HIV-1 RNA ≥ 50 c/mL after initial response < 50 c/mL on study; or confirmed HIV-1 RNA
> 1 log increase from nadir after a > 1 log decrease vs BL on study); or nonresponse (HIV-1 RNA ≥ 200 c/mL at any time from
Wk 24 through Wk 48; or confirmed HIV-1 RNA ≥ 50 c/mL at Wk 48)
 Initial PDVF HIV-1 RNA level must be confirmed by subsequent measurement within 2 wks
Orkin. AIDS 2020. Abstr OAB0302. DeJesus. AIDS 2020. Abstr OAB0305.
Treatment-naive adults with
HIV-1 RNA ≥ 1000 c/mL,
CD4+ count ≥ 200 cells/mm3,
no ARV drug resistance,
no active HCV or HBV
coinfection
(N = 121)
Part 1:
3-Drug Dose Ranging
ISL 0.25 mg + DOR + 3TC QD*
(n = 29)
DOR/3TC/TDF QD†
(n = 31)
ISL 0.75 mg + DOR + 3TC QD*
(n = 30)
ISL 2.25 mg + DOR + 3TC QD*
(n = 31)
Stratified by screening HIV-1 RNA
(≤ vs > 100,000 c/mL)
ISL 0.25 mg + DOR QD
(n = 29)
DOR/3TC/TDF QD
(n = 28)
ISL 0.75 mg + DOR QD
(n = 30)
ISL 2.25 mg + DOR QD
(n = 27)
Part 2:
2-Drug Dose Ranging
If HIV-1 RNA < 50 c/mL at Wk 20
without meeting any VF criteria‡
Wk 24 Wk 48
Maintenance phase
*Received placebo for DOR/3TC/TDF QD.
†Received placebo for ISL + DOR + 3TC QD.
‡If HIV-1 RNA ≥ 50 c/mL at Wk 20,
continued Part 1 until HIV-1 RNA < 50 c/mL
and, if not meeting any VF criteria,
transitioned to Part 2.
Slide credit: clinicaloptions.com

41. P011: Virologic Outcomes Through Wk 48 (FDA Snapshot)
Orkin. AIDS 2020. Abstr OAB0302. Reproduced with permission.
HIV-1 RNA < 50 copies/mL HIV-1 RNA ≥ 50 copies/mL No Virologic Data in Window
ISL 0.25 mg + DOR* QD
ISL 0.75 mg + DOR* QD
ISL 2.25 mg + DOR* QD
DOR/3TC/TDF QD
Patients(%)
26/29 27/30 24/31 26/31 2/29 2/30 4/31
*Participants initially received ISL + DOR + 3TC and switched to ISL + DOR during the Wk 24-48 period of the study.
Slide credit: clinicaloptions.com
n/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

42. Lenacapavir Pharmacokinetic Profile
 Lenacapavir (GS-6207): First-in-class selective HIV-1 capsid protein inhibitor with PO and
SC long-acting formulations in development
 Randomized, double-blind, placebo controlled, single-ascending SC dose phase I study in HIV-negative
participants (N = 30)
Begley. AIDS 2020. Abstr PEB0265. Slide credit: clinicaloptions.com
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 Profiles
6 mos
(26 wks)
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)
*Protein-adjusted EC95:
macrophages, 1.16 ng/mL;
CD4+ cells, 2.32 ng/mL, MT-4
cells, 3.87 ng/mL.

43. clinicaloptions.com/hiv
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