2 Drug Therapy: Revolution or Regression?

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2-Drug Therapy:
Revolution or Regression?
Joel Gallant, MD, MPH
Executive Director, HIV Medical Affairs
Gilead Sciences

‡
Disclosures
 I am an employee of Gilead Sciences
3

‡
ARS Question
 Which of the following best describes your use of 2-drug
combinations?
A. I am comfortable starting them in some naïve patients
B. I use them only in selected treatment-experienced patients who are
adherent and virologically suppressed
C. I rarely use them
D. A & B
4

‡
2-Drug Therapy:
 Efficacy
 Safety and Tolerability
 Resistance
 Guidelines
5

‡
2-Drug Therapy:
 Efficacy
 Resistance
 Guidelines
6

‡
Study Design
Two Phase 3, randomized, double-blind, multicenter, non-inferiority studies
71. Cahn P, et al. IAS 2019. Mexico City, Mexico. Oral WEAB0404LB
2. Cahn P, et al. Lancet 2019;393:143–55
Primary Endpoint
• HIV-1 RNA <50 c/mL by FDA Snapshot
algorithm at Week 48
• 10% non-inferiority margin
Secondary Endpoint
• Treatment-emergent resistance to DTG and
3TC or FTC/TDF
Treatment-Naïve Adults
HIV-1 RNA 1000 to 500,000 c/mL
Key inclusion criteria:
• No evidence of any pre-existing major resistance-
associated mutation to PIs, NNRTIs, or NRTIs
• No HBV coinfection
• No need for HCV therapy
• eGFRCG ≥50 mL/min
DTG + 3TC (N=716)
W144
DTG + FTC/TDF (N=717)
W96W48
1:1
W24
Double-blind phase Open-label phase
Baseline Characteristics
DTG + 3TC
(n=716)
DTG + FTC/TDF
(N=717)
Age, median (IQR) 32 (26-40) 33 (26-42)
Female, n (%) 113 (16) 98 (14)
HIV RNA, log10 c/mL, mean (SD) 4.42 (0.66) 4.45 (0.65)
CD4 count, cells/mm3, mean (SD) 462.0 (219.2) 461.3 (213.1)
3. Clinicaltrials.gov NCT02831673
4. Clinicaltrials.gov NCT02831764
GEMINI 1 and 2: DTG + 3TC vs. DTG + FTC/TDF (Treatment-Naïve)

‡‡
Virologic Outcomes at Week 48 & 96
BL, baseline
* Adjusted for plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL), CD4 count (≤200 cells/mm3 vs >200 cells/mm3), and study
† TRDF W48 and W96 virologic outcomes were 98 vs 98% & 98 vs 100% and 97 vs 96% and 94 vs 96% respectively (DTG+3TC vs DTG + FTC/TDF for CD4>200 & ≤200 cells/mm3)
1. Cahn P, et al. IAS 2019. Mexico City, Mexico. Oral WEAB0404LB
2. Cahn P, et al. AIDS 2018. Amsterdam, NL. Oral TUAB0106LB
Pooled GEMINI 1 & 2 Studies: DTG + 3TC vs. DTG + FTC/TDF in Treatment-Naïve Adults
At W48 & W96, DTG + 3TC was non-inferior but with lower viral suppression rates
in participants with BL CD4 <200 compared to DTG + FTC/TDF
OVERALL1,2
91
86
93 90
0
20
40
60
80
100
Week 96Week 48
HIV-1RNA<50c/mL,%
79
68
93
87
0
20
40
60
80
100
Week 96Week 48
BL CD4 ≤ 200 cells/μL3,4†
43
63
48
55
50
63
51
55
HIV-1RNA<50c/mL,%
DTG + 3TC DTG + FTC/TDF
3. Orkin C, et al. HIV Drug Therapy 2018. Glasgow, UK. 021
4. Van Wyk J, et al. ID Week 2019. Washington, DC. Oral 2482
8
Adjusted Treatment Difference
(95% CI)*
-10 0 10
-4.4 1.1
-1.7
Percentage-point difference
Favors
DTG + 3TC
-6.7 0.0007
-3.4
GEMINI 2
Week 48
-4.9
0.03-9.8
-1.8
2.7-6.4
Week 96
Favors
DTG + FTC/TDF
GEMINI 1
Treatment related discontinuation equals failure (TRDF)
analysis was reported at IDWeek4†

‡
TAF-based regimen
Study Design
Phase 3, randomized, open-label, multicenter, non-inferiority study
to evaluate switching to DTG + 3TC vs remaining on current TAF-based regimen
9
Primary Endpoint
• HIV-1 RNA ≥ 50 c/mL by FDA Snapshot
algorithm at Week 48
• 4% non-inferiority margin
Secondary Endpoint
• HIV-1 RNA ≥ 50 c/mL by FDA Snapshot
algorithm at Week 24,96, and 144
Virologically Suppressed Adults
on TAF-based initial regimen
Key inclusion criteria:
• FTC/TAF plus PI or INSTI or NNRTI regimen
• No prior VF
• No documented NRTI or INSTI resistance
• Virologically suppressed for >6 months
• No HBV coinfection
• No need for HCV therapy
DTG/3TC
Week 0 48
N=369
Primary
endpoint
N=372
96 148
DTG/3TC
Van Wyk J, et al. IAS 2019. Mexico City, MX. Oral WEAB0403LB
TANGO: DTG/3TC Switch Study (Virologically Suppressed)
200
DTG / 3TC
(N=369)
TAF-based regimen
(N=372)
Age, median (IQR) 40 (20-74) 39 (18-73)
Female, n (%) 25 (7) 33 (9)
CD4 count, cells/mm3,
median (range)
682 (113-1904) 720 (119-1810)
CD4 <350 cell/mm3, n (%) 35 (9) 30(8)
INSTI / NNRTI / PI, % 78% / 14% / 8% 80% / 13% / 8%
(Late Switch)

‡
Adjusted Treatment Difference
(95% CI)*
-8 -6 -4 -2 0 2 4 6 8
-1.2 0.7
Difference %
4% non-
inferiority
margin
-0.3
Favored TAF-
based regimen
Virologic Outcomes and Resistance at Week 48
10
Van Wyk J, et al. IAS 2019. Mexico City. Abstract WEAB0403LB
DTG + 3TC was non-inferior to TAF-based triple therapy at W48
with no treatment-emergent resistance in either arm
Virologic Outcomes
Participants, n
DTG/3TC
n=369
TAF-based
regimen
n=372
Confirmed
Virologic
Withdrawals
0 1 (<1%)
Treatment-
emergent
Resistance
0 0
Resistance
0.3
93.2
6.5
0.5
93.0
6.5
0
20
40
60
80
100
HIV-1 RNA ≥50 c/mLa HIV-1 RNA <50 c/mL No virologic data
DTG/3TC
(N=369)
TAF-based regimen
(N=372)
Proportion,%
Favored
DTG/3TC

‡
Triple Therapy vs 2-Drug Combinations:
Clinical Characteristics & Regimens
11
VACH Cohort (Spain)
2DC participants were older and more treatment experienced
but a higher proportion were virologically suppressed at switch.
TT
n=5047
2DC
n=617
p-value
Age (years), Mean (SD) 48.1 (10.7) 52.0 (10.3) <0.001
Gender, % Female 23.4 28.4 0.002
PWID, % 26.6 30.3 0.029
AIDS diagnosis, % 23.2 26.7 0.026
CD4 count, % > 350 cells/μL 81.8 82.9 0.453
Viral Load, % < 50 c/mL 81.0 90.2 <0.001
N of previous ART regimens,
Mean (SD)
5.3 (3.6) 7.4 (4.6) <0.001
Duration of ART regimens
(years), Mean (SD)
12.0 (8.4) 14.9 (8.1) <0.001
N of previous VF, Mean (SD) 1.1 (2.4) 1.5 (2.9) <0.001
HCV (Ab+), % 32.6 35.3 0.132
HBV, % 4.1 1.8 0.004
Triple Therapy
(N=5,047)
2-Drug Combination
(N=617)
DTG + 3TC
68%
DTG + RPV
32%
5,047 TT and 617 2DC Participants
• 8,617 person-years on TT
• 756 person years on 2DC
A retrospective analysis using data from VACH cohort including all patients switching to INSTI-based triple therapy (TT)
or to a 2-drug combination (2DC) consisting of DTG+RPV or DTG+3TC between May 2016 and May 2019
Tiera R, et al. EACS 2019. Basel, Switzerland. PS 8/5
Gilead Investigator-Sponsored Study
DTG/ABC/3TC
40%
EVG/c/F/TAF
51%
RAL + F/TDF (3%)
RAL + ABC/3TC (3%)
EVG/c/F/TDF (2%)
DTG + ABC/3TC (1%)

‡
0 1 2 3
Time on Treatment (years)
A retrospective analysis using data from VACH cohort including all patients switching to
INSTI-based TT (n=5,047) or to a 2DC (n=617) consisting of DTG+RPV or DTG+3TC between 02/05/2016 and 15/05/2019
Risk of Discontinuation due to Treatment Failure* and AEs
12
Treatment Failure* AEs
Cox Model aHR [95% CI]† P-value
2DC vs. TT 2.3 [1.3, 4.1] 0.003
After controlling for demographic and clinical characteristics,
risk of discontinuation due to treatment failure was 2.3 times higher on 2DC vs TT (p=0.003).
No difference between groups in time to and risk of discontinuation due to AEs
2DC vs. TT 0.8 [0.4, 1.5] 0.488
TT 4977 4313 3620 2952 2250 1376 326
2DC 615 492 299 208 132 64 10
4977 4313 3620 2952 2250 1376 326
615 492 299 208 132 64 10
Gilead Investigator-Sponsored Study
* Defined as clinician report of switch due to virological failure, immunological failure or disease progression. † Adjusted for demographic and clinical characteristics
0.75
0.80
0.85
0.90
0.95
1.00
Probabilityofpersistence
0 1 2 3
Log-rank p = 0.002
TT
2DC
0.75
0.80
0.85
0.90
0.95
1.00
.
0 1 2 3
Log-rank p = 0.908
TT
2DC
Virological Failure
4977 4313 3620 2952 2250 1376 326
615 492 299 208 132 64 10
0.75
0.80
0.85
0.90
0.95
1.00
.
Log-rank p = 0.037
TT
2DC
2DC vs. TT 2.2 [1.1, 4.5] 0.024
Tiera R, et al. EACS 2019. Basel, Switzerland. PS 8/5
VACH Cohort (Spain)

‡
0.75
0.80
0.85
0.90
0.95
1.00
0 1 2 3
0 1 2 3
0.75
0.80
0.85
0.90
0.95
1.00
Discontinuation due to Treatment Failure - Subanalyses1
VACH Cohort (Spain)
Risk of discontinuation due to treatment failure was consistently > 2-fold higher on 2DC vs TT
in suppressed at switch and the matched sample2
2DC vs. TT 2.3 [1.2, 4.3] 0.011
2DC n=467; TT n=934
Treatment Failure*
Suppressed at Switch
2DC n=554; TT n=3996
Treatment Failure
Matched Participants‡
3941 3474 2968 2455 1895 1155 274
552 446 266 185 120 58 7
920 804 685 587 442 259 62
465 377 224 157 102 48 7
1. Tiera R, et al. EACS 2019. Basel, Switzerland. PS 8/5
2. Data on File. Gilead Sciences Gilead Investigator-Sponsored Study
TT
2DC
TT
2DC
Log-rank p = 0.001 Log-rank p = 0.023
* Defined as clinician report of switch due to virological failure, immunological failure or disease progression. † Adjusted for demographic and clinical characteristics
‡ Matched by age, gender, number of previous VFs and treatment line. ** Adjusted for HBV and time on ART
Cox Model2 aHR [95% CI]** P-value
2DC vs. TT 3.0 [1.2, 7.4] 0.017
13

‡
2-Drug Therapy:
 Efficacy
 Resistance
 Guidelines
14

‡GEMINI 1 and 2: DTG + 3TC vs. DTG + FTC/TDF (Treatment-Naïve)
Adverse Events Through Week 96
15
Cahn P, et al. IAS 2019. Mexico City, Mexico. Oral WEAB0404LB
n (%)
DTG + 3TC
(N=716)
DTG + FTC/TDF
(N=717)
Any AE 591 (83) 609 (85)
AE (≥ 10% of participants in either group)
Nasopharyngitis
Diarrhea
Headache
71 (10)
89 (12)
79 (11)
114 (16)
93 (13)
87 (12)
Any serious AE* 64 (9) 67 (9)
Drug-related AE†
Any Grade 2-4 drug-related AE
Any Grade 2-4 drug-related AE (≥1% of participants)
Headache
140 (20)
50 (7)
8 (1)
179 (25)
57 (8)
8 (1)
AEs leading to withdrawal from the study
Neuropsychiatric AEs leading to withdrawal
Renal-related AEs leading to withdrawal
Osteoporosis AEs leading to withdrawal
24 (3)
10 (1)
2 (<1)
0
23 (3)
5 (1)
7 (1)
2 (<1)
*3 deaths (acute myocardial infarction, n=1; Burkitt’s lymphoma, n=1; coronary artery disease, n=1), 1 in GEMINI-1 and 2 in GEMINI-2; all were in the DTG + 3TC group and were considered unrelated to the study
drug regimen. †Relative risk (95% CI) for the DTG + 3TC vs DTG + FTC/TDF group was 0.78 (0.64, 0.95).
DTG+3TC associated with numerically lower drug-related AEs
and comparable discontinuations due to AEs compared to DTG + FTC/TDF through W96

‡
Changes in renal and bone biomarkers favored DTG + 3TC over DTG + FTC/TDF;
lipid levels were lower with DTG + FTC/TDF
Other Safety Results through Week 96
16
GEMINI 1 and 2: DTG + 3TC vs. DTG + FTC/TDF (Treatment-Naive)
Cahn P, et al. IAS 2019. Mexico City, Mexico. Oral WEAB0404LB
* p<0.001; ** p<0.05
BL, baseline; β2M: beta-2-microglobulin, Cr: creatinine, RBP: retinol binding protein, UACR: urine albumin to creatinine ratio
DTG + 3TC DTG + FTC/TDF
-12.2
16.2
-18.7
3.2
50.8
35.0
-60
0
60
ChangefromBL,%
β2M:CrRBP:CrUPCR
• eGFR (cystatin C) changes from BL: 10.7 vs 8.8 mL/min/1.73 m2
0.29 0.27
11.00
0.102.36 4.21
23.70
0.24
0
15
30
Bone specific
alkaline phosphatase
Osteocalcin Procollagen 1
N-terminal propeptide
Type 1 collagen
C-telopeptide
Meanchange
fromBL,(µg/L) * *
*
*
-1
013.92
5.41 7.35 10.63
-4.64 -6.19
3.09
-9.74
-30
0
30
TC:HDL
**
TC LDL HDL TG
MeanChange
fromBL,mgl/dL
* * * *
* * *
RenalBoneLipids
-0.16
-0.40

‡
Adverse Events through Week 48
17
DTG/3TC had comparable AE rates and numerically more drug-related AEs
and discontinuations due to AEs vs.TAF-based triple therapy through W48
n (%)
DTG/3TC
(N=369)
TAF-based
regimen (N=371)
Any AE 295 (80) 292 (79)
Any AE (≥ 10% in either group)
Nasopharyngitis 43 (12) 41 (11)
Any drug-related AE NR NR
Any Grade 2-5 AE 17 (5) 3 (1)
Grade 2-5 AEs (≥ 0.5% in either group)*
Insomnia 4 (1) 0
Constipation 2 (1) 1 (<1)
Flatulence 2 (1) 0
Headache 2 (1) 0
Any SAE 21 (6) 16 (4)
NR: not reported
* All drug-related AEs were Grade 2, † 1 fatal homicide, **Participants may have ≥ 1 AE
n (%)
DTG/3TC
(N=369)
TAF-based
regimen (N=371)
AEs leading to study withdrawal
(>0.5%)**
13 (4)†
2 (1)
Anxiety 3 (1) 0
Insomnia 3 (1) 0
Weight increased 2 (1) 1 (<1)
Fatigue 2 (1) 0

‡
Other Safety Results through Week 48
18
* p<0.001; ** p<0.05
BL, baseline; β2M: beta-2-microglobulin, Cr: creatinine, RBP: retinol binding protein, UACR: urine albumin to creatinine ratio
DTG + 3TC TAF-based Triple Therapy
-2.9
6.3
-2.7
1.6
6.7
-7.8-10
0
10
ChangefromBL,%
β2M:CrRBP:CrUPCR
• eGFR (cystatin C) changes from BL were small (0.1 vs -1.6 mL/min/1.73 m2)
Renal
*
** **
-0.03 -1.15
9.30
0.06
-0.34
0.69
6.40
0.03
-10
0
10
Bone specific
alkaline phosphatase
Osteocalcin Procollagen 1
N-terminal propeptide
Type 1 collagen
C-telopeptide
Meanchange
fromBL,(µg/L)
Bone
Comparable changes
in eGFR by cystatin C and renal
biomarkers
Inconsistent changes among bone
biomarkers of unknown clinical
significance
DTG+3TC vs TAF-TT

‡
GEMINI: DTG + 3TC or DTG + FTC/TDF
TANGO: DTG/3TC or TAF-based regimen
Weight Analyses
19
GEMINI1,2 TANGO3
Evaluation of differences in the changes in body weight
in GEMINI and TANGO
HIV-1 Adults
ART naive
(N=1,433)
DTG + 3TC
DTG + FTC/TDF
24 weeks 48 weeks 96 weeks 48 weeks 144 weeks 196 weeks
1. Cahn P, et al. IAS 2019. Mexico City, Mexico. Oral WEAB0404LB 3. Van Wyk J, et al. IAS 2019. Mexico City, MX. Oral WEAB0403LB
2. Cahn P, et al. Lancet 2019;393:143–55
 At Week 96, overall mean change from baseline was 3.1
kg in the DTG + 3TC group and 2.1 kg in the DTG +
FTC/TDF group
 Increased weight was reported as an AE in:
 13 (1.8%) participants on DTG + 3TC
 10 (1.4%) participants on DTG + FTC/TDF
HIV-1 suppressed
adults on TAF-based
initial regimen
(N=741)
DTG + 3TC
 At Week 48, a similar adjusted mean increase from baseline
in weight of 0.8 kg was observed in both treatment groups
 Increased weight reported as an AE in:
 3 (1%) participants on DTG/3TC
 6 (2%) participants on TAF-based regimens
DTG/3TC
(late switch)
TAF-based
regimen

‡
2-Drug Therapy:
 Efficacy
 Resistance
 Guidelines
20

‡‡
Confirmed Virologic Withdrawals (CVW) & Resistance through W48 & W96
GEMINI 1 and 2: DTG + 3TC vs. DTG + FTC/TDF (Treatment-Naïve)
21
1. Cahn P, et al. IAS 2019. Mexico City, Mexico. Oral WEAB0404LB 2. Cahn P, et al. Lancet 2019;393:143–55 3. Cahn P, et al. AIDS 2018. Amsterdam, NL. Oral TUAB0106LB
Participants, n
DTG + 3TC
n=716
DTG + FTC/TDF
n=717
W48 Confirmed Virologic Withdrawals* 6 4
W96 Confirmed Virologic Withdrawals 11 7‡
Treatment-emergent resistance† 0 0
There was no emergent resistance through 96 weeks for both arms
in these studies where individuals with NRTI, NNRTI, and PI resistance were excluded
* Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound
resulting in the participant being withdrawn from the study.
– Virologic non-response is defined as either a decrease in plasma HIV-1 RNA of less than 1 log10 c/mL by Week 12 with subsequent
confirmation unless plasma HIV-1 RNA is <200 c/mL, or confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24.
– Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL after prior confirmed suppression to <200
c/mL.
† Treatment-emergent INSTI or NRTI mutations
‡One participant met the criteria for CVW at Week 12 but was not reported at the Week 48 analysis because of a laboratory reporting error
identified after the Week 48 analysis.

‡
Resistance Exclusion in Clinical Trials
22
B/F/TAF and DTG+3TC Treatment-Naïve & Virologic Suppressed Adults Studies
Screening criteria in DTG+3TC studies limited eligible patients
and may have implications on generalizability of the GEMINI results
1. Gallant J, et al. Lancet 2017;390:2063-72
2. Sax P, et al. Lancet 2017;390:2073-82
3. White K, et al . CROI 2018. Boston, MA. Poster 532
4. Gilead Sciences. Data on File.
5. Cahn P, et al. Lancet 2019;393:143–55.
6. Taiwo B, et al. CID 2018;66(11):1689–97
NR, Not reported
* Only 49% had historical genotypes; suspected resistance was also an exclusion criteria, † 1% (7/626 M184V/I detected with proviral DNA test
7. Molina JM, et al. Lancet HIV 2018;5:e357–65
8. Van Wyk J, et al. IAS 2019. Mexico City, MX. Oral WEAB0403LB
Criteria n/N %
Treatment
-Naïve
1489 & 1490 (Pooled)1-4
B/F/TAF vs DTG/ABC/3TC & DTG+FTC/TAF
FTC, TFV, ABC, or 3TC (1489)
FTC, TFV (1490)
Genotypic resistance
3/1481 0.2%
GEMINI 1&25
DTG+3TC vs DTG + FTC/TDF
NNRTIs, NRTIs, and PIs
Major mutations
246/1974 12.5%
ACTG 53536
DTG+3TC
NNRTIs, NRTIs, and PIs
Major mutations
11/165 6.7%
Virologically
suppressed
Study 18444,7
B/F/TAF vs DTG/ABC/3TC
FTC, TFV, DTG, ABC, or 3TC
Documented resistance*
5/646 0.8%
TANGO8
DTG/3TC vs TAF-based TT
NRTIs and INSTIs
Documented resistance
NR NR†

‡
90
2
7
89
8
3
0
20
40
60
80
100
Virologic Success HIV-1 RNA ≥50cpm No Virologic Data
≤100K c/mL (n=83)
>100K c/mL (n=37)
23
Participants,%
Virological Outcomes at Week 24: FDA Snapshot
ACTG 5353: DTG + 3TC (Treatment-Naïve)
Baseline VL HIV-1 RNA ≥50cpm* (n=5)
Mutations
INSTI NRTI NNRTI
>100,000 3 - - -
≤100,000 1 R263R/K M184V -
≤100,000 1 - - V106I
Virologic Outcome at Week 24 by Baseline Viral Load
At Week 24, 5 patients had early virologic failure and
one patient had mutations against both DTG and 3TC
*Includes Protocol Defined Virologic Failures, n=3 (confirmed VL>400 c/mL at Week 16 or 20 or confirmed VL>200 c/mL
at/after Week 24) and lack of virologic success, n=2 (VL≥50 c/mL at Week 24)
1. Taiwo B, et al. IAS 2017. Paris. Oral #MOAB0107LB 2. Taiwo B, et al. CID. 2018;66(11):1689–97

‡
DTG + 3TC Virologic Failure with 2-Class Resistance
ACTG 5353: DTG + 3TC (Treatment-Naïve)
24
Study Week
HIV-1RNA
(c/mL)
M184V
1000000
100000
10000
1000
100
50
0 2 4 8 12 16 20 24 32
M184V
R263R/K
None
0 2 4 8 12 16 20 24 32
0
1000
2000
3000
4000
DTG
concentration
(ng/mL)
DTG + 3TC
LLOQ
Emergence of 2-class resistance observed at W14 in setting of non-adherence
Phase II, single-arm, 52-week, study of DTG 50 mg + 3TC 300 mg in treatment-naïve participants
1. Taiwo B, et al. IAS 2017. Paris, France. Oral #MOAB0107LB 2. Taiwo B, et al. CID. 2018;66(11):1689–97

‡
Pt
BL 3rd agent
(with F/TDF)
Timing
of Failure
HIV-RNA at
Failure (c/ml)
Integrase Sequence
at Failure
1 RPV W4 71,600 No RAMs
2 EFV W12 678 Not successful
4 RPV W30 1,570 S230R
5 DTG W36 1,440 Not successful
7 NVP W60 3,470 R263K
8 NVP W72 4,180 N155H
Study prematurely discontinued due to predefined stopping rule
(emergent INSTI resistance in 2 or more subjects)
DTG as Maintenance Monotherapy
Characteristics of Virologic Failures on DTG Monotherapy*,†
* All CD4 T-cell nadir ≥210 cellsmm3 and >95% adherence (according to clinician)
† 8% (8/96) of participants on DTG monotherapy experienced virologic failure at Week 48
Multicenter randomized non-inferiority trial comparing
96 participants on DTG 50mg QD monotherapy vs standard ART
Wijting I, et al. CROI 2017. Seattle, WA. Poster #451LB
25
DOMONO

‡
Emergent INSTI Resistance After Switch to DTG Monotherapy
 International, multicenter retrospective
study
– Evaluated virologically suppressed pts
switched to DTG monotherapy
– Pts with history of VF on INSTI and
INSTI resistance excluded
 11 of 122 pts (9%) switched to DTG
monotherapy experienced VF
– 9 of 11 had genotypic INSTI resistance
at VF
INSTI resistance pathways varied
Blanco JL, et al. CROI 2017. Abstract 42.
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)

‡
Study Design
27
SINGLE and SPRING2
Treatment-Naïve
HIV-1 RNA ≥ 1,000 c/mL
HLA-B*5701 negative
EFV/TDF/FTC QD
+ DTG QD + ABC/3TC QD Placebo
DTG QD + ABC/3TC QD
+ EFV/TDF/FTC Placebo
Stratified by baseline
viral load and CD4 cell count
1:1
414
419
Treatment-Naïve
HIV-1 RNA ≥ 1000 c/mL
RAL BID + 2 NRTIs* QD
+ DTG QD Placebo
DTG QD + 2 NRTIs* QD
+ RAL BID Placebo
96 Weeks
Stratified by baseline
viral load and NRTI backbone
*TDF/FTC or ABC/3TC
(investigator’s selection)
1:1
411
411
96 Weeks
1. Walmsley S, et al. N Engl J Med 2013. 369(19):1807-18. DOI: 10.1056/NEJMoa1215541
2. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;70(5):515-9. doi: 10.1097/QAI.0000000000000790.
3. Raffi F, et al. Lancet. 2013 Mar 2;381(9868):735-43. doi: 10.1016/S0140-6736(12)61853-4

‡
Resistance Consequences of Virologic Failure
28
SINGLE and SPRING2
SINGLE
DTG + ABC/3TC
(n=414)
EFV/TDF/FTC
(n=419)
Participants with PDVF, n 25 25
NRTI major mutations, n 0 1
NNRTI major mutations, n 0 6
INSTI major mutations, n 0 0
SPRING2 DTG QD + 2 NRTIs
(n=411)
RAL BID + 2 NRTIs
(n=419)
Participants with PDVF, n 22 29
NRTI major mutations, n 0 4
INSTI major mutations, n 0 1
No integrase mutations or major RT mutations
detected on DTG + 2 NRTIs through Week 96
.
.
1. Walmsley S, et al. CROI 2014. Boston, MA. Poster#543
2. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;70(5):515-9. doi: 10.1097/QAI.0000000000000790.
3. Raffi F, et al. Lancet. 2013 Mar 2;381(9868):735-43. doi: 10.1016/S0140-6736(12)61853-4

‡
Resistance Outcomes at Week 144
29
Studies 1489 & 1490: B/F/TAF vs DTG/ABC/3TC and DTG+FTC/TDF in ART-Naïve Adults
No treatment-emergent resistance to any components of the regimens
was detected in any treatment group
Participants, n
Pooled B/F/TAF
n=634
DTG/ABC/3TC
n=315
DTG + F/TAF
n=325
Resistance testing* 8 6 7
NRTI-R 0 0 0
INSTI-R 0 0 0
* Performed for participants with confirmed HIV-1 RNA ≥50 c/mL, with confirmation sample being ≥200 c/mL or ≥200 c/mL at last
visit, and no resuppression of HIV-1 RNA to <50 c/mL while on study drug
• 1 participant with baseline DTG resistance (Q148H + G140S) was randomized to B/F/TAF,
suppressed <50 c/mL at Week 4, and remained suppressed at Week 144
Orkin C, et al. EACS 2019. Basel, Switzerland. PE3/14

‡
Study Design:
Resistance with Triple Therapy (TT) vs. 2-Drug Combination (2DC)
Methods: Resistance testing completed on the second plasma sample
30
Resistance Analysis (Italy and France)
Calvez V , et al. EACS 2017. Milan, Italy. Oral #PS1/4
Jan. 2012
• Initiating or switching ART
• No past drug failures* to class of
ARVs being initiated or switched to
• Experienced virologic failure (2
consecutive VL > 50 c/mL)
TT (NRTI-based)
2DC (DTG, RAL or PI/r-based)
Jan. 2017
Multi-site analysis of resistance development in TT and 2DC-treated patients experiencing
virologic failure from > 30 centers in Italy and France
N =300
N =165
*Recorded in center’s medical records
TRIPLE THERAPY 2-DRUG COMBINATION
• 2 NRTIs based regimen:
• NNRTI (EFV or RPV) (n=100)
• INSTI (RAL or EVG/c or DTG) (n=100)
• PI/r (DRV/r or ATV/r) (n=100)
• PI/r based regimen:
• DRV/r + RAL (n= 55); 3TC (n= 49); DTG (n=21)
• RAL based regimen:
• DRV/r (n=55); ETR (n= 15)
• DTG based regimen:
• RPV (n=14) ; 3TC (n= 11); PI/r (n = 21)

‡
ARV Resistance Selected at Failure in HIV-Infected Patients
on Triple Therapy vs. 2-Drug Combination
Calvez V, et al. EACS 2017. Milan, Italy. Oral #PS1/4
More resistance observed in patients
after failing 2-drug combinations than triple therapies containing INSTIs or PIs
31
Retrospective analysis to compare resistance profiles for patients failing INSTI or PI/r based
triple therapy and 2-drug combinations (> 30 centers); 1/12-1/17
11%
3% 4%
28% 27%
4%
14%
4%
46%
1%
7%*
38%
5%
22%
0
10
20
30
40
50
60
70
80
90
100
2 NRTIs+
NNRTI
2 NRTIs+
Pl/r
2 NRTIs+
INSTIs
DTG+
RPV
DTG+
3TC
DRV/r+
RAL
Pl/r+
DTG
Pl/r+
3TC
CaseswithResistanceatFailure,%
NRTIs
NNRTIs
PIs
INSTIs
2-Drug CombinationTriple Therapy
N=100 N=100 N=100 N=55N=11N=14 N=21 N=49
* Resistance observed only with RAL and EVG, not with DTG triple therapy regimens

‡
0 1 2 3 4 5
3.0
7.0
21.7
37.5
0
20
40
60
80
100
PI TT (n=100) INSTI TT
(n=100)
DTG 2DC
(n=23)
PI 2DC (n=32)
Clinical Consequences of Failing DTG- or PI-based
2DC vs TT Without Previous Virologic Failure
Retrospective analysis to compare the resistance profiles
in those failing INSTI or PI/r based 2-drug combinations (2DC) or triple therapy (TT)
with no history of previous virologic failure (> 30 centers, Italy and France, 2015 - 2018)
32
• Failure occurred more rapidly in those on 2DC than on TT
2DC, 2-drug combination; INSTI, integrase inhibitor; MTR, multi-tablet regimen; PI, protease inhibitor; TT, triple therapy
‡
Participants(%)
Time to Virologic Failure, median years (IQR)
PI TT (n=100)
3.1
INSTI TT (n=100)
DTG 2DC (n=23)
1.2
2.7
0.8
PI 2DC (n=32)
PI TT
(n=100)
INSTI TT
(n=100)
DTG 2DC
(n=23)
PI 2DC
(n=32)
Emergent Resistance after VF
Calvez V, et al. HIV Drug Therapy 2018. Glasgow, UK. Poster 295
• 2DC failures subsequently switched to more complex regimens (greater PI and MTR use) and had more frequent
HIV clinic visits (both before and after failure) vs. TT failures
• Higher rates of drug resistance selection observed in
patients failing a DTG 2DC or PI 2DC compared to INSTI
TT or PI TT (3-fold and 12.5-fold, respectively)

‡
ARS Question
 If a patient had the M184V mutation (3TC/FTC resistance), would
you be willing to use DTG/3TC?
A. Yes
B. No
C. Only if the viral load was already suppressed
33

‡
Study Design
 Primary Endpoint
 Time to virologic failure (VF)
 M184V+ vs M184V-
 Secondary Endpoint
 Time to virologic blips (VB)
 M184V+ vs M184V-
 Predictors of virologic failure and virologic blips
34
ARCA Database - Italy: 3TC + INSTI or boosted PI (Virologically Suppressed)
HIV Suppressed Adults Switching
to 3TC + INSTI or PI/r
 HIV-1 RNA ≤ 50 c/mL
 ≥ 1 previous genotype done
M184V-
N=349 patients
M184V+
N= 87 patients
2-Drug Combinations Previous Regimens
1. Gagliardini R, et al. CROI 2018. Boston, MA. Poster 498 2. Gagliardini R, et al. Open Forum Infect Dis. 2018; 5(6): ofy113
Retrospective analysis evaluating effect of M184V (87 M184V and 349 WT M184)
on time to VF and blip in HIV suppressed adults switching to 3TC + INSTI or PI/r
2 NRTI + INSTI

‡
M184V Impact on 3TC-Based 2 Drug Combinations (2DC)
35
ARCA Database - Italy: 3TC+ boosted PI or INSTI (Virologically Suppressed)
1. Gagliardini R, et al. CROI 2018. Boston, MA. Poster 498 2. Gagliardini R, et al. Open Forum Infect Dis. 2018; 5(6): ofy113
Retrospective analysis evaluating effect of M184V presence (87 M184V and 349 WT M184)
on time to VF and blip in HIV suppressed adults switching to 3TC + INSTI or PI/r
3-year VF risk with BL VS duration:
• ≤6 yr: 17% M184V+ vs 7% M184V-, p=0.080
• ≤3 yr: 32% M184V+ vs 4% M184V-, p=0.002
With <3 years of viral suppression,
M184V associated with VF
VS, viral suppression
1.0
0.8
0.6
0.4
0.2
0
0 0.5 1.0 1.5 2.0 2.5 3.0
Years from treatment initiation
ProportionofptsfreefromVF
Time to Virologic Failure (VF)
Suppression up to 6 years
Suppression up to 3 years
M184V- M184V+
Time to Virologic Blip
3-year blips risk:
• 20% M184V+ vs 10% M184V-, log rank p=0.016
M184V associated with increased risk of blips
1.0
0.8
0.6
0.4
0.2
0
0 0.5 1.0 1.5 2.0 2.5 3.0
Years from treatment initiation
ProportionofptsfreefromVF
3-year probability of remaining free from blip
M184V+ 79.8% (95% CI 67.8; 91.8)
M184V- 90.1% (95% CI 84.0; 96.2)
M184V+
M184V-

‡
ARS Question
What is the frequency of transmitted M184V in treatment-naïve
patients?
A. <1%
B. 1-10%
C. 11-25%
D. 25-50%
E. >50%
38

‡
Prevalence and Persistence of Transmitted M184V/I
39
Reversion
of Resistant
Virus
M184V: 0.5-2 yrs
K103N: 3.7 yrs
• Pop Seq:
M184V (<1%)
• AS-PCR:
M184V/I (1%)
• Population
sequencing
(Pop Seq):
M184V (68%)
Transmission of
Resistant Virus
• Pop Seq:
M184V (11%)
• AS-PCR:
M184V/I (23%)
In plasma:
Chronic Infection
Treatment Naïve
Patient With
Drug
Resistance
Primary Infection
Treatment Naïve
WTM184V
Baseline After
6 Months
After
1 Year
0
25
50
75
100
Reversion of Resistance in
Primary/Early Infection
MutationFrequency(%)
NNRTI-R
M184V
AS-PCR: Allele-specific PCR (sensitive method of mutant detection)
Castro el al. JID. 2013; Jain et al. JID. 2011; Wainberg et al. JAC. 2011

‡
Key inclusion criteria
• HIV-1 RNA <50 c/mL for ≥ 6 months
• Booster (RTV or COBI), NRTIs (ABC/3TC or FTC/TDF)
 Estimated GFRCG ≥ 50 mL/min
 Documentation of no M184V/I on available historical genotypes*
Detection of Pre-existing, Unrecognized M184V/I
Unexpectedly High Level of Pre-existing, Unrecognized M184V/I at Switch
40
Study 1878: B/F/TAF vs Boosted PI + 2 NRTIs in Virologically Suppressed Adults
Retrospective evaluation of impact of pre-existing, unrecognized M184V/I
(by retrospective proviral DNA) on efficacy through Week 48
Switch to B/F/TAF QD
Stay on baseline regimen
(PI + 2 NRTIs)
N=290
N=287
1:1
HIV Suppressed Adults on Boosted
DRV or ATV + 2 NRTIs1
1. Daar E, et al. Lancet HIV 2018.
2. Andreatta K, et al. HIV Drug Therapy 2018, Glasgow, UK. Poster 298
* 149 participants were enrolled in the B/F/TAF arm with no M184V/I suspected based on treatment history alone as no historical genotype was available
NRTI Resistance
Historical Genotype Proviral DNA (archived)
0%
(0/141)
15%
(42/277)

‡
Key inclusion criteria
 Estimated GFRCG ≥ 30 mL/min
 No prior VF on PI or INSTI-based regimens
Unexpectedly High Level of Existing M184V/I Missed by Proviral DNA Test at Switch
41
Study 1824: E/C/F/TAF in Virologically Suppressed Adults with M184V/I
Retrospective evaluation of ability of proviral DNA genotype to identify M184V/I in 87 screened individuals
Switch to E/C/F/TAF QD
HIV Suppressed Adults
on FTC/TDF or ABC/3TC + third agent
1. Margot N, et al. DART 2018. Miami, FL. Oral 3. 2. Clinicaltrials.gov; NCT02616029
Detection of Existing M184V/I
NRTI Resistance
Historical Genotype Proviral DNA (archived)
100% 48%

‡‡
Virologic Outcomes in Participants with M184V/I at W48*
B/F/TAF and DTG/3TC
100 100
0
20
40
60
80
100
HIV-1 RNA <50
TANGO
n=4 n=3
Proportion,%
• Limited pre-existing M184V/I in DTG/3TC switch
study
― 1% (7/626) M184V/I across the 2 arms
* Based on proviral DNA resistance test. LOCF, last observation carried forward
Virologic suppression rates were high with M184V/I
but conclusions are limited by the sample size
Excluded: NRTI & INSTI resistance
• With N=4, even when no VF
is observed, the true VF rate
can be as high as 54%
DTG/3TC
DTG + FTC/TAF

‡
Analyses of Baseline M184V/I and Blips at Week 48
Study 1878: B/F/TAF vs Boosted PI + 2 NRTIs in Virologically Suppressed Adults
43
Blips*
• Blips occurred in similar proportion
of B/F/TAF participants with or
without M184V/I
− 5% vs 6%, p=1.0
• Significantly fewer blip events with
B/F/TAF vs boosted PI regimen
− 15 vs 31, p=0.03
− Only 2/42 B/F/TAF participants
with M184V/I had a blip
40/42 232/235
* Blip: single HIV-1 RNA value ≥50 c/mL
46 Blips in 38 Participants
B/F/TAF
PI + 2 NRTIs
M184V/I
Same participant
Andreatta K, et al. HIV Drug Therapy 2018, Glasgow, UK. Poster 298
‡

‡
Andreatta, EACS 2019, Poster # PE13/21
Virologic Outcomes by Pre-existing Resistance, Pooled B/F/TAF Analysis
44
B/F/TAF efficacy was not affected by M184V/I resistance at baseline and
no participant failed with emergent drug resistance
a. One participant was off study drug at the time of virologic failure (plasma BIC concentration was BLQ) and had no
new resistance development, one participant with poor adherence (71% by pill count) discontinued with HIV-1 RNA
61 c/mL, and one participant had a HIV-1 RNA 87 c/mL at their last study visit then switched to commercial B/F/TAF
and resuppressed at their follow-up visit
Most M184V/I was
identified by baseline
proviral DNA genotyping

‡
Prevalence and Risk Factors for Pre-existing M184V/I
Andreatta K, et al. EACS 2019. Basel, Switzerland. PE13/21 45
B/F/TAF Studies 1844, 1878, 4030, 4449, and 1474 (Virologically Suppressed)
Pooled analysis on prevalence and risk factors for pre-existing M184V/I among virologically suppressed clinical trial
participants and the impact of pre-existing M184V/I on virologic outcomes after switching to B/F/TAF (n=1545)
M184V/I at baseline was associated with resistance (non-M184V/I NRTI, NNRTI, or PI),
Black race, CD4 count <500 and a longer ART duration
Risk Factors for Pre-Existing M184V/I† OR (95% CI) p-value
History of Non-M184V/I NRTI resistance 4.6 (2.9, 7.3) < 0.001
History of NNRTI resistance 2.8 (1.9, 4.2) < 0.001
Black race (vs non-Black) 2.6 (1.7, 4.0) < 0.001
History of PI resistance 1.9 (1.1, 3.3) 0.029
CD4 <500 cells/µL (vs ≥500) 1.6 (1.0, 2.4) 0.035
Hispanic ethnicity 1.8 (1.1, 3.0) 0.014
HIV status: symptomatic or AIDS
(vs asymptomatic)
1.7 (1.1, 2.8) 0.024
Time since ART start (per year) 1.1 (1.1, 1.1) < 0.001
M184V/I with Other Mutations
(N=101)
+ NNRTI-R 52%
+ Other NRTI-R 47%
+ TAMs 40%
+ PI-R 20%
+ Primary INSTI-R* 4%
• Of the 132 participants with M184V/I
detected, 77% had other resistance
mutations
* Primary INSTI-R substitutions observed with M184V/I: T97A (n=2) and Y143H, Q148R, and N155H (n=1 each)
† Studies 4449 and 1474 excluded from analysis

‡
Impact of M184V & TAMs
on 3TC, TDF and ABC Susceptibility
46
M184V
0 1 2 3 4 5 6
100
10
1
-1
TDF
0 1 2 3 4 5 6
100
10
1
-1
3TC
0 1 2 3 4 5 6
100
10
1
-1
ABC
Whitcomb JM, et al. JID 2003; 188:992-1000
Foldchangein
NRTI
M184wtNumber of TAMs
M184V increases phenotypic susceptibility to tenofovir,
including in the presence of TAMS

‡
• TAF sensitivity increases in
viruses with M184V and TAMs
Impact of M184V & TAMs
on FTC and TAF Susceptibility
In vitro study of FTC and TAF susceptibility with HIV-1 clinical isolates
Number of TAMs
47
• FTC sensitivity decreases in
viruses with M184V and TAMs
TAF susceptibility
TAMs: thymidine analog mutations
1. Data on File. Gilead Sciences.
Maintaining FTC+TAF selective pressure in a triple therapy regimen
may ensure antiviral activity in presence of M184V
0 1 2 3 4 5 6
0.1
1
10
100
Number of TAMs
0 1 2 3 4 5 6
0.1
1
10
100
FTC susceptibility
M184V- M184V+
EC50FoldChange
EC50FoldChange

‡
Antiviral Activity of TAF Against HIV-1 with K65R ± M184V/I
48
RelativeLoading
[TFV-DP]
1x
4xTAF
TDF
(TFV*)
No Viral Breakthrough
Viral Breakthrough
• Higher intracellular TFV-DP delivered by TAF resulted in fewer
viral breakthroughs of K65R-containing HIV-1 (2/42 vs. 10/42)
These results suggest that TAF has a higher resistance barrier than TDF
in vitro assessment of TAF activity evaluating phenotypic range of resistance and resistance barrier
against 42 K65R patient-derived HIV-1 viruses compared to TDF
Mutant
Class
N
Median EC50 Fold-
Change Compared
to Wild-Type
TAF ABC FTC
All
viruses
42 3.3 11.8 >186
K65R 14 3.5 3.9 11.4
K65R +
M184V/I
28 3.3 15.8 >186
• Increased resistance with M184V seen for ABC
• Decreased resistance with M184V seen for TAF
TAF Activity: TAMs-containing K65R ± M184V HIV-1 in vitro Assay
Cox S, et al. CROI 2019. Seattle, WA. Poster 546
VB, viral breakthrough; *TFV is the in vitro equivalent of TDF
18.1
6.63.3
3.1
3.0
3.3
VB
2/42
10/42
Fold Change

‡
In Vitro Breakthrough Selection Methodology
 In vitro viral breakthrough selection experiments are comparative in vitro studies; clinical
trials of missed doses for these ARV combinations have not been conducted
Drugs at
Constant
ConcentrationMT-2 Cells HIV-1
1. Infect MT-2 cells with HIV-1
2. Add drug to wells
3. Split cultures into new plate with fresh media
and drugs; maintain for 5 weeks
4. Virus breakthrough by cytopathic effect
scoring
5. Deep sequence supernatant virus at time of
breakthrough
I. Fixed Drug Concentrations
Drugs: BIC + FTC + TAF DTG + 3TCor
II. Low-Level M184V Starting
Virus; HIV: xxLAI
0 0.4 4 % M184V
Cmin minus 1 dose
Cmin minus 2 doses
Cmin minus 3 doses
Cmin
HIV: IIIb
49

‡
II. Time to Viral Breakthrough:
Using Low-Level M184V xxLAI Starting Virus Mixtures
0 1 0 2 0 3 0
0
2 0
T im e p o s t-in fe c tio n (d a y s )
Viral
B IC + F T C + T A F
D T G + 3 T C
0%
M184V
Starting
Virus
0.4%
M184V
4%
M184V
0/12
0/12
0/12
0/12
0/12
0/12
Cmin (no missed doses) Cmin after missing 1 Dose Cmin after missing 2 Doses
* P-value < 0.05 by Fisher’s Exact test
0/12
2/12
0/12
4/12 *
0/12
0/12
11/12
*
*
*
* *
* * * * *
0/12
12/12
0/12
1/12
*
*
11/12
50

‡
II. Resistance in Breakthrough Viruses:
Low-Level M184V Starting Virus
M184V M184V+M184I+E157K M184V+E157K
M184V+E138KM184V+D67N M184V+S153Y*
5
10
15
0.4% M184V inoculum
4% M184V inoculum
ViruswithResistance(N)
BIC+FTC+TAF DTG+3TC
20
(Resistance in 0/72) (Resistance in 40/72)
†
† M184V and M184I cause high-level resistance to FTC and 3TC; all breakthroughs with M184V were >68%
*S153Y has been previously selected by DTG and causes reduced susceptibility to DTG
M184V
†
5
10
15
20
M184V+M50I
• All 15 breakthroughs had
M184V as the majority species
• All 25 breakthroughs had
M184V as the majority species
NRTI and INSTI-R
NRTI and INSTI-R
NRTI-R only
NRTI-R only
51

‡
2-Drug Therapy:
 Efficacy
 Resistance
 Guidelines
52

‡
53
Recommended regimens are those with demonstrated durable virologic
efficacy, favorable tolerability and toxicity profiles, and ease of use.
CLASS RECOMMENDED REGIMENS
INSTI*
BIC/FTC/TAF (AI)
DTG/3TC/ABC (AI)
If HLA-B*5701 negative
DTG + FTC/TAF‡ (AI) or FTC†/TDF‡ (AI)
RAL§ + (FTC or 3TC/TAF‡ (BII) or (FTC or 3TC)†/TDF‡ (BI)
DTG/3TC (AI) – except if HIV RNA >500,000 c/mL, HBV coinfection, or if ART
started before RT genotype or HBV results available
DHHS. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV, December 2019. Available at: http://aidsinfo.nih.gov/guidelines
Recommended Initial Regimens for Most People with HIV
DHHS Guidelines
Only integrase inhibitor-based regimens are recommended as
Initial Regimens for Most People with HIV

‡
Recommended Initial Regimens
54
EACS Guidelines (2019)
EACS Guidelines version 10.0. November 2019. Accessed November 2019
Regimen Main Requirements Additional Guidance (see footnotes)
RECOMMENDED REGIMENS (PREFERRED)*
INSTI
+ 2NRTIs
B/F/TAF
DTG + ABC/3TCI or DTG/ABC/3TCI HLA-B*5701 negative
HBsAg negative
I ABC: HLA-B*5701, cardiovascular risk
DTGIII + TAF/FTCII,III or TDF/FTC or 3TCII,III II TDF: prodrug types. Renal and bone toxicity. TAF dosing
III Weight increase
RALIV + TAF/FTCII or TDF/FTC or 3TCII II TDF: prodrug types. Renal and bone toxicity. TAF dosing
IV RAL: dosing
RECOMMENDED REGIMENS
INSTI
+ 1NRTIs
DTG + 3TC
HBsAg negative
HIV-VL < 500.000 c/ml
CD4 count > 200 cells/µl
NNRTI
+ 2NRTIs
DORV + TAF/FTCII or TDF/FTCII or TDF/3TCII II TDF: prodrug types. Renal and bone toxicity. TAF dosing
V DOR: HIV-2
RPVVI + TAF/FTCII or TDF/FTC or 3TCII
R/F/TAF or R/F/TDFVI
CD4 count > 200 cells/µl
HIV-VL < 100.000 cps/ml
Not on proton pump inhibitor
With food
II TDF: prodrug types. Renal and bone toxicity. TAF dosing
VI RPV: HIV-2
PI/r or PI/c
+ 2NRTIs
DRV/c or rVII + TAF/FTCII
DRV/c or rVII + TDF/FTC or 3TCII
DRVc/TAF/FTCVII
With food
II TDF: prodrug types. Renal and bone toxicity. TAF dosing
VII DRV/r: cardiovascular risk
I ABC contraindicated if HLA-B*5701 positive. Even if HLA-B*57:01 negative, counselling on HSR risk still mandatory. ABC should be used with caution in persons with a high CVD risk (> 20%); II In certain countries, TDF is labelled as 245 mg rather than 300 mg to reflect the amount of the prodrug (tenofovir disoproxil) rather than the
fumarate salt (tenofovir disoproxil fumarate). There are available generic forms of TDF, which instead of fumarate use phosphate, maleate, and succinate salts. They can be used interchangeably. When available, combinations containing TDF can be replaced by the same combinations containing TAF. TAF is used at 10 mg when
coadministered with drugs that inhibit P-gp, and at 25 mg when coadministered with drugs that do not inhibit P-gp The decision whether to use TDF or TAF depends on individual characteristics as well as availability. So far, there are only limited long-term data on TAF. If the ART regimen does not include a booster, TAF and TDF have a
similar shortterm risk of renal adverse events leading to discontinuation and bone fractures.TAF*** should be considered as a first choice**** over TDF in individuals with: (1) established or high risk of CKD, (2) coadministration of medicines with nephrotoxic drugs or prior TDF toxicity, (3) osteoporosis / progressive osteopenia, high FRAX
score or risk factors, (4) history of fragility fracture *** There are limited data on use of TAF with eGFR < 30 mL/min **** Expert opinion pending clinical data; III Two randomized controlled trials (performed in South Africa and Cameroon) showed that, in comparison with EFV, treatment with DTG in naïve persons was associated with
increased weight gain when combined with TAF/FTC, TDF/FTC or TDF/3TC. The effect on increased weight was more important for women under treatment containing both DTG and TAF; IV RAL can be given as RAL 400 mg bid or RAL 1200 mg (two, 600 mg tablets); qd. Note: RAL qd should not be given in presence of an inducer (i.e. TB
drugs, antiepileptics) or divalent cations (i.e. calcium, magnesium, iron), in which case RAL should be used bid; V DOR is not active against HIV-2; VI RPV is not active against HIV-2; VII A single study has shown increase in CVD risk with cumulative use of DRV/r;
* Use of an unboosted INSTI with a high genetic barrier (DTG or BIC) as preferred third agent is favored

Rapid ART Initiation:
DHHS Guidelines
55
Recommended Regimens
• BIC/FTC/TAF
• DTG + (TAF or TDF) + (FTC or 3TC)
• (DRV/c or (DRV/r) + (FTC or 3TC) + (TAF or TDF)
Not Appropriate for Rapid Initiation
• ABC/3TC
• Requires HLA-B*5701
• Requires HBsAg, inadequate HBV activity without another HBV agent
• Not recommended for eGFRCG < 50 mL/min
• NNRTI - Concerns about transmitted drug resistance
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 2019.

 2-drug combinations that include 3TC appear to have lower barriers to resistance
than DTG- and BIC-based triple therapy.
 M184V/I is present in both treatment-naïve and -experienced patients, although
frequently undetectable. With 2-drug combinations containing 3TC, M184V/I may
increase the risk of virologic failure, and possibly INSTI resistance.
 M184V/I increases susceptibility to TDF and TAF. TAF appears to have a higher
resistance barrier than TDF.
 To date, there is no evidence of greater toxicity with 3-drug TAF-based regimens
than with 2-drug combinations. Assertions that 3 drugs must be more toxic than 2
drugs are purely speculative.
 In contrast, resistance should be viewed as a real and irreversible toxicity.
Conclusions
56

ARS Question
Which regimen has less drug?
A. DTG/3TC
B. BIC/FTC/TAF
C. EVG/COBI/FTC/TDF
57

Post-script:
Grammatical problems in the discussion of 2-drug combinations
 DTG/3TC contains fewer drugs than BIC/FTC/TAF
 BIC/FTC/TAF contains less drug than DTG/3TC (275 vs. 350 mg)
 Which is better, less or fewer?
– Fewer: The 2-drug combination of d4T + ddI was far more toxic than
many subsequent 3-drug regimens
– Less: At the minuscule dose of only 0.75 mg tid, ddC was perhaps the
most toxic ARV ever developed
 Summary: less and fewer are not meaningful terms to
describe the attributes of ARV regimens. Evidence is better.
58

2 Drug Therapy: Revolution or Regression?

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2 Drug Therapy: Revolution or Regression?