1. Keeping the Pressure on Archived NRTI Resistance: Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) Triple Therapy in Study 4030
Rima Acosta, Madeleine Willkom, Kristen Andreatta, Hui Liu, Ross Martin, Aiyappa Parvangada, Hal Martin, Sean Collins, and Kirsten L. White
Gilead Sciences, Inc., Foster City, CA, USA
Presented at: The 10th IAS Conference on HIV Science (IAS 2019)
July 21-24, 2019, Mexico City, Mexico
Poster: MOPEB241

2. Background
Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is approved in Mexico, by the US FDA, EMA, and in other countries for treatment of HIV-1 infection; treatment-naïve and virologically suppressed without resistance to the components1,2
B/F/TAF safety and efficacy have been demonstrated in controlled clinical trials
Treatment-naïve adults: 2 Phase 3 studies of 634 participants through 96 weeks3-6
Suppressed switch adults: 4 Phase 3 studies of 1090 participants through 48 weeks7-10
Suppressed switch in adolescents and children: 1 Phase 2/3 study of 100 participants through 48 weeks11
No treatment-emergent resistance has been detected in clinical trial participants taking B/F/TAF
Proviral DNA genotyping (archive assays) can detect transmitted or acquired drug resistance in suppressed patients but can be insensitive in reporting all prior resistance substitutions12-14
Study GS-US allowed for enrollment of participants with known or suspected resistance to NRTIs, PIs, and/or NNRTIs and randomized them in a 1:1 ratio to switch to B/F/TAF or dolutegravir (DTG) + F/TAF
Here, we present viral resistance analyses of Study GS-US from baseline through Week 48
Acosta, IAS, 2019, Poster #MOPEB241

3. Methods: Figure 1. GS-US-380-4030 Study Design
Phase 3, randomized, double-blind, multicenter, active-controlled study
Week 0 48
Adults with HIV on DTG + F/TAF or DTG + F/TDF
HIV-1 RNA < 50 c/mL for
≥ 3 months if no NRTI resistance
≥ 6 months if NRTI resistance is known or suspected
Any NRTI, NNRTI, or PI resistance was allowed
No documented INSTI resistance or confirmed virologic failure on an INSTI-containing regimen
DTG + F/TAF placebo QD
B/F/TAF QD
B/F/TAF placebo QD
DTG + F/TAF QD
n=284
n=281
Primary Endpoint
HIV-1 RNA ≥ 50 c/mL
(4% non-inferiority margin)
1:1
N=565
Randomization stratified by:
F/TAF vs F/TDF at baseline
Documented or suspected history of NRTI resistance
Acosta, IAS, 2019, Poster #MOPEB241

4. Methods, cont.
NRTI resistance was classified into 3 categories used to stratify at randomization. For participants that qualified for more than one resistance category, the higher resistance category was prioritized: 1, then 2, then 3 as shown below
Category
NRTI Resistance Mutation
Resistance 1
K65R/E/N, ≥ 3 TAMsa that include M41L or L210W, or T69 insertions
High 2
M184V/I, K70E/G/M/Q/S/T, L74V/I, V75A/S/M/T, Y115F, T69D, Q151M, or other TAMa patterns
Low 3
No NRTI resistance associated mutations
None
a. TAMs are M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/R/N.
Acosta, IAS, 2019, Poster #MOPEB241

5. Methods, cont.
Stratification Category: Assigned by the investigator at randomization based on review of HIV-1 historical genotypes, phenotypes (if available), and antiretroviral treatment history
Final Category: Assigned post-randomization based on cumulative historical data, investigator assessment of suspected resistance, and baseline genotyping using proviral DNA genotype (GenoSure Archive assay, Monogram Biosciences)
No genotypic data and no suspicion of resistance was assigned to category 3
36% (206/565) of participants had both a historical and proviral genotype
If one genotype showed resistance and the other did not, the resistant genotype was used
Proviral assay limitations
Cellular APOBEC-mediated hypermutation may introduce STOP codons and some substitutions associated with drug resistance (E138K, M184I, and M230I in RT; G163R in IN). Utilization of bioinformatics filters to remove hypermutated deep sequence reads mitigates over-reporting of these substitutions
Lack of sensitivity to detect resistance substitutions that had been previously reported by plasma HIV-1 RNA genotyping. For example only 43% of previously documented M184V/I was detected by the archive assay in one recent study12
Historical Genotype
HIV-1 RNA ≥ 400 c/mL
Proviral DNA
HIV-1 RNA < 50 c/mL +
50% (285/565)
69% (391/565) =
Any Genotypic Data
83% (470/565)
Acosta, IAS, 2019, Poster #MOPEB241

6. Methods, cont.
Virologic outcomes were assessed at Week 48 by U.S. FDA-defined Snapshot algorithm and the LOCF (Last Observation Carried Forward) method
Resistance analysis population (RAP) included any participant with virologic rebound and no subsequent resuppression of HIV-1 RNA
Confirmed virologic failure: Two consecutive HIV-1 RNA tests ≥ 50 c/mL, with HIV-1 RNA ≥ 200 c/mL at the confirmation test
HIV-1 RNA ≥ 200 c/mL at Week 48 or last visit on study drug (did not require confirmation)
Population genotype and phenotype were conducted at confirmed virologic failure, Week 48, or last visit for reverse transcriptase (RT), protease (PR), and integrase (IN) (Monogram Biosciences)
A multivariate logistic regression model (n=470 with documented historical or proviral genotype) assessed risk factors for baseline NRTI resistance and for M184V/I mutation using stepwise selection with significance level for entry (SLE) α = 0.20 and significance level for stay (SLS) α = 0.05
Intrinsic predictors—Age group, sex, race, ethnicity, BMI, CKD stage, region
HIV specific variables at baseline—CD4, HIV RNA, HIV acquisition risk factor, HIV disease status, time since ART start, prior use of each class of ART 3rd agent, number of prior 3rd agents, baseline ARV regimen and duration, PI resistance or NNRTI resistance at baseline
Acosta, IAS, 2019, Poster #MOPEB241

7. Table 1. Study GS-US-380-4030 HIV-1 Primary Drug Resistance Substitutions
Coding region
Resistance Category
Amino Acid Substitutions RT
NRTI-R
K65R/E/N, T69 insertions, T69D, K70E/G/M/Q/R/S/T, L74V/I, V75A/M/S/T, Y115F, Q151M, M184V/I
TAMs: M41L, D67N, K70R, L210W, T215F/Y, K219E/N/Q/R
NNRTI-R
L100I, K101E/P, K103N/S, V106A/M, V108I, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188C/H/L, G190A/E/Q/S, H221Y, P225H, F227C, M230I/L PR
PI-R
D30N, V32I, M46I/L, I47A/V, G48V, I50L/V, I54M/L, Q58E, T74P, L76V, V82A/F/L/S/T, N83D, I84V, N88S, L90M IN
INSTI-R
T66I/A/K, E92Q/G, T97A, F121Y, Y143R/H/C, S147G, Q148H/K/R, N155H/S, R263K
Acosta, IAS, 2019, Poster #MOPEB241

8. Results: Table 2. Baseline Characteristics
B/F/TAF
n=284
DTG + F/TAF
n=281
Median age, years (range)
51 (22-79)
50 (20-79)
Male, % 86 85
Race/Ethnicity, %
White 71 72
Black or African descent 24 22
Hispanic/Latino 18
Median CD4 cell count, cells/µL (IQR)
659 (486,885)
642 (462,791)
Median eGFRCG, mL/min (IQR)
97 (79,114)
100 (83,124)
NRTIs at baseline: F/TAF, % 68 69
Acosta, IAS, 2019, Poster #MOPEB241

9. Table 3. Pre-Existing NRTI Resistance
Category
NRTI Resistance Mutation
At Stratificationa
N=565
Finala
B/F/TAFa
n=284
DTG + F/TAFa
n=281 1
K65R/E/N or ≥ 3 TAMsb, n (%)
15 (3%)
30 (5%)
16 (6%)
14 (5%) 2
Other NRTI Resistance, n (%)
63 (11%)
108 (19%)
55 (19%)
53 (19%) 3
No NRTI Mutation, n (%)
487 (86%)
427 (76%)
213 (75%)
214 (76%)
20 participants stratified to categories 1 or 2 based on investigator suspected NRTI resistance (19 participants category 2, and 1 participant category 1) which were not confirmed by historical genotype or proviral DNA genotype.
Includes K65R/E/N, or 3 or more thymidine analogue mutations (TAMs) that include M41L or L210W, or T69 insertions.
Acosta, IAS, 2019, Poster #MOPEB241

10. Treatment Difference in % with RNA ≥ 50 c/mL, (95.001% CI)
Figure 2. Virologic Outcome by FDA Snapshot at Week 48 (Overall Population)
HIV-1 RNA < 50 c/mL
HIV-1 RNA ≥ 50 c/mL
No Virologic
Data
 1 
284
 3 
281
265
256
 22 
 18 
Treatment Difference in % with RNA ≥ 50 c/mL, (95.001% CI) 4%
Favors
B/F/TAF
DTG + F/TAF
DTG+ F/TAF (n=281)
B/F/TAF (n=284)
Virologic Outcome
Participants, %
Switching to B/F/TAF was non-inferior to remaining on DTG + F/TAF
No participant with pre-existing NRTI resistance had HIV-1 RNA ≥ 50 c/mL at Week 48 or last visit
Acosta, IAS, 2019, Poster #MOPEB241

11. Number of Participants, n (%) Historical or Proviral DNAa
Table 4. Frequency of Baseline NRTI Resistance-Associated Substitutions
Resistance Category
Number of Participants, n (%)
Historical or Proviral DNAa
N=565
B/F/TAF
n=284
DTG + F/TAF
n=281
Participants with PR-RT Data
470 (83%)
238 (84%)
232 (83%)
Primary NRTI-R
118/470 (25%)
63/238 (26%)
55/232 (24%)
M184V/Ib
81 (17%)
47 (20%)
34 (15%)
By Historical Genotype
41 (9%)
22 (9%)
19 (8%)
By Proviral DNA
57 (12%)
35 (15%)
K65R
5 (1%)
3 (1%)
2 (1%)
T69D
7 (1%)
4 (2%)
K70E
4 (1%)
1 (0.4%)
L74V/I
10 (2%)
7 (3%)
Y115F
2 (0.4%)
Q151M
Any TAMs
65 (14%)
32 (13%)
33 (14%)
1-2 TAMs
32 (7%)
16 (7%)
≥ 3 TAMs
33 (7%)
17 (7%)
a. Substitutions were detected by historical genotype, proviral DNA Archive genotype, or both.
b. Of the 81 participants with M184V/I, 71 had M184V alone; 6 had M184I alone; and 4 had both M184V and I.
Acosta, IAS, 2019, Poster #MOPEB241

12. Table 5. Frequency of Other Resistance-Associated Substitutions
Resistance Category
Number of Participants, n (%)
Historical or Proviral DNAa
N=565
B/F/TAF
n=284
DTG + F/TAF
n=281
Participants with PR-RT Data
470 (83%)
238 (84%)
232 (83%)
Primary NNRTI-R
118/470 (25%)
61/238 (26%)
57/232 (25%)
RPV-Rb
52 (11%)
22 (9%)
30 (13%)
K103N/S
65 (14%)
37 (16%)
28 (12%)
E138A/G/K/Q/R
17 (4%)
5 (2%)
12 (5%)
Y181C
15 (3%)
10 (4%)
Primary PI-R
38/470 (8%)
15/238 (6%)
23/232 (10%)
M46I/L
Q58E
4 (1%)
4 (2%)
L90M
8 (2%)
Participants with IN Data
413 (73%)
213 (75%)
200 (71%)
Primary INSTI-R
20/413 (5%)
15/213 (7%)
5/200 (3%)
T97A
12 (3%)
8 (4%)
Y143H
2 (0.5%)
2 (1%)
S147G
1 (0.2%)
1 (0.5%)
Q148H
N155H/S
1 (1%)
R263K
a. Substitutions were detected by historical genotype, proviral DNA Archive genotype, or both.
b. Rilpivirine resistance substitutions (RPV-R) are L100I, K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C, and M230I/L in RT.
Acosta, IAS, 2019, Poster #MOPEB241

13. Number of Participants, n (%) Treatment Difference % (95% CI)
Table 6. Week 48 Virologic Outcome by FDA Snapshot, NRTI Resistance Categories
HIV-1 RNA < 50 c/mL at Week 48 by Snapshot
Number of Participants, n (%)
B/F/TAF
n=284
DTG + F/TAF
n=281
Treatment Difference % (95% CI)
Overall
265 (93%)
256 (91%)
2.2% (-2.3% to 6.8%)
1: K65R/E/N or ≥ 3 TAMsa
15/16 (94%)b
14/14 (100%)b
-6.3% (-30.7% to 19.4%)
2: Other NRTI Resistance
51/55 (93%)b
51/53 (96%)b
-3.5% (-14.2% to 6.9%)
3: No NRTI Mutation
199/213 (93%)
191/214 (89%)
4.2% (-1.3% to 9.9%)
No participant from either treatment arm with known or suspected NRTI resistance had HIV-1 RNA ≥ 50 copies/mL at Week 48 or last visit
Includes K65R/E/N, or 3 or more thymidine analogue mutations (TAMs) that include M41L or L210W, or T69 insertions.
All participants with known or suspected NRTI resistance who did not have HIV-1 RNA < 50 c/mL at Week 48 had missing data in the Week 48 window and were virologically suppressed at their last visits.
Acosta, IAS, 2019, Poster #MOPEB241

14. Figure 3. Week 48 Virologic Outcome by the LOCF Method, NRTI Resistance Categories
Virologic Outcome HIV-1 RNA < 50 c/mL by LOCFa
No NRTI resistance
Overall
M184V/I
Participants, %
 16  16
 14  14
 55  55
 53  53
 211 
212
 209 
K65R or ≥ 3 TAMsb
Other NRTI resistance
 47  47
 34  34
 282 
283
 276 
279
DTG+ F/TAF (n=281)
B/F/TAF (n=284)
a. The LOCF outcome analysis did not include 3 participants (1 B/F/TAF; 2 DTG + F/TAF) who had no on-treatment post-baseline data.
b. Includes K65R/E/N, or 3 or more TAMs that include M41L or L210W, or T69 insertions.
Acosta, IAS, 2019, Poster #MOPEB241

15. Figure 4. Week 48 Virologic Outcome by the LOCF Method, Genotypic Resistance
Virologic Outcome HIV-1 RNA < 50 c/mL by LOCFa
DTG+ F/TAF (n=281)
B/F/TAF (n=284)
INSTI-R
NRTI-R
Participants, %
60  61
 57  57
 15  15
 23  23
 5  5
NNRTI-R
PI-R
 63  63
 55  55
The LOCF outcome analysis did not include 3 participants (1 B/F/TAF; 2 DTG + F/TAF) who had no on-treatment post-baseline data.
Acosta, IAS, 2019, Poster #MOPEB241

16. Table 7. Week 48 Resistance Analysis of Virologic Failures
B/F/TAF
n=284
DTG + F/TAF
n=281
Resistance analysis population 3
Emergent resistance
Resistance analysis population included any participant with a confirmed viral rebound of HIV-1 RNA ≥ 50 c/mL, with the confirmatory HIV-1 RNA ≥ 200 c/mL through Week 48, or without confirmation if at the last visit, who did not resuppress while on study drug.
No participant developed treatment-emergent resistance through Week 48
The LOCF outcome analysis did not include 3 participants (1 B/F/TAF; 2 DTG + F/TAF) who had no on-treatment post-baseline data.
Acosta, IAS, 2019, Poster #MOPEB241

17. Any NRTI Mutation Present
Table 8. Predictors of Pre-Existing NRTI Resistance or M184V/I by Multivariate Logistic Regression Model
Any NRTI Mutation Present
M184V/I Present
OR (95% CI)
p-value
Time since ART start (per year)
1.1 (1.1, 1.2)
<
1.1 (1.1, 1.1)
Prior PI-containing regimen
2.0 (1.2, 3.5)
0.0116
2.2 (1.1, 4.2)
0.0189
Black race (vs non-Black)
2.1 (1.2, 3.6)
0.0106
2.5 (1.4, 4.6)
0.0026
History of PI resistance
3.0 (1.3, 6.9)
0.0123
2.6 (1.1, 6.0)
0.0295
History of NNRTI resistance
2.4 (1.4, 4.0)
0.0014
2.7 (1.5, 4.7)
0.0007
Independent predictors of NRTI mutations and of M184V/I include a longer time since starting ART, a prior-PI containing regimen, Black race, and PI or NNRTI resistance
M184V/I was present in:
42% (16/38) of participants with PI resistance, vs 15% (65/432) of participants without PI resistance
35% (41/118) of participants with NNRTI resistance, vs 11% (40/352) of participants without NNRTI resistance
Acosta, IAS, 2019, Poster #MOPEB241

18. Conclusions
Study 4030 was the first study of B/F/TAF to prospectively allow NRTI, NNRTI, and PI resistance
At Week 48, there were high rates of virologic suppression regardless of pre-existing NRTI resistance (93.3% B/F/TAF vs. 91.1% DTG + F/TAF)
High levels of NRTI resistance were present in the virologically suppressed participants enrolled in the study
14% had known or suspected NRTI resistance at screening, which increased to 24% using historical data and additional baseline proviral HIV-1 DNA genotyping
M184V/I was present in 81 participants, who all had HIV-1 RNA < 50 c/mL at Week 48 or last visit
Similar efficacy was shown in studies 1844 and 1878, where a high rate of virologic suppression was maintained in participants with M184V/I taking B/F/TAF (52/54, 96%)15
No participant with pre-existing NRTI resistance had HIV-1 RNA ≥ 50 c/mL at Week 48 or last visit
No treatment emergent resistance was observed in either arm
Presence of NRTI resistance at baseline, including M184V/I, was associated with a longer duration of ART, a prior PI-containing regimen, black race, and baseline PI or NNRTI resistance
A triple therapy regimen of B/F/TAF or DTG + F/TAF may be an effective treatment option for virologically suppressed patients with or without evidence of pre-existing NRTI resistance including M184V/I
Acosta, IAS, 2019, Poster #MOPEB241

19. References
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Molina JM, et al., The Lancet HIV (2018) 5(7): e357-e365.
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Andreatta K, et al., HIV Glasgow (2018) Presentation #P298.
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Acosta, IAS, 2019, Poster #MOPEB241

20. Acknowledgments
We extend our thanks to the participants and their families, study investigators and staff. These studies were funded by Gilead Sciences, Inc.
Acosta, IAS, 2019, Poster #MOPEB241