In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravir-abacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTG+F-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies.
KEYWORDS: bictegravir, clinical trial, resistance, treatment naive
ABSTRACT
In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravir-abacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTG+F-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.
INTRODUCTION
Current guidelines for initial treatment of HIV-1 infection recommend an integrase strand transfer inhibitor (INSTI) in combination with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) as the preferred choice for treatment due to the favorable efficacy and safety profile of INSTIs compared with the profiles of other drug classes (1, 2). The currently approved INSTIs include elvitegravir (EVG), raltegravir (RAL), dolutegravir (DTG), and bictegravir (BIC) (3). BIC is a potent, once-daily, unboosted INSTI with low potential for drug-drug interactions, a high in vitro barrier to resistance, and in vitro activity against most RAL- and EVG-resistant variants, including several variants that have reduced susceptibility to DTG (4). Two unboosted INSTIs are available as coformulations in single-tablet regimens with two NRTIs: BIC with emtricitabine (FTC) and tenofovir alafenamide (TAF) (B-F-TAF) and DTG with abacavir (ABC) and lamivudine (3TC) (DTG-ABC-3TC). The B-F-TAF registrational treatment-naive clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490) are randomized, double-blind, multicenter, active-control, 144-week phase 3 studies evaluating the safety and efficacy of B-F-TAF in HIV-1-infected adults. Both studies found B-F-TAF to be statistically noninferior at the week 48 primary endpoint to regimens containing DTG in combination with a dual-NRTI backbone (DTG-ABC-3TC in study 1489 and DTG plus FTC and TAF [DTG+F-TAF] in study 1490) (5, 6). Here, we describe integrated resistance analyses of both studies at baseline and virologic failure.
(This work was presented in part at the Conference on Retroviruses and Opportunistic Infections, Boston, MA, 4 to 7 March, 2018.)
In studies 1489 and 1490, preexisting, transmitted resistance substitutions causing reduced susceptibility to FTC, TAF, ABC, or 3TC were excluded. At screening, HIV-1 population genotypic data for the protease (PR) and reverse transcriptase (RT) genes were obtained (GenoSure MG assay; Monogram Biosciences, South San Francisco, CA). Of the 1,421 participants with screening genotypes, only 3 had protocol-defined exclusion mutations (1 with M184V, 1 with M184M/V, and 1 with M184V, M41L, L210W, T215F/Y, and K219Q in RT) and were excluded for drug resistance reasons. The studies enrolled and dosed 1,274 participants who showed full sensitivity to FTC and TAF based on the proprietary genotypic algorithm from Monogram Biosciences. No participant had HIV-1 with the tenofovir or FTC-3TC resistance-associated substitutions K65R/E/N or M184V/I, respectively, according to the population genotype at screening. Retrospective deep-sequencing analyses of PR, RT, and integrase (IN) were performed on baseline samples of enrolled participants using the deepType HIV assay (Seq-IT GmbH & Co. KG, Kaiserslautern, Germany), and resistance mutations seen at frequencies of ≥15% were tabulated and combined with population sequencing results (Table 1). The 15% cutoff was chosen to mirror population sequencing thresholds and to ensure that mutations were above the background error of the assay. Primary NRTI resistance (NRTI-R) substitutions were observed in 2.7% (35 of 1,274) of participants, and the most frequent substitutions were M41L and K219E/N/Q/R in RT. These are thymidine analog resistance mutations (TAMs) and remain sensitive to FTC and tenofovir when fewer than three TAMs are present (7). Although not detected by population sequencing at screening, K65R/E was observed by deep sequencing above the 15% threshold in three participants (two with K65E in the B-F-TAF group; frequencies of 15% to 23%). Primary NNRTI resistance (NNRTI-R) substitutions were observed in 14.1% (179 of 1,274) of participants, and the most frequent substitutions were K103N/S and E138A/G/K/Q in RT. Primary protease inhibitor (PI) resistance substitutions were observed in 3.5% (44 of 1,274) of participants, and the most frequent substitutions were M46I/L, Q58E, and L90M in PR. The frequencies of baseline-transmitted resistance to antiretrovirals (ARVs) were consistent with findings of other reports (8–10).
TABLE 1.
Pretreatment genotypic analysis of PR, RT, and IN
| Resistance type and substitution(s) at baselinea | Substitution frequency (no. of participants [%]) by groupe |
|||
|---|---|---|---|---|
| B-F-TAF (n = 634) | DTG-ABC-3TC (n = 315) | DTG+F-TAF (n = 325) | All (n = 1,274) | |
| Primary INSTI-associatedb | 7 (1.1) | 4 (1.3) | 6 (1.9) | 17 (1.3) |
| T97A | 6 (0.9) | 4 (1.3) | 6 (1.9) | 16 (1.3) |
| Q148H | 1 (0.2) | 0 | 0 | 1 (0.1) |
| Secondary INSTI-associatedb | 326 (51.6) | 152 (48.4) | 160 (49.4) | 638 (50.2) |
| M50I | 126 (19.9) | 48 (15.3) | 62 (19.1) | 236 (18.6) |
| H51Y | 0 | 1 (0.3) | 1 (0.3) | 2 (0.2) |
| L68I/V | 4 (0.6) | 2 (0.6) | 2 (0.6) | 8 (0.6) |
| V72T | 3 (0.5) | 1 (0.3) | 3 (0.9) | 7 (0.6) |
| L74M | 1 (0.2) | 5 (1.6) | 2 (0.6) | 8 (0.6) |
| Q95K | 1 (0.2) | 0 | 0 | 1 (0.1) |
| S119P/R/T | 197 (31.2) | 103 (32.8) | 100 (30.9) | 400 (31.5) |
| A128T | 3 (0.5) | 0 | 0 | 3 (0.2) |
| E138A/K | 1 (0.2) | 2 (0.6) | 2 (0.6) | 5 (0.4) |
| G140S | 1 (0.2) | 0 | 0 | 1 (0.1) |
| Q146R | 1 (0.2) | 0 | 0 | 1 (0.1) |
| S153A | 3 (0.5) | 1 (0.3) | 2 (0.6) | 6 (0.5) |
| E157K/Q | 35 (5.5) | 12 (3.8) | 12 (3.7) | 59 (4.6) |
| G163K/R | 6 (0.9) | 5 (1.6) | 6 (1.9) | 17 (1.3) |
| Primary NRTI-associatedc | 21 (3.3) | 8 (2.5) | 6 (1.8) | 35 (2.7) |
| 1 to 2 TAMs | 19 (3.0) | 6 (1.9) | 6 (1.8) | 31 (2.4) |
| M41L | 4 (0.6) | 2 (0.6) | 1 (0.3) | 7 (0.5) |
| K65E/Rd | 2 (0.3) | 1 (0.3) | 0 | 3 (0.2) |
| D67N | 3 (0.5) | 2 (0.6) | 1 (0.3) | 6 (0.5) |
| K70R | 3 (0.5) | 0 | 1 (0.3) | 4 (0.3) |
| L74V | 1 (0.2) | 0 | 0 | 1 (0.1) |
| Y115F | 0 | 1 (0.3) | 0 | 1 (0.1) |
| L210W | 0 | 0 | 1 (0.3) | 1 (0.1) |
| K219E/N/Q/R | 11 (1.7) | 3 (1.0) | 2 (0.6) | 16 (1.3) |
| Primary NNRTI-associatedc | 81 (12.8) | 53 (16.8) | 45 (13.8) | 179 (14.1) |
| L100I | 3 (0.5) | 0 | 0 | 3 (0.2) |
| K101E/P | 5 (0.8) | 2 (0.6) | 0 | 7 (0.5) |
| K103N/S | 42 (6.6) | 27 (8.6) | 23 (7.1) | 92 (7.2) |
| V106A | 0 | 1 (0.3) | 2 (0.6) | 3 (0.2) |
| V108I | 1 (0.2) | 4 (1.3) | 2 (0.6) | 7 (0.5) |
| E138A/G/K/Q | 27 (4.3) | 17 (5.4) | 14 (4.3) | 58 (4.6) |
| V179L | 0 | 0 | 1 (0.3) | 1 (0.1) |
| Y181C | 3 (0.5) | 2 (0.6) | 2 (0.6) | 7 (0.5) |
| Y188C/L | 2 (0.3) | 2 (0.6) | 1 (0.3) | 5 (0.4) |
| G190A/E/Q/S | 5 (0.8) | 2 (0.6) | 3 (0.9) | 10 (0.8) |
| H221Y | 1 (0.2) | 1 (0.3) | 0 | 2 (0.2) |
| P225H | 3 (0.5) | 1 (0.3) | 1 (0.3) | 5 (0.4) |
| M230I | 1 (0.2) | 0 | 0 | 1 (0.1) |
| Primary PI-associatedc | 19 (3.0) | 13 (4.1) | 12 (3.7) | 44 (3.5) |
| D30N | 2 (0.3) | 2 (0.6) | 0 | 4 (0.3) |
| V32I | 1 (0.2) | 0 | 1 (0.3) | 2 (0.2) |
| M46I/L | 7 (1.1) | 3 (1.0) | 6 (1.8) | 16 (1.3) |
| I47V | 1 (0.2) | 1 (0.3) | 0 | 2 (0.2) |
| I50L/V | 1 (0.2) | 0 | 1 (0.3) | 2 (0.2) |
| Q58E | 3 (0.5) | 5 (1.6) | 3 (0.9) | 11 (0.9) |
| L76V | 0 | 0 | 1 (0.3) | 1 (0.1) |
| V82A/L | 4 (0.6) | 0 | 0 | 4 (0.3) |
| I84V | 0 | 0 | 1 (0.3) | 1 (0.1) |
| L90M | 3 (0.5) | 2 (0.6) | 4 (1.2) | 9 (0.7) |
For this analysis, population sequencing results and deep sequencing results at frequencies of ≥15% were combined. The 15% cutoff for deep sequencing was chosen to ensure that mutations were well above the background false-positive rate of approximately 2%. The list of resistance substitutions used in these analyses is based on IAS-USA guidelines with some modifications (33). Primary INSTI-R substitutions assessed were T66A/I/K, E92G/Q, T97A, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H/S, and R263K in IN. Secondary INSTI-R substitutions were M50I, H51Y, L68I/V, V72A/N/T, L74M, Q95K/R, G118R, S119P/R/T, F121C, A128T, E138A/K, G140A/C/S, P145S, Q146I/K/L/P/R, V151A/L, S153A/F/Y, E157K/Q, G163K/R, and E170A in IN. Primary NRTI-R substitutions were M41L, K65E/N/R, D67N, T69 insertions, K70E/R, L74I/V, Y115F, Q151M, M184I/V, L210W, T215F/Y, and K219E/N/Q/R in RT. Secondary NRTI-R substitutions were E44D, A62V, T69D/N, V75I, F77L, F116Y, V118I, and T215A/C/D/E/G/H/I/L/N/S/V in RT. Primary NNRTI-R substitutions were 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, and M230I/L in RT. Secondary NNRTI-R substitutions were V90I, A98G, K101H, V106I, and V179D/F/T in RT. Primary PI resistance substitutions were D30N, V32I, M46I/L, I47A/V, G48V, I50L/V, I54M/L, Q58E, T74P, L76V, V82A/F/L/S/T, N83D, I84V, N88S, and L90M in PR.
The denominators for the IN gene analyses are 632 for the B-F-TAF, 314 for the DTG-ABC-3TC, and 324 for the DTG+F-TAF groups and 1,270 for all. Population sequencing data were available for 12 B-F-TAF, 8 DTG-ABC-3TC, and 10 DTG+F-TAF participants and for 30 participants in all. Deep-sequencing data were available for all of these participants.
The denominators for the PR and RT gene analyses are 634 for the B-F-TAF, 315 for the DTG-ABC-3TC, and 325 for the DTG+F-TAF groups and 1,274 for all. Population sequencing data were available for all of these participants. Deep-sequencing data were available for 632 B-F-TAF, 314 DTG-ABC-3TC, and 324 DTG+F-TAF participants and for 1,270 participants in all.
The K65E/R mutation was not detected in any participants at screening by population genotype. The K65E/R mutations listed here were detected retrospectively by deep sequencing.
The data are from the studies as follows: for B-F-TAF, studies 1489 and 1490; DTG-ABC-3TC, study 1489; DTG+F-TAF, study 1490.
No genotyping of HIV integrase (IN) was conducted at screening in studies 1489 and 1490. However, retrospective baseline IN genotypic data were obtained by deep sequencing for 1,270 of 1,274 participants (four assay failures due to low plasma viral load). Primary INSTI resistance (INSTI-R) substitutions were infrequent and were observed in 1.3% (17 of 1,270) of participants at frequencies ranging from 16% to >99% and consisted of the polymorphic T97A mutation (16 participants) (11, 12), and Q148H (with G140S) in 1 participant (Table 1). The presence of the primary INSTI resistance substitutions was confirmed by standard population sequencing for Q148H plus G140S, and 14 of the 16 T97A samples. Six of the T97A samples showed phenotypic resistance to the INSTIs elvitegravir (EVG) and/or raltegravir (RAL). Secondary INSTI resistance substitutions are common and generally do not confer resistance to an INSTI on their own. They were observed in 50.2% (638 of 1,270) of participants in these studies; the most frequent secondary substitutions were M50I, S119P/R/T, and E157K/Q in IN.
The HIV-1 subtype was determined for participants by the screening PR/RT genotype. Some participants with complex subtypes had their subtypes resolved using the REGA HIV-1 subtyping tool, version 3.0. Subtype B was predominant in all groups (89.3%; 1,138 of 1,274 participants), followed by complex subtypes (2.2%), subtype A1 (1.8%), subtype AG (1.6%), subtype C (1.3%), and subtype AE (1.1%). Other HIV-1 subtypes were found in less than 1% of participants and consisted of subtypes A, BC, BF, D, F, F1, F2, G, and H.
The impact of pretreatment resistance substitutions and subtype on treatment outcomes was assessed for all participants in all treatment groups in these studies using the week 48 U.S. FDA Snapshot outcomes of participants with HIV-1 RNA levels of <50 copies/ml, those with HIV-1 RNA levels of ≥50 copies/ml, or those for whom there were no data in the week 48 window (Table 2). The outcomes of patients with or without key resistance substitutions or with HIV-1 subtype B versus non-B infections were also evaluated using the Fisher’s exact test. No statistical significance was found in any of the comparisons tested (P > 0.05), indicating that treatment response was not affected by the presence of preexisting resistance substitutions or HIV-1 subtype. In the B-F-TAF group, the two participants with retrospectively identified K65E in RT had HIV-1 RNA of <50 copies/ml at week 48. Similarly, in the DTG-ABC-3TC group, the one participant with K65R in RT had no virologic data at week 48 but was virologically suppressed at study discontinuation at week 24. Primary INSTI-R substitutions are rare in treatment-naive patients, and baseline IN genotyping should be guided by the frequency of INSTI-R in the local population (13, 14). The exception is the T97A mutation, which is naturally occurring at approximately 3% and is likely due to immune escape (15–17). Of the 16 participants with T97A, 15 achieved rapid suppression of HIV-1 RNA to <50 copies/ml and maintained HIV-1 RNA at <50 copies/ml through week 48, and 1 participant had no virologic data at week 48 but had HIV-1 RNA of <50 copies/ml at study discontinuation at week 4. Additional analyses of week 48 outcomes found no significant role of preexisting resistance for the B-F-TAF group (Table 3). It is important to note that these results came from controlled clinical trial settings, and data from real-world treatment have not been described.
TABLE 2.
Impact of pretreatment resistance substitutions and HIV-1 subtype on treatment outcome
| Categorya | Frequency by treatment group of participants with HIV-1 RNA levels of <50 copies/ml at week 48 (no. positive/no. tested [%])b |
||
|---|---|---|---|
| B-F-TAF (n = 634) | DTG-ABC-3TC (n = 315) | DTG+F-TAF (n = 325) | |
| All subjects | 576/634 (90.9) | 293/315 (93.0) | 302/325 (92.9) |
| HIV-1 subtype B | 513/563 (91.1) | 266/286 (93.0) | 269/289 (93.1) |
| HIV-1 subtype non-B | 63/71 (88.7) | 27/29 (93.1) | 33/36 (91.7) |
| P value | 0.51 | 1.0 | 0.73 |
| Primary INSTI-R | 7/7 (100) | 3/4 (75.0) | 6/6 (100) |
| No primary INSTI-R | 568/625 (90.9) | 289/310 (93.2) | 295/318 (92.8) |
| P value | 1.0 | 0.25 | 1.0 |
| T97A in IN | 6/6 (100) | 3/4 (75.0) | 6/6 (100) |
| No T97A in IN | 569/626 (90.9) | 289/310 (93.2) | 295/318 (92.8) |
| P value | 1.0 | 0.25 | 1.0 |
| Secondary INSTI-R | 298/326 (91.4) | 140/152 (92.1) | 150/160 (93.8) |
| No secondary INSTI-R | 277/306 (90.5) | 152/162 (93.8) | 151/164 (92.1) |
| P value | 0.78 | 0.66 | 0.67 |
| Primary NRTI-R | 19/21 (90.5) | 6/8 (75.0) | 5/6 (83.3) |
| No primary NRTI-R | 557/613 (90.9) | 287/307 (93.5) | 297/319 (93.1) |
| P value | 1.0 | 0.10 | 0.36 |
| 1 to 2 TAMs in RT | 17/19 (89.5) | 5/6 (83.3) | 5/6 (83.3) |
| No TAMs in RT | 559/615 (90.9) | 288/309 (93.2) | 297/319 (93.1) |
| P value | 0.69 | 0.35 | 0.36 |
| Primary NNRTI-R | 73/81 (90.1) | 50/53 (94.3) | 42/45 (93.3) |
| No primary NNRTI-R | 503/553 (91.0) | 243/262 (92.7) | 260/280 (92.9) |
| P value | 0.84 | 1.0 | 1.0 |
| K103N/S in RT | 39/42 (92.9) | 25/27 (92.6) | 22/23 (95.7) |
| No K103N/S in RT | 537/592 (90.7) | 268/288 (93.1) | 280/302 (92.7) |
| P value | 1.0 | 1.0 | 1.0 |
| Primary PI-R | 17/19 (89.5) | 12/13 (92.3) | 12/12 (100) |
| No primary PI-R | 559/615 (90.9) | 281/302 (93.0) | 290/313 (92.7) |
| P value | 0.69 | 1.0 | 1.0 |
P values for comparisons of results for each category pair were determined using Fisher's exact test.
Data are for participants with HIV-1 RNA levels of <50 copies/ml at week 48. The data are from the studies as follows: for B-F-TAF, studies 1489 and 1490; DTG-ABC-3TC, study 1489; DTG+F-TAF, study 1490.
TABLE 3.
Impact of pretreatment resistance substitutions on treatment outcome in the B-F-TAF group
| Resistance type and substitution(s) at baselinea | No. (%) of B-F-TAF participants | Week 48 Snapshot result |
||
|---|---|---|---|---|
| HIV-1 RNA of <50 copies/ml | HIV-1 RNA of ≥50 copies/ml | No data | ||
| Primary INSTI-associatedb | 7 (1.1) | 7 (100) | 0 | 0 |
| T97A | 6 (0.9) | 6 (100) | 0 | 0 |
| Q148H | 1 (0.2) | 1 (100) | 0 | 0 |
| Secondary INSTI-associatedb | 326 (51.6) | 298 (91.4) | 7 (2.1) | 21 (6.4) |
| M50I | 126 (19.9) | 120 (95.2) | 0 | 6 (4.8) |
| L68I/V | 4 (0.6) | 4 (100) | 0 | 0 |
| V72T | 3 (0.5)c | 2 (66.7) | 1 (33.3) | 0 |
| L74M | 1 (0.2) | 1 (100) | 0 | 0 |
| Q95K | 1 (0.2) | 1 (100) | 0 | 0 |
| S119P/R/T | 197 (31.2) | 179 (90.9) | 6 (3.0) | 12 (6.1) |
| A128T | 3 (0.5) | 3 (100) | 0 | 0 |
| E138A/K | 1 (0.2) | 1 (100) | 0 | 0 |
| G140S | 1 (0.2) | 1 (100) | 0 | 0 |
| Q146R | 1 (0.2) | 1 (100) | 0 | 0 |
| S153A | 3 (0.5) | 2 (66.7) | 0 | 1 (33.3) |
| E157K/Q | 35 (5.5) | 29 (82.9) | 1 (2.9) | 5 (14.3) |
| G163K/R | 6 (0.9) | 5 (83.3) | 1 (16.7) | 0 |
| Primary NRTI-associatedd | 21 (3.3) | 19 (90.5) | 0 | 2 (9.5) |
| 1-2 TAMs | 19 (3.0) | 17 (89.5) | 0 | 2 (10.5) |
| M41L | 4 (0.6) | 3 (75.0) | 0 | 1 (25.0) |
| K65E/R | 2 (0.3) | 2 (100) | 0 | 0 |
| D67N | 3 (0.5) | 3 (100) | 0 | 0 |
| K70R | 3 (0.5) | 3 (100) | 0 | 0 |
| L74V | 1 (0.2) | 0 | 0 | 1 (100) |
| K219E/N/Q/R | 11 (1.7) | 10 (90.9) | 0 | 1 (9.1) |
| Primary NNRTI-associatedd | 81 (12.8) | 73 (90.1) | 0 | 8 (9.9) |
| L100I | 3 (0.5) | 2 (66.7) | 0 | 1 (33.3) |
| K101E/P | 5 (0.8) | 4 (80.0) | 0 | 1 (20.0) |
| K103N/S | 42 (6.6) | 39 (92.9) | 0 | 3 (7.1) |
| V108I | 1 (0.2) | 1 (100) | 0 | 0 |
| E138A/G/K/Q | 27 (4.3) | 24 (88.9) | 0 | 3 (11.1) |
| Y181C | 3 (0.5) | 2 (66.7) | 0 | 1 (33.3) |
| Y188C/L | 2 (0.3) | 2 (100) | 0 | 0 |
| G190A/E/Q/S | 5 (0.8) | 4 (80.0) | 0 | 1 (20.0) |
| H221Y | 1 (0.2) | 0 | 0 | 1 (100) |
| P225H | 3 (0.5) | 3 (100) | 0 | 0 |
| M230I | 1 (0.2) | 1 (100) | 0 | 0 |
| Primary PI-associatedd | 19 (3.0) | 17 (89.5) | 1 (5.3) | 1 (5.3) |
| D30N | 2 (0.3) | 2 (100) | 0 | 0 |
| V32I | 1 (0.2) | 1 (100) | 0 | 0 |
| M46I/L | 7 (1.1) | 6 (85.7) | 0 | 1 (14.3) |
| I47V | 1 (0.2) | 1 (100) | 0 | 0 |
| I50L/V | 1 (0.2) | 0 | 0 | 1 (100) |
| Q58E | 3 (0.5) | 3 (100) | 0 | 0 |
| V82A/L | 4 (0.6) | 2 (50.0) | 1 (25.0) | 1 (25.0) |
| L90M | 3 (0.5) | 3 (100) | 0 | 0 |
See footnote a in Table 1 for details.
The denominator for the IN gene analyses is 632 for B-F-TAF. Population sequencing data were available for 12 B-F-TAF participants. Deep-sequencing data were available for all 632 B-F-TAF participants.
One participant had V72T at day 1 at 2.83% and was included in this analysis.
The denominator for the PR and RT gene analyses is 634 for B-F-TAF. Population sequencing data were available for all 634 B-F-TAF participants. Deep-sequencing data were available for 632 B-F-TAF participants.
In these studies, one participant in the B-F-TAF group had transmitted primary INSTI resistance at the baseline visit. This isolate had Q148H plus G140S in IN, high-level phenotypic resistance to RAL and EVG, partial sensitivity to DTG (4.45-fold change compared to the wild-type level and above the 4-fold cutoff for reduced susceptibility to DTG), and full sensitivity to BIC (fold-change of 2.14 and below the 2.5-fold cutoff for BIC) by the PhenoSense IN assay (Monogram Biosciences). In addition, this participant had the primary NRTI substitution K70R and the primary NNRTI substitution K103N in RT. Upon treatment with B-F-TAF, this participant achieved HIV-1 RNA of <50 copies/ml at week 4 and maintained HIV-1 RNA at <50 copies/ml through week 48 (Fig. 1).
FIG 1.
HIV-1 RNA results for participant with transmitted Q148H plus G140S in IN and K70R and K103N in RT and treated with B-F-TAF. The dotted line represents plasma HIV-1 RNA equal to 50 copies/ml. Plasma HIV-1 RNA values below 20 copies/ml are qualified as <20 copies/ml HIV-1 RNA detected or no HIV-1 RNA detected in this assay and are plotted here as 20 copies/ml or 10 copies/ml, respectively.
Study participants who had confirmed virologic rebound to HIV-1 RNA of ≥50 copies/ml after achieving <50 copies/ml while on study drugs were considered to have virologic failure and were included in the resistance analysis population (RAP). The second sample was analyzed if the HIV-1 RNA level was ≥200 copies/ml, and the participant did not resuppress HIV-1 RNA in the analysis window. In addition, participants with unconfirmed rebound at their last study visit or week 48 were analyzed if the HIV-1 RNA level was ≥200 copies/ml. Of the 1,274 randomized and treated participants, a total of 13 (1.0%) met all the criteria for inclusion in the RAP (Table 4). Reasons for inclusion in the RAP were confirmed virologic failure (4 participants), HIV-1 RNA of ≥200 copies/ml at the last visit at or after week 8 (early study drug discontinuation or lost to follow-up) (8 participants), or HIV-1 RNA of ≥200 copies/ml at the week 48 visit (1 participant). By treatment group, 8 of 634 (1.3%) participants in the combined B-F-TAF groups, 2 of 315 (0.6%) in the DTG-ABC-3TC group, and 3 of 325 (0.9%) in the DTG+F-TAF group were analyzed for resistance development. No participant in any treatment group developed treatment-emergent genotypic or phenotypic resistance to study drugs (Table 5). Since there was no treatment-emergent resistance, the reasons for virologic rebound were likely adherence based. In the B-F-TAF arm, BIC pharmacokinetic data at the virologic failure time points were available for 8/8 participants, and 5 participants had BIC levels below the level of quantitation (BLQ). Interestingly, pharmacokinetic simulations suggest that missing 8 or more consecutive days of B-F-TAF treatment would be required to have a BLQ BIC plasma concentration (data on file). In addition, 5/8 participants in the B-F-TAF RAP had study drug adherence of <95%, quantified by pill return count, or had unreturned pill bottles. However, overall adherence was high in these studies, and study discontinuation was low (5, 6).
TABLE 4.
Summary of emergent genotypic resistance through week 48
| Categoryc | Frequency by treatment group (no. of participants [% of RAP, % of group])a |
||
|---|---|---|---|
| B-F-TAF (n = 634) | DTG-ABC-3TC (n = 315) | DTG+F-TAF (n = 325) | |
| RAP | 8 (1.3)b | 2 (0.6) | 3 (0.9) |
| Confirmed virologic failure | 2 (25, 0.3) | 1 (50, 0.3) | 1 (33, 0.3) |
| ESDD HIV-1 RNA of ≥200 copies/ml | 5 (63, 0.8) | 1 (50, 0.3) | 2 (67, 0.6) |
| Week 48 HIV-1 RNA of ≥200 copies/ml | 1 (13, 0.2) | 0 | 0 |
| Developed resistance substitutions to study drugs | 0 | 0 | 0 |
The data are from the studies as follows: for B-F-TAF, studies 1489 and 1490; DTG-ABC-3TC, study 1489; DTG+F-TAF, study 1490. Single percentage values are those for the group.
No participant on B-F-TAF had follow-up HIV-1 RNA data available at the time of this analysis, and therefore resuppression data were not available.
RAP, resistance analysis population; ESDD, early study drug discontinuation.
TABLE 5.
Details of participants in the week 48 resistance analysis population
| Treatment group and participant no.a | Time pointb | HIV-1 RNA (copies/ml)c | CD4 (cells/μl) | BIC plasma concn BLQd | Resistance-associated substitution(s)e |
Drug susceptibility (fold change)f |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| IN | RT | BIC | DTG | ABC | 3TC | FTC | TFV | |||||
| B-F-TAF | ||||||||||||
| 1g | BL | 6,370 | 502 | ND | None | None | 0.80 | 0.95 | 0.80 | 1.23 | 0.97 | 0.68 |
| Wk 36 | 2,120 | 452 | Yes | None | None | 0.68 | 0.98 | 0.79 | 1.21 | 1.17 | 0.68 | |
| Wk 48 | 4,450 | 387 | Yes | None | None | 0.87 | 0.97 | 0.84 | 1.29 | 1.21 | 0.77 | |
| 2g | BL | 2,770 | 948 | ND | None | None | 0.93 | 0.99 | 1.03 | 1.06 | 0.85 | 1.01 |
| Wk 24 | 4,440 | 801 | Yes | None | None | 0.92 | 0.90 | 1.01 | 0.96 | 0.85 | 1.06 | |
| 3 | BL | 25,200 | 943 | ND | V72T/I,h S119P | None | ND | ND | AF | AF | AF | AF |
| Wk 48 | 22,200 | 954 | Yes | V72T/I, S119P | None | 0.84 | 0.95 | 1.25 | 1.53 | 1.26 | 1.19 | |
| 4 | BL | 16,800 | 900 | ND | S119P, E157E/K | None | 0.95 | 1.00 | 1.00 | 1.02 | 1.02 | 0.77 |
| Wk 24 | 23,400 | 742 | Yes | S119P | None | 0.90 | 1.10 | 1.07 | 1.06 | 1.01 | 0.88 | |
| 5g | BL | 3,560,000 | 289 | ND | S119P | None | 0.91 | 0.98 | 0.97 | 1.26 | 0.97 | 0.79 |
| Wk 8 | 317,000 | 533 | Yes | S119P | None | 0.79 | 0.88 | 0.91 | 0.95 | 1.07 | 0.82 | |
| 6g | BL | 97,200 | 2 | ND | None | None | 0.96 | 1.16 | 0.85 | 1.24 | 1.09 | 0.76 |
| Wk 8 | 19,000 | 11 | No | None | None | 0.87 | 0.85 | 0.57 | 0.97 | 0.94 | 0.6 | |
| 7g | BL | 184,000 | 430 | ND | S119P | V179V/D | AF | AF | 1.06 | 1.13 | 0.94 | 1.04 |
| Wk 36 | 8,630 | 462 | No | S119P | None | 0.59 | 0.84 | 1.04 | 1.16 | 0.99 | 1.17 | |
| 8 | BL | 3,830,000 | 31 | ND | None | None | 0.79 | 0.91 | 0.82 | 0.94 | 0.95 | 1.04 |
| Wk 24 | 967 | 217 | No | None | None | 0.98 | 0.84 | 0.99 | 1.35 | 1.00 | 1.25 | |
| Wk 48 | 688 | 195 | No | None | None | 0.81 | 0.88 | 0.86 | 1.00 | 0.91 | 1.03 | |
| DTG-ABC-3TC | ||||||||||||
| 9g | BL | 55,600 | 307 | ND | S119P | None | 0.59 | 0.51 | 0.95 | 1.41 | 1.26 | 1.00 |
| Wk 24 | 80,100 | 361 | ND | S119P | None | 0.46 | 0.49 | 1.06 | 1.66 | 1.57 | 1.05 | |
| 10g | BL | 15,700 | 712 | ND | M50I | None | 0.61 | 0.76 | AF | AF | AF | AF |
| Wk 48 | 3,000 | 604 | ND | AF | AF | AF | AF | AF | AF | AF | AF | |
| DTG+F-TAF | ND | |||||||||||
| 11 | BL | 42,300 | 358 | ND | None | None | 1.04 | 0.98 | 0.85 | 1.02 | 0.98 | 0.76 |
| Wk 8 | 22,800 | 278 | ND | AF | None | AF | AF | 0.87 | 0.96 | 0.87 | 0.81 | |
| 12g | BL | 23,800 | 8 | ND | M50M/I | K103K/N | AF | AF | 1.00 | 1.40 | 1.55 | 0.87 |
| Wk 48 | 221 | 228 | ND | AF | K103K/N | AF | AF | AF | AF | AF | AF | |
| 13g | BL | 56,400 | 385 | ND | None | None | 0.76 | 1.00 | 0.74 | 0.74 | 0.83 | 0.91 |
| Wk 12 | 5,480 | 279i | ND | None | None | 0.84 | 0.93 | 0.90 | 0.93 | 0.89 | 0.99 | |
| Wk 36 | 12,000 | 339 | ND | None | None | 0.82 | 0.98 | 0.68 | 0.83 | 0.89 | 0.86 | |
B-F-TAF, bictegravir-emtricitabine-tenofovir alafenamide; DTG-ABC-3TC, dolutegravir-abacavir-lamivudine; DTG+F-TAF, dolutegravir plus emtricitabine-tenofovir alafenamide.
Wk, week; BL, baseline.
Baseline viral load is the day 1 visit. All participants were infected with HIV-1 subtype B.
ND, no data available; BLQ, below the limit of quantitation.
Drug resistance mutations are defined in Table 1. Baseline sequences are the composite of screening and baseline data. Primary resistance-associated mutations are shown in bold text, and secondary resistance-associated mutations are shown in plain text. IN, integrase; RT, reverse transcriptase; AF, assay failure.
Phenotypic fold change compared to the level of the wild-type control. The clinical or biological cutoffs were as follows: bictegravir (BIC), 2.5; dolutegravir (DTG), 4.0; abacavir (ABC), 4.5; lamivudine (3TC), 3.5; emtricitabine (FTC), 3.5; tenofovir (TFV), 1.4. The Monogram Biosciences PhenoSense GT Assay was performed with TFV, the parent compound of TAF.
Adherence was <95% and/or there were unreturned pill bottles.
Participant 3 had V72T present at 2.83% by deep sequencing at day 1.
CD4 cell count was not assessed at study visit. CD4 cell count from a prior visit in the same analysis window is reported.
Both BIC and DTG have demonstrated a high barrier to resistance in vitro (4), which is confirmed in these clinical studies where no treatment-emergent resistance to either RT or IN was observed through 48 weeks on any regimen: B-F-TAF, DTG-ABC-3TC, or DTG+F-TAF (5, 6). Four phase 3 studies have been conducted with DTG+ABC-3TC in treatment-naive participants: SINGLE, SPRING-2, FLAMINGO, and ARIA (18–21). These studies showed high efficacy of the INSTI-containing regimen and demonstrated a high barrier to resistance for DTG in vivo, with no emergent resistance in any of the DTG-containing arms of the studies. Any virologic failure with resistance development to DTG as part of a three-drug regimen has been rare in treatment-naive patients but has occurred when DTG was not used with two fully active antiretroviral drugs. In the ACTG A5353 study investigating the use of DTG plus 3TC in treatment-naive participants, one participant developed M184V in RT plus the DTG-selected mutation R263R/K in IN (22). The mutation R263K has additionally been reported in four patients who were ART experienced but INSTI naive and received a DTG-containing regimen (23, 24). Other mutations, including Q148H/R, N155H, G118R, S230R, and R263K, have been reported following failure after DTG monotherapy (25–27). While BIC resistance has not yet been detected across five phase 3 studies through week 48 (5, 6, 28–30), in vitro resistance selection experiments over long periods confirm that HIV-1 resistance to BIC can develop and consist of S153F/Y or R263K with or without M50I in IN (4, 31, 32). These resistance substitutions have low-level reduced susceptibility to BIC and may occur in vivo after wider use of B-F-TAF; however, the lack of emergent resistance in the BIC development program to date supports its classification as a drug with a high resistance barrier.
Overall, treatment with B-F-TAF, DTG-ABC-3TC, or DTG+F-TAF led to the rapid achievement and maintenance of high rates of virologic suppression in HIV-1 treatment-naive participants. The presence of transmitted, preexisting resistance substitutions not associated with the study drugs did not affect treatment outcomes in these clinical trial settings. Development of primary drug resistance substitutions to study drug was not observed through week 48. Future studies will continue to explore the efficacy of B-F-TAF in the face of preexisting IN and RT resistance and B-F-TAF’s utility in immediate treatment initiation of antiretroviral drugs in people newly diagnosed with HIV-1.
ACKNOWLEDGMENTS
We thank the investigators, study site staff, and Gilead staff who took part in these studies. We also thank the staff at Monogram Biosciences and Seq-IT for performing the resistance analyses.
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