Emtricitabine/Tenofovir disoproxil Krka d.d.

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations, ATC code: J05AR20 Mechanism of action and pharmacodynamic effects Bictegravir is an integrase strand transfer inhibitor (INSTI) that binds to the integrase active site and blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.‍‍‍‍‍‍​​​‍​​​​​​ Bictegravir has activity against HIV‑1 and HIV‑2. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and analogue of 2'‑deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase (RT), which results in DNA chain-termination. Emtricitabine has activity against HIV‑1, HIV‑2 and HBV. Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonamidate prodrug of tenofovir (2'‑deoxyadenosine monophosphate analogue). Tenofovir alafenamide is permeable into cells and due to increased plasma stability and intracellular activation through hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil in loading tenofovir into peripheral blood mononuclear cells (PBMCs) (including lymphocytes and other HIV target cells) and macrophages. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV RT, which results in DNA chain-termination. Tenofovir has activity against HIV‑1, HIV‑2 and HBV. Antiviral activity in vitro The antiviral activity of bictegravir against laboratory and clinical isolates of HIV‑1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T‑lymphocytes. The 50% effective concentration (EC50) values for bictegravir were in the range of < 0.05 to 6.6 nM. The protein-adjusted EC95 of bictegravir was 361 nM (0.162 µg/mL) for wild type HIV‑1 virus. Bictegravir displayed antiviral activity in cell culture against HIV‑1 group (M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from < 0.05 to 1.71 nM), and activity against HIV‑2 (EC50 = 1.1 nM). The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV‑1 was assessed in lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The EC50 values for emtricitabine were in the range of 0.0013 to 0.64 µM. Emtricitabine displayed antiviral activity in cell culture against HIV‑1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 µM) and showed activity against HIV‑2 (EC50 values ranged from 0.007 to 1.5 µM). The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV‑1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T‑lymphocytes. The EC50 values for tenofovir alafenamide were in the range of 2.0 to 14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV‑1 groups (M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and activity against HIV‑2 (EC50 values ranged from 0.91 to 2.63 nM). Resistance In vitro HIV‑1 isolates with reduced susceptibility to bictegravir have been selected in cell culture. In one selection, amino acid substitutions M50I and R263K emerged and phenotypic susceptibility to bictegravir was reduced 1.3‑, 2.2‑, and 2.9‑fold for M50I, R263K, and M50I + R263K, respectively. In a second selection, amino acid substitutions T66I and S153F emerged and phenotypic susceptibility to bictegravir was shifted 0.4‑, 1.9‑, and 0.5‑fold for T66I, S153F, and T66I + S153F, respectively. HIV‑1 isolates with reduced susceptibility to emtricitabine have been selected in cell culture and had M184V/I mutations in HIV‑1 RT. HIV‑1 isolates with reduced susceptibility to tenofovir alafenamide have been selected in cell culture and had the K65R mutation in HIV‑1 RT; in addition, a K70E mutation in HIV‑1 RT has been transiently observed. HIV‑1 isolates with the K65R mutation have low level reduced susceptibility to abacavir, emtricitabine, tenofovir, and lamivudine. In vitro drug resistance selection studies with tenofovir alafenamide have shown no development of high-level resistance after extended culture. In vivo In patients who were treatment‑naïve (Studies GS‑US‑380‑1489 and GS‑US‑380‑1490), through Week 144 of the double‑blind phase or 96 weeks of the open‑label extension phase, no patient receiving Biktarvy, with HIV‑1 RNA ≥ 200 copies/mL at the time of confirmed virologic failure or early study drug discontinuation, had HIV‑1 with treatment‑emergent genotypic or phenotypic resistance to bictegravir, emtricitabine, or tenofovir alafenamide in the final resistance analysis population (n = 11 with data). At the time of study entry, one treatment-naïve patient had pre-existing INSTI resistance-associated mutations Q148H + G140S and had HIV‑1 RNA < 50 copies/mL at Week 4 through Week 144. In addition, 6 patients had the pre-existing INSTI resistance-associated mutation T97A; all had HIV-1 RNA < 50 copies/mL at Week 144 or the last visit. In patients who were virologically‑suppressed (Studies GS‑US‑380‑1844 and GS‑US‑380‑1878), no patients receiving Biktarvy, with HIV‑1 RNA ≥ 200 copies/mL at the time of confirmed virologic failure, Week 48, or early study drug discontinuation, had HIV‑1 with treatment-emergent genotypic or phenotypic resistance to bictegravir, emtricitabine, or tenofovir alafenamide in the final resistance analysis population (n = 2). No patient receiving Biktarvy had HIV-1 with treatment-emergent genotypic or phenotypic resistance to bictegravir, emtricitabine, or tenofovir alafenamide through the end of the blinded treatment phase of 284 patients with virologically-suppressed HIV-1, and switched from dolutegravir plus either emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate, to Biktarvy (Study GS-US-380-4030). Cross-resistance The susceptibility of bictegravir was tested against 64 INSTI-resistant clinical isolates (20 with single substitutions and 44 with 2 or more substitutions). Of these, all single and double mutant isolates lacking Q148H/K/R and 10 of 24 isolates with Q148H/K/R with additional INSTI resistance associated substitutions had ≤ 2.5‑fold reduced susceptibility to bictegravir; > 2.5‑fold reduced susceptibility to bictegravir was found for 14 of the 24 isolates that contained G140A/C/S and Q148H/R/K substitutions in integrase. Of those, 9 of the 14 isolates had additional mutations at L74M, T97A, or E138A/K. In a separate study, site-directed mutants with G118R and T97A+G118R had 3.4‑ and 2.8‑fold reduced susceptibility to bictegravir, respectively. The relevance of these in vitro cross-resistance data remains to be established in clinical practice. Bictegravir demonstrated equivalent antiviral activity against 5 nonnucleoside reverse transcriptase inhibitor (NNRTI)‑resistant, 3 NRTI‑resistant, and 4 protease inhibitor (PI)‑resistant HIV‑1 mutant clones compared with the wild-type strain. Emtricitabine‑resistant viruses with the M184V/I substitution were cross‑resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine. The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine. Multinucleoside resistant HIV‑1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R showed reduced susceptibility to tenofovir alafenamide. Clinical data The efficacy and safety of Biktarvy in adults with HIV‑1, who are treatment-naïve are based on 48-week and 144‑week data from two randomised, double-blind, active-controlled studies, GS‑US‑380‑1489 (n = 629) and GS‑US‑380‑1490 (n = 645). Furthermore, additional efficacy and safety data are available from adults who received open-label Biktarvy for an additional 96 weeks after Week 144 in an optional extension phase of these studies (n = 1025). The efficacy and safety of Biktarvy in adults with virologically‑suppressed HIV‑1 are based on 48‑week data from a randomised, double-blind, active-controlled study, GS‑US‑380‑1844 (n = 563); a randomised, open‑label, active-controlled study, GS‑US‑380‑1878 (n = 577), and a randomised, double-blind, active-controlled study, GS‑US‑380‑4030 (N = 284; 47 of whom had the emtricitabine-associated resistance mutation M184V/I in HIV at baseline). Patients with treatment-naïve HIV-1 In Study GS‑US‑380‑1489, patients were randomised in a 1:1 ratio to receive either bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (n = 314) or abacavir/dolutegravir/lamivudine (600/50/300 mg) (n = 315) once daily. In Study GS‑US‑380‑1490, patients were randomised in a 1:1 ratio to receive either B/F/TAF (n = 320) or dolutegravir + emtricitabine/tenofovir alafenamide (50+200/25 mg) (n = 325) once daily. In Studies GS‑US‑380‑1489 and GS‑US‑380‑1490, the mean age was 35 years (range 18‑77), 89% were male, 58% were White, 33% were Black, and 3% were Asian. Twenty-four percent of patients identified as Hispanic/Latino. The prevalence of different subtypes was comparable across all three treatment groups, with subtype B predominant in both groups; 11% were non‑B subtypes. The mean baseline plasma HIV‑1 RNA was 4.4 log 10 copies/mL (range 1.3‑6.6). The mean baseline CD4+ cell count was 460 cells/mm 3 (range 0‑1,636) and 11% had CD4+ cell counts less than 200 cells/mm 3 . Eighteen percent of patients had baseline viral loads greater than 100,000 copies/mL. In both studies, patients were stratified by baseline HIV‑1 RNA (less than or equal to 100,000 copies/mL, greater than 100,000 copies/mL to less than or equal to 400,000 copies/mL, or greater than 400,000 copies/mL), by CD4+ cell count (less than 50 cells/µL, 50‑199 cells/µL, or greater than or equal to 200 cells/µL), and by region (US or ex‑US). Treatment outcomes of Studies GS‑US‑380‑1489 and GS‑US‑380‑1490 through Weeks 48 and 144 are presented in Table 3. Table 3: Pooled virologic outcomes of Studies GS‑US‑380‑1489 and GS‑US‑380‑1490 at Weeks 48 a and 144 b Week 48 Week 144 B/F/TAF (n = 634) c ABC/DTG/3TC (n = 315) d DTG + F/TAF (n = 325) e B/F/TAF (n = 634) c ABC/DTG/3TC (n = 315) d DTG + F/TAF (n = 325) e HIV‑1 RNA < 50 copies/mL 91% 93% 93% 82% 84% 84% Treatment difference (95% CI) B/F/TAF vs Comparator - -2.1% (-5.9% to 1.6%) -1.9% (-5.6% to 1.8%) - -2.7% (‑7.8% to 2.4%) -1.9% (‑7.0% to 3.1%) HIV‑1 RNA ≥ 50 copies/mL f 3% 3% 1% 3% 3% 3% No virologic data at week 48 or 144 window 6% 4% 6% 16% 13% 13% Discontinued study drug due to AE or death g <1% 1% 1% 2% 2% 3% Discontinued study drug due to other reasons and last available HIV-1 RNA < 50 copies/mL h 4% 3% 4% 13% 11% 9% Missing data during window but on study drug 2% <1% 1% 1% <1% 1% Proportion (%) of patients with HIV‑1 RNA < 50 copies/mL by subgroup By baseline viral load ≤ 100,000 copies/mL > 100,000 copies/mL 92% 87% 94% 90% 93% 94% 82% 79% 86% 74% 84% 83% By baseline CD4+ cell count < 200 cells/mm 3 ≥ 200 cells/mm 3 90% 91% 81% 94% 100% 92% 80% 82% 69% 86% 91% 83% HIV‑1 RNA < 20 copies/mL 85% 87% 87% 78% 82% 79% ABC = abacavir DTG = dolutegravir 3TC = lamivudine F/TAF = emtricitabine/tenofovir alafenamide a Week 48 window was between Day 295 and 378 (inclusive). b Week 144 window was between Day 967 and 1050 (inclusive). c Pooled from Study GS‑US‑380‑1489 (n = 314) and Study GS‑US‑380‑1490 (n = 320). d Study GS‑US‑380‑1489. e Study GS‑US‑380‑1490. f Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack or loss of efficacy (n = 0); patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy (B/F/TAF n = 12 and 15; ABC/DTG/3TC n = 2 and 7; DTG+F/TAF n = 3 and 6, at Weeks 48 and 144, respectively) and at the time of discontinuation had a viral value of ≥ 50 copies/mL. g Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. h Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g. withdrew consent, loss to follow-up, etc. B/F/TAF was non‑inferior in achieving HIV‑1 RNA < 50 copies/mL at both Weeks 48 and 144 when compared to abacavir/dolutegravir/lamivudine and to dolutegravir + emtricitabine/tenofovir alafenamide, respectively. Treatment outcomes between treatment groups were similar across subgroups by age, sex, race, baseline viral load, baseline CD4+ cell count, and region. In Studies GS‑US‑380‑1489 and GS‑US‑380‑1490, the mean increase from baseline in CD4+ cell count at Week 144 was 288, 317, and 289 cells/mm 3 in the pooled B/F/TAF, abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups, respectively. In the optional 96 week open-label extension phase of Studies GS-US-380-1489 and GS-US-380-1490, high rates of virologic suppression were achieved and maintained. Patients with virologically‑suppressed HIV‑1 In Study GS‑US‑380‑1844, the efficacy and safety of switching from a regimen of dolutegravir + abacavir/lamivudine or abacavir/dolutegravir/lamivudine to B/F/TAF were evaluated in a randomised, double-blind study of adults with virologically‑suppressed HIV-1 (HIV‑1 RNA < 50 copies/mL) (n = 563). Patients must have been stably suppressed (HIV‑1 RNA < 50 copies/mL) on their baseline regimen for at least 3 months prior to study entry. Patients were randomised in a 1:1 ratio to either switch to B/F/TAF at baseline (n = 282), or stay on their baseline antiretroviral regimen (n = 281). Patients had a mean age of 45 years (range 20‑71), 89% were male, 73% were White, and 22% were Black. Seventeen percent (17%) of patients identified as Hispanic/Latino. The prevalence of different HIV‑1 subtypes was comparable between treatment groups, with subtype B predominant in both groups; 5% were non‑B subtypes. The mean baseline CD4+ cell count was 723 cells/mm 3 (range 124‑2,444). In Study GS‑US‑380‑1878, the efficacy and safety of switching from either abacavir/lamivudine or emtricitabine/tenofovir disoproxil fumarate (200/300 mg) plus atazanavir or darunavir (boosted by either cobicistat or ritonavir) to B/F/TAF were evaluated in a randomised, open-label study of adults with virologically‑suppressed HIV-1 (n = 577). Patients must have been stably suppressed on their baseline regimen for at least 6 months and must not have been previously treated with any INSTI. Patients were randomised in a 1:1 ratio to either switch to B/F/TAF (n = 290) or stay on their baseline antiretroviral regimen (n = 287). Patients had a mean age of 46 years (range 20‑79), 83% were male, 66% were White, and 26% were Black. Nineteen percent (19%) of patients identified as Hispanic/Latino. The mean baseline CD4+ cell count was 663 cells/mm 3 (range 62‑2,582). The prevalence of different subtypes was comparable across treatment groups, with subtype B predominant in both groups; 11% were non‑B subtypes. Patients were stratified by prior treatment regimen. At screening, 15% of patients were receiving abacavir/lamivudine plus atazanavir or darunavir (boosted by either cobicistat or ritonavir) and 85% of patients were receiving emtricitabine/tenofovir disoproxil fumarate plus atazanavir or darunavir (boosted by either cobicistat or ritonavir). Treatment outcomes of Studies GS‑US‑380‑1844 and GS‑US‑380‑1878 through Week 48 are presented in Table 4. Table 4: Virologic outcomes of Studies GS‑US‑380‑1844 and GS‑US‑380‑1878 at Week 48 a Study GS‑US‑380‑1844 Study GS‑US‑380‑1878 B/F/TAF (n = 282) ABC/DTG/3TC (n = 281) B/F/TAF (n = 290) Baseline ATV- or DRV-based regimen (n = 287) HIV‑1 RNA < 50 copies/mL 94% 95% 92% 89% Treatment difference (95% CI) ‑1.4% (‑5.5% to 2.6%) 3.2% (‑1.6% to 8.2%) HIV‑1 RNA ≥ 50 copies/mL b 1% < 1% 2% 2% Treatment difference (95% CI) 0.7% (‑1.0% to 2.8%) 0.0% (‑2.5% to 2.5%) No virologic data at Week 48 window 5% 5% 6% 9% Discontinued study drug due to AE or death and last available HIV‑1 RNA < 50 copies/mL 2% 1% 1% 1% Discontinued study drug due to other reasons and last available HIV‑1 RNA < 50 copies/mL c 2% 3% 3% 7% Missing data during window but on study drug 2% 1% 2% 2% ABC = abacavir ATV = atazanavir DRV = darunavir DTG = dolutegravir 3TC = lamivudine a Week 48 window was between Day 295 and 378 (inclusive). b Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL. c Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g. withdrew consent, loss to follow-up, etc. B/F/TAF was non-inferior to the control regimen in both studies. Treatment outcomes between treatment groups were similar across subgroups by age, sex, race, and region. In GS‑US‑380‑1844, the mean change from baseline in CD4+ cell count at Week 48 was ‑31 cells/mm 3 in patients who switched to B/F/TAF and 4 cells/mm 3 in patients who stayed on abacavir/dolutegravir/lamivudine. In GS‑US‑380‑1878, the mean change from baseline in CD4+ cell count at Week 48 was 25 cells/mm 3 in patients who switched to B/F/TAF and 0 cells/mm 3 in patients who stayed on their baseline regimen. In Study GS-US-380-4030, the efficacy and safety of switching from dolutegravir plus either emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate to B/F/TAF were evaluated in a randomised, double-blind study of adults with virologically suppressed HIV-1 infection. Participants must have been stably suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 6 months (if documented or suspected nucleoside reverse transcriptase inhibitor [NRTI] resistance), or at least 3 months (if no documented or suspected NRTI resistance) prior to study entry. Participants were randomised to switch to B/F/TAF (N=284) or to continue dolutegravir plus emtricitabine/tenofovir alafenamide (N=281). The primary endpoint was the proportion of participants with HIV RNA ≥ 50 copies/mL at Week 48. At Week 48, B/F/TAF was non-inferior to dolutegravir plus emtricitabine/tenofovir alafenamide; the proportion of participants with HIV-1 RNA ≥50 copies/mL was 0.4% (1/284) in the B/F/TAF group and 1.1% (3/281) in the dolutegravir plus emtricitabine/tenofovir alafenamide group (difference: -0.7% [95% CI: -2.8%, 1.0%]). Of the participants receiving B/F/TAF, 47 had HIV-1 with the emtricitabine-associated M184V/I resistance mutation at baseline. At Week 48, no participant with M184V/I had HIV RNA ≥ 50 copies/mL. Eighty-nine percent (42/47) of participants with M184V/I remained suppressed (HIV-1 RNA < 50 copies/mL) and 11% (5/47 participants) did not have virologic data at Week 48 due to discontinuation. Patients with HIV and HBV co-infection The number of patients with HIV and HBV co-infection treated with B/F/TAF is limited. In Study GS‑US‑380‑1490, 8 patients with HIV/HBV co‑infection at baseline were randomised to receive B/F/TAF. At Week 48, 7 patients were HBV suppressed (HBV DNA < 29 IU/mL) and had HIV‑1 RNA < 50 copies/mL. One patient had missing HBV DNA data at Week 48. At Week 144, 5 patients were HBV suppressed and had HIV-1 RNA < 50 copies/mL. Three patients had missing HBV DNA data at Week 144 (1 lost to follow-up from Week 48, 1 lost to follow-up after Week 72, and 1 lost to follow-up after Week 120). In Study GS‑US‑380‑1878, at Week 48, 100% (8/8) of the patients with HIV/HBV co-infection at baseline in the B/F/TAF arm maintained HBV DNA < 29 IU/mL (missing = excluded analysis) and HIV RNA < 50 copies/mL. Pregnancy In Study GS-US-380-5310, the pharmacokinetics, efficacy and safety of once-daily B/F/TAF were evaluated in an open-label clinical study of virologically suppressed pregnant adults with HIV-1 from the second or third trimester through postpartum (n = 33). All 32 adult participants who completed the study maintained viral suppression during pregnancy, at delivery, and through Week 18 postpartum. The median (Q1, Q3) CD4+ cell count at baseline was 558 (409, 720) cells/μL, and the median (Q1, Q3) change in CD4+ cell count from baseline to Week 12 postpartum was 159 (27, 296) cells/μL. All 29 neonate participants had negative/nondetectable HIV-1 PCR results at birth and/or 4 to 8 weeks of age. Paediatric population In Study GS-US-380-1474, the pharmacokinetics, safety and efficacy of B/F/TAF in children and adolescents with virologically‑suppressed HIV between the ages of 12 to < 18 years (≥ 35 kg) (n = 50), between the ages of 6 to < 12 years (≥ 25 kg) (n = 50), and ≥ 2 years of age (≥ 14 to < 25 kg) (n = 22) were evaluated. Cohort 1: Adolescents with virologically‑suppressed HIV (n = 50; 12 to < 18 years; ≥ 35 kg) Patients in Cohort 1 had a mean age of 14 years (range: 12 to 17) and a mean baseline weight of 51.7 kg (range: 35 to 123), 64% were female, 27% were Asian, and 65% were Black. At baseline, median CD4+ cell count was 750 cells/mm 3 (range: 337 to 1207), and median CD4+% was 33% (range: 19% to 45%). After switching to B/F/TAF, 98% (49/50) of patients in Cohort 1 remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 48. The mean change from baseline in CD4+ cell count at Week 48 was ‑22 cells/mm 3 . Two of 50 participants met the criteria for inclusion in the resistance analysis population through Week 48. No emergent resistance to B/F/TAF was detected through Week 48. Cohort 2: Children with virologically-suppressed HIV (n = 50; 6 to < 12 years; ≥ 25 kg) Patients in Cohort 2 had a mean age of 10 years (range: 6 to 11) and a mean baseline weight of 31.9 kg (range: 25 to 69), 54% were female, 22% were Asian and 72% were Black. At baseline, median CD4+ cell count was 898 cells/mm 3 (range 390 to 1991) and median CD4+% was 37% (range: 19% to 53%). After switching to B/F/TAF, 98% (49/50) of patients in Cohort 2 remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 48. The mean change from baseline in CD4+ cell count at Week 48 was ‑40 cells/mm 3 . No patient qualified for resistance analysis through Week 48. Cohort 3: Children with virologically‑suppressed HIV (n = 22; ≥ 2 years; ≥ 14 kg to < 25 kg) Patients in Cohort 3 had a mean age of 5 years (range: 3 to 9) and a mean baseline weight of 18.8 kg (range: 14 to 24), 50% were female, 23% were Asian and 73% were Black. At baseline, median CD4+ cell count was 962 cells/mm 3 (range 365 to 1986) and median CD4+% was 32% (range: 24% to 46%). After switching to B/F/TAF, 91% (20/22) of patients in Cohort 3 remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 24. The mean change from baseline in CD4+ cell count at Week 24 was −126 cells/mm 3 , and the mean change in CD4+% from baseline to Week 24 was 0.2% (range: ‑7.7% to 7.5%). No patient qualified for resistance analysis through Week 24.