Biktarvy® (BIC/FTC/TAF)

Coadministration With Darunavir

This document is in response to your request for information regarding Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide [BIC/FTC/TAF]) and coadministration with darunavir (DRV).

Some data may be outside of the US FDA-approved prescribing information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA-approved prescribing information.

The full indication, important safety information, and boxed warnings are available at:
www.gilead.com/~/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi;
www.gilead.com/~/media/files/pdfs/medicines/hiv/descovy/descovy_pi.

Summary

Product Labeling1

Because BIC/FTC/TAF is a complete regimen, coadministration with other ARV medications for the treatment of HIV-1 infection is not recommended. Comprehensive information regarding potential drug-drug interactions with other ARV medications is not provided because the safety and efficacy of concomitant HIV-1 ARV therapy is unknown.

Clinical Studies of BIC/FTC/TAF With DRV

A phase 4, prospective study of 63 HTE VS and PWH evaluated the efficacy and safety of switching to BIC/FTC/TAF + DRV/COBI. At Week 48, 95% and 100% of participants in ITT and PP analyses, respectively, maintained VL <50 c/mL. Treatment was well tolerated, and 3 participants discontinued treatment due to AEs.2

A retrospective cohort analysis of 46 TE patients evaluated the safety and efficacy of BIC/FTC/TAF + boosted DRV. At Week 24, 85% of patients who had a baseline VL <200 c/mL and 35% of patients who had a baseline VL ≥200 c/mL maintained or achieved VL <50 c/mL with BIC/FTC/TAF + boosted DRV. Treatment was well tolerated, and no significant safety concerns were reported.3

PK Studies: BIC, FTC/TAF, or BIC/FTC/TAF With DRV

A phase 1, open-label study evaluated the effects of probe drugs, including DRV/COBI, on the PK and safety of BIC in healthy adult volunteers (N=13). Coadministration of multiple doses of BIC once daily with DRV/COBI under fed conditions resulted in increases of 74% in AUCτ and 52% in Cmax relative to BIC administered once daily alone.4

Based on drug interaction studies conducted with the components of FTC/TAF, no clinically significant drug interactions have been either observed or are expected when FTC/TAF is combined with DRV + RTV or COBI.5

A prospective study evaluated the PK profile and safety of BIC, TAF, TFV, and DRV in TE participants (N=9) who received BIC/FTC/TAF and DRV/COBI for ≥1 month before PK sampling. BIC and TAF AUC0–τ and Cmax values were higher in those who received BIC/FTC/TAF + DRV/COBI than previously reported PK data in participants who received BIC/FTC/TAF only. All participants remained virally suppressed (VL <200 c/mL).6

Clinical Studies of BIC/FTC/TAF With DRV

BIC/FTC/TAF + DRV/COBI in HTE PWH2

Study design and demographics

A phase 4, multicenter, prospective, single‑arm, open‑label pilot study evaluated the efficacy and safety of switching to once daily BIC/FTC/TAF + DRV/COBI 800 mg/100 mg in 63 HTE VS PWH. Eligible participants experienced prior virological failure and/or toxicities, were receiving >2 ARV drug classes, were receiving ≥3 pills/day, and had no known or suspected INSTI-R or DRV resistance (≥15 points on Stanford HIV Drug Resistance Database). The primary endpoint was VL <50 c/mL at Week 48 in the ITT analysis, and other endpoints included virological efficacy evaluated by PP analysis, AEs, changes in laboratory parameters, participant satisfaction assessed with HIV Treatment Satisfaction Questionnaire, and quality of life evaluated using EQ-5D-5L.

The median (IQR) age at baseline was 57.5 (49.9–60.6) years, 95.1% were male, and the median (IQR) years on ARV therapy was 24.3 (15.9–27.8) years, with median (IQR) number of 4 (3–‍6) ARV pills. Most participants (90%) were taking a PI + INSTI + other ARV regimen. According to the genotypic sensitivity score calculated from the proviral DNA genotype data, 95% of participants with available data (n=39) were sensitive to ≥2 drugs, whereas 33% were sensitive to <3.

Efficacy, participant satisfaction, and quality of life

At Week 48, 95% and 100% of participants in the ITT and PP analyses, respectively, maintained VL <50 c/mL. CD4 counts showed no significant differences between baseline and Week 48 (P-values not provided). Significant increases from baseline to Week 48 were reported in participant satisfaction with treatment (from 55% to 70%; P<0.001) and adherence perception (from 44% to 71%; P<0.001), with no changes in quality of life (data were not provided).

Safety and PK

AEs that resulted in treatment discontinuation in 3 patients consisted of Grade 2 cutaneous rash (n=1), Grade 2 headache and anxiety (n=1), and Grade 1 increase in Cr and Grade 2 eGFR decrease from 83 to 65 mL/min/1.73 m² (n=1; participant had a history of low eGFR, which was associated with prior use of TDF).

Significant changes from baseline to Week 48 in some laboratory parameters were observed. The median levels of alkaline phosphatase and Cr increased from 74.5 to 78 IU/L (P=0.021) and from 0.89 to 0.97 mmol/L (P<0.001), respectively, whereas median eGFR decreased from 90 to 80.4 mL/min/1.73 m² (P<0.001). Changes in both eGFR and Cr primarily occurred during the first 4 weeks of treatment, though eGFR levels remained relatively stable thereafter; Cr levels continued to minimally increase, although staying within the normal range through Week 48. No significant differences were found between baseline and Week 48 in urine protein/Cr index (P=0.09), or blood cell counts, transaminase levels, or lipid levels (P-values not provided).

Pre-dose concentrations of BIC were 11% to 13% higher, and Cmax values were 24% higher compared to those reported in the literature for unboosted BIC/FTC/TAF.

BIC/FTC/TAF + DRV in TE PWH and ARV Resistance3

Study design and demographics

A retrospective cohort analysis evaluated the safety and efficacy of BIC/FTC/TAF + boosted DRV in 46 TE patients who began treatment between February 2018 and June 2019. Follow-up data were recorded for 24 to 48 weeks.

Table 1. Baseline Demographics and Disease Characteristics (Hill et al)3

Efficacy

At Week 24, 85% of patients who had a baseline VL <200 c/mL and 35% of patients who had a baseline VL ≥200 c/mL maintained or achieved VL <50 c/mL with BIC/FTC/TAF + boosted DRV (Figure 1). All patients with baseline INSTI-R maintained or achieved VL <50 c/mL with BIC/FTC/TAF + boosted DRV treatment. VL <200 c/mL was achieved in 70.6% of patients who had a baseline VL ≥200 c/mL.

Figure 1. Virologic Outcomes at Week 24 (Hill et al)3

aThe VLs ranged from 205 to 880 c/mL.

Safety

Treatment with BIC/FTC/TAF + boosted DRV was well tolerated, and no significant safety concerns were reported. Seven patients discontinued treatment (mean time to discontinuation: 176 days); reasons for discontinuation included drug‑drug interactions (n=2), ongoing low-level viremia (n=2), rash (n=1), diarrhea (n=1), and simplification of therapy (n=1). No significant changes in weight or BMI were reported.

PK Studies: BIC, FTC/TAF, or BIC/FTC/TAF With DRV

BIC With DRV/COBI4

Study GS-US-141-1485

A phase 1, open-label, multiple-dose, multiple-cohort, adaptive design study evaluated the effects of probe drugs on the PK and safety of BIC in healthy adult volunteers. Healthy volunteers were administered BIC 75 mg with DRV/COBI 800/150 mg once daily (N=13). Coadministration of multiple daily doses of BIC with DRV/COBI under fed conditions resulted in increases in AUCτ by 74%, in Cmax by 52%, and in observed drug concentration at the end of the dosing interval by 111%, relative to BIC administered once daily alone.

FTC/TAF With DRV5

Based on drug interaction studies conducted with the components of FTC/TAF, no clinically significant drug interactions have been either observed or are expected when FTC/TAF is combined with DRV + RTV or COBI.

BIC/FTC/TAF + DRV/COBI in TE PWH6

Study design and demographics

A prospective, single-center, nonrandomized study evaluated the PK profile and safety of BIC, TAF, TFV, and DRV in 9 TE PWH and with CrCl ≥30 mL/min who had received BIC/FTC/TAF (50 mg/200 mg/25 mg) and DRV/COBI (800 mg/150 mg) for ≥1 month. Participants had previously received a median of 12 ARVs, with a median duration of 19 years of ARV treatment. Requirements included 2 weeks of self-reported adherence to the administration of BIC/FTC/TAF + DRV/COBI and consistent dosing intervals for the last 3 doses received before PK sampling. Plasma samples were drawn pre‑dose and at 0.5, 1, 2, and 4 hours post‑dose. The area under the plasma concentration-time curve at steady state was estimated by substituting C0 for plasma concentration at 24 hours for each participant (AUC0–τ). For concentration values below the limit of quantification, a value of half the lower limit of quantification was assigned to calculate summary statistics.

Table 2. Baseline Demographics and Disease Characteristics (Salama et al)6

aVLs were undetectable in 5 of 9 participants.

PK results

PK parameters of BIC/FTC/TAF and DRV/COBI are summarized in Table 3.

Compared with previously reported PK data in participants who received BIC/FTC/TAF only, BIC AUC0–τ and Cmax values were 26% and 12% higher, respectively, in TE participants who received BIC/FTC/TAF + DRV/COBI. In a similar comparison with previously reported PK data, TAF AUC0–τ and Cmax values in those treated with BIC/FTC/TAF + DRV/COBI were 165% and 128% higher, respectively. Despite increases in plasma TFV PK with COBI‑boosted TAF 25 mg, plasma concentrations of TFV were lower in comparison to those previously observed with unboosted TDF 300 mg in participants receiving TDF/FTC (mean Cmax, 0.3 mg/mL; AUC0–τ, 2.29 mcg·h/mL). In participants who received BIC/FTC/TAF + DRV/COBI, DRV AUC0–τ was approximately 20% higher than those who received DRV/COBI alone, whereas DRV Cmax values were similar between groups.

Table 3. PK Parameters of BIC/FTC/TAF and DRV/COBI in TE PWH (Salama et al)6

Abbreviation: AUC0–4=area under the plasma concentration-time curve at sampling time points 0–4 hours.

Efficacy and safety

All participants who received BIC/FTC/TAF + DRV/COBI remained virally suppressed (VL <200 c/mL). Treatment with BIC/FTC/TAF and DRV/COBI was well tolerated, and no AEs or treatment-emergent clinical laboratory abnormalities were reported.

References

1. Enclosed, Gilead Sciences Inc. BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use. US Prescribing Information. Foster City, CA.
2. Podzamczer D, Imaz A, Lopez-Lirola A, et al. Switching to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat in heavily antiretroviral-experienced, virologically suppressed HIV-infected adults receiving complex regimens. J Antimicrob Chemother. 2023;78(11):2696-2701.
3. Hill L, Momper J, Abulhosn K, Ballard C, Young M. Efficacy and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Combination with Boosted Darunavir in Treatment Experienced Patients with HIV [Poster]. 2019:
4. Gilead Sciences Inc. Data on File.
5. Enclosed. Gilead Sciences Inc, DESCOVY® (emtricitabine and tenofovir alafenamide) tablets, for oral use. U. S. Prescribing Information. Foster City, CA.
6. Salama E, Hill L, Patel N, Best BM, Momper JD. Brief Report: Pharmacokinetics of Bictegravir and Tenofovir in Combination With Darunavir/Cobicistat in Treatment-Experienced Persons With HIV. J Acquir Immune Defic Syndr. Dec 1 2021;88(4):389-392. doi:10.1097/QAI.0000000000002765

Abbreviations

AE=adverse event
ARV=antiretroviral
AUC0–τ=extrapolated area under the plasma concentration-time curve
AUCτ=area under the concentration-time curve over the dosing interval
BIC=bictegravir
c/mL=copies/mL
C0=initial plasma concentration
CD4=clusters of differentiation 4
Cmax=maximum observed concentration
COBI=cobicistat
DRV=darunavir
FTC=emtricitabine
HTE=heavily treatment experienced
INSTI-R=integrase strand transfer inhibitor-resistance
PI=protease inhibitor
PK=pharmacokinetic(s)
PP=per protocol
PWH=people with HIV
RTV=ritonavir
TAF=tenofovir alafenamide
TDF=tenofovir disoproxil fumarate
TE=treatment experienced
TFV=tenofovir
VL=viral load
VS=virologically suppressed

Product Label

For the full indication, important safety information, and boxed warning(s), please refer to the Biktarvy and Descovy US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi;
www.gilead.com/-/media/files/pdfs/medicines/hiv/descovy/descovy_pi.

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