Biktarvy® (BIC/FTC/TAF)

Hepatic Safety

This document is in response to your request for information regarding Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide [BIC/FTC/TAF]) and its hepatic safety profile from the registrational phase 3 clinical trials.

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.

Summary

Product Labeling1

Prior to or when initiating BIC/FTC/TAF, test patients for HBV infection.

Severe acute exacerbations of hepatitis B (eg, liver decompensation and liver failure) have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of BIC/FTC/TAF. Patients co-infected with HIV-1 and HBV who discontinue BIC/FTC/TAF should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC, a component of BIC/FTC/TAF, and TDF, another prodrug of tenofovir, alone or in combination with other ARVs. Treatment with BIC/FTC/TAF should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Clinical Data on BIC/FTC/TAF and Hepatic Safety

Studies 1489 and 1490 compared outcomes with BIC/FTC/TAF with those of DTG‑containing regimens in ARV-naive, adult PWH.2

• There were no study drug-related hepatobiliary serious AEs among participants taking BIC/FTC/TAF through Week 144.2,3
• Study participants were offered to continue treatment with or switch to treatment with BIC/FTC/TAF during the OLE phase; no study drug-related hepatobiliary serious AEs were reported through Week 240. No treatment discontinuations due to hepatobiliary AEs or abnormal liver function tests occurred.4

In clinical studies that compared outcomes of VS participants who switched to BIC/FTC/TAF with those who remained on their baseline regimens (boosted DRV or ATV + 2 NRTIs, DTG/ABC/3TC, or DTG + ABC/3TC), no study drug-related hepatobiliary serious AEs were reported through Week 48.5,6

Clinical Data on BIC/FTC/TAF and Hepatic Safety

GS-US-380-1489 and GS-US-380-1490

Study designs and demographics

Study 1489 was a phase 3, randomized, double-blind, active-controlled, non‑inferiority clinical study that compared outcomes in ARV-naive, adult PWH who were treated with BIC/FTC/TAF (n=314) or DTG/ABC/3TC (n=315).7 Study 1490 was a phase 3, randomized, double-blind, active-controlled, non‑inferiority clinical study that compared outcomes in ARV-naive, adult PWH who were treated with BIC/FTC/TAF (n=320) or DTG + FTC/TAF (n=325).8 Key inclusion criteria for both studies were HIV-1 RNA ≥500 c/mL and no known resistance to FTC, tenofovir, ABC, or 3TC.2

Table 1. Studies 1489 and 1490: Baseline Demographics and Disease Characteristics of BIC/FTC/TAF Participants2

Participants with HIV and HBV at Week 1443

Study 1490 permitted participants with HBV, and 14 participants (2%) had HBV at baseline (BIC/FTC/TAF, n=8; DTG + FTC/TAF, n=6). At Week 144, 11 had HBV DNA <29 IU/mL and HIV RNA <50 c/mL by missing=excluded analysis. No hepatic AEs were reported in these participants.

Hepatobiliary AEs through Week 1443,9

Through Week 144, no hepatobiliary serious AEs related to BIC/FTC/TAF were reported, and no discontinuations due to hepatic laboratory abnormalities or hepatobiliary AEs occurred. Grade 3 or 4 hepatobiliary laboratory abnormalities are reported in Table 2.

Table 2. Studies 1489 and 1490: Grade 3 or 4 Hepatic Laboratory Abnormalities Through Week 1449

Abbreviation: GGT=γ-glutamyl transferase.

aTotal n=314. bTotal n=313.

Hepatobiliary AEs through Week 240 – OLE phase4

At Week 144, all participants were offered enrollment in the OLE phase with BIC/FTC/TAF. A total of 252 participants in Study 1489 and 254 participants in Study 1490 from the BIC/FTC/TAF group continued into the OLE phase.

Table 3. Studies 1489 and 1490: Laboratory Abnormalities in BIC/FTC/TAF Participants Through Week 2404a

aIncluded only participants who were initially randomly assigned to receive BIC/FTC/TAF.

bNo cases of drug-related hepatitis were reported.

GS-US-380-1844

Study design and demographics

Study 1844 was a phase 3, randomized, double-blind study that compared the safety and efficacy of switching to BIC/FTC/TAF (n=282) with that of continuing with their baseline regimen of DTG + ABC/3TC or DTG/ABC/3TC (n=281) in VS, adult PWH.5,10

Table 4. Study 1844: Baseline Demographics and Disease Characteristics5

Hepatic lab abnormalities through Week 4811

Among the 282 participants who received BIC/FTC/TAF, 17% (n=47) experienced Grade 3 or 4 treatment-emergent toxicity, with 2% (n=6) having ALT level elevation. Hepatic AEs or medical histories associated with ALT level elevation included the following: incident HCV (n=3), acute hepatitis A (n=1), suspected alcohol abuse (n=1), and medical history of non‑alcoholic steatohepatitis (n=1). Among the 281 participants in the DTG/ABC/3TC group, 11% (n=32) experienced Grade 3 or 4 treatment-emergent toxicity, and no instances of ALT level increase were observed.

Hepatobiliary AEs through Week 168 – OLE phase12

In the OLE phase, the all-BIC/FTC/TAF group consisted of participants who received ≥1 dose of BIC/FTC/TAF; this was defined as the first dose of BIC/FTC/TAF in the OLE for participants who switched at Week 48. Increased ALT level was reported as a Grade 3 or 4 laboratory abnormality by 11 participants (2%).

GS-US-380-1878

Study design and demographics

Study 1878 was a phase 3, prospective, randomized, open-label clinical trial that compared outcomes in VS, adult PWH who switched to BIC/FTC/TAF (n=290) with those who continued with their baseline regimen of boosted DRV or ATV + 2 NRTIs (n=287).6,13

Table 5. Study 1878: Baseline Demographics and Disease Characteristics6,13

Hepatic lab abnormalities through Week 4814

Among the 290 participants who took BIC/FTC/TAF, 16% (n=45) experienced Grade 3 or 4 treatment-emergent toxicity, with 2% (n=6) having ALT level elevations. Among the 287 participants in the boosted DRV or ATV + 2 NRTIs group, 29% (n=83) experienced Grade 3 or 4 treatment-emergent toxicity and only 1% (n=4) had ALT level elevations.

Hepatobiliary AEs through Week 96 – extension phase15

Of the 532 participants who completed the 48-week randomized phase, 515 entered the OLE phase. The all-BIC/FTC/TAF group consisted of participants who received ≥1 dose of BIC/FTC/TAF; safety was assessed at the first dose of BIC/FTC/TAF in the OLE for participants who switched at Week 48. Of the 534 participants in the BIC/FTC/TAF group, 2% had each Grade 3 or 4 AST and ALT level elevations.

References

1. Enclosed, Gilead Sciences Inc. BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use. US Prescribing Information. Foster City, CA.
2. Johnson M, Taylor S, Wei X, Collins SE, Martin H. Hepatic Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide [Poster P061]. Paper presented at: 25th Annual Conference of the British HIV Association; 02-05 April, 2019; Bournemouth, United Kingdom.
3. Orkin C, DeJesus E, Sax PE, et al. Three-Year Outcomes of the Fixed-Dose Combination Bictegravir, Emtricitabine, and Tenofovir Alafenamide vs Dolutegravir-Containing Regimens for Initial Treatment of HIV-1 Infection: Week 144 Results from Two Randomised, Double-Blind, Multicentre, Phase 3, Non-Inferiority Trials. The Lancet HIV. 2020;7:e389–400.
4. Wohl DA, Pozniak A, Workowski K, et al. B/F/TAF Five-Year Outcomes in Treatment-Naïve Adults [Poster 494]. Paper presented at: Virtual Conference on Retroviruses and Opportunistic Infections (CROI) 2022; 12-16 February, 2022.
5. Molina JM, Ward D, Brar I, et al. Switch to Bictegravir/F/TAF From DTG and ABC/3TC [Presentation 022]. Paper presented at: Conference on Retroviruses and Opportunisitc Infections (CROI); 04-07 March, 2018; Boston, MA.
6. Daar ES, DeJesus E, Ruane P, et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial. The Lancet HIV. 2018;5(7):e347-e356. http://www.ncbi.nlm.nih.gov/pubmed/29925490
7. Wohl DA, Yazdanpanah Y, Baumgarten A, et al. Bictegravir Combined with Emtricitabine and Tenofovir Alafenamide Versus Dolutegravir, Abacavir, and Lamivudine for Initial Treatment of HIV-1 Infection: Week 96 Results from a Randomised, Double-Blind, Multicentre, Phase 3, Non-Inferiority Trial. The Lancet HIV. 2019;6(6):e355-e363.
8. Stellbrink HJ, Arribas JR, Stephens JL, et al. Co-Formulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide Versus Dolutegravir with Emtricitabine and Tenofovir Alafenamide for Initial Treatment of HIV-1 Infection: Week 96 Results from a Randomised, Double-Blind, Multicentre, Phase 3, Non-Inferiority Trial. The Lancet HIV. 2019;6(6):e364-e372.
9. Orkin C, DeJesus E, Sax PE, et al. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials [Supplementary Appendix]. The Lancet HIV. 2020;7(6):e389-e400. https://www.ncbi.nlm.nih.gov/pubmed/32504574
10. Molina JM, Ward D, Brar I, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. The Lancet HIV. 2018;5(7):e357-365. http://www.ncbi.nlm.nih.gov/pubmed/29925489
11. Molina JM, Ward D, Brar I, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. [Supplementary appendix]. The Lancet HIV. 2018;5(7):e357-365.
12. Brar I, Ruane P, Ward D, et al. Long-term Follow-up After a Switch to Bictegravir, Emtricitabine, and Tenofovir Alafenamide From Dolutegravir, Abacavir, and Lamivudine [Poster 1028]. Paper presented at: IDWeek Virtual; 21-25 October, 2020.
13. Daar ES, DeJesus E, Ruane P, et al. Phase 3 Randomized, Controlled Trial of Switching to Fixed-Dose Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) from Boosted Protease Inhibitor-Based Regimens in Virologically Suppressed Adults: Week 48 Results [Presentation# 67504]. Paper presented at: ID Week 2017; 04-08 October, 2017; San Diego, CA.
14. Daar ES, DeJesus E, Ruane P, et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial [Supplementary Appendix]. The Lancet HIV. 2018;5(7):e347-e356. https://www.ncbi.nlm.nih.gov/pubmed/29925490
15. Rockstroh JK, Molina JM, Post F, et al. Long-Term Follow-Up After a Switch to Bictegravir, Emtricitabine, Tenofovir Alafenamide (B/F/TAF) from a Boosted Protease Inhibitor-Based Regimen [Poster P036]. Paper presented at: HIV GLASGOW Drug Therapy Virtual; 05-08 October, 2020; Glasgow, UK.

Abbreviations

3TC=lamivudine
ABC=abacavir
AE=adverse event
ARV=antiretroviral
ATV=atazanavir
BIC=bictegravir
c/mL=copies/mL
CD4=cluster of differentiation 4
DRV=darunavir
DTG=dolutegravir
FTC=emtricitabine
eGFRCG=eGFR by Cockcroft-Gault
NRTI=nucleos(t)ide analog reverse transcriptase inhibitor
OLE=open-label extension
PWH=people with HIV
TAF=tenofovir alafenamide
VS=virologically suppressed

Product Label

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

Follow-Up

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