Biktarvy® (BIC/FTC/TAF)

Use in Participants With HIV/HBV Co‑Infection

This document is in response to your request for information on the use of Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide [BIC/FTC/TAF]) in participants with HIV and HBV. BIC/FTC/TAF is not indicated for the treatment of HIV/HBV co‑infection.

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

Patients with HIV-1 should be tested for the presence of chronic HBV infection before or when initiating ARV therapy.

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.

BIC/FTC/TAF in Participants With HIV and HBV in Phase 3 and 4 Clinical Studies

The ALLIANCE study evaluated BIC/FTC/TAF vs DTG + FTC/TDF in participants with HIV and HBV (N=243). At Week 48, BIC/FTC/TAF was noninferior to DTG + FTC/TDF in the achievement of HIV‑1 RNA <50 c/mL (95% vs 91%, respectively) and was superior in the achievement of HBV DNA <29 IU/mL (63% vs 43%, respectively). Rates of HIV and HBV suppression remained high through Week 144 among participants who received BIC/FTC/TAF throughout the study and those who switched from DTG + FTC/TDF to open-label BIC/FTC/TAF at Week 96. No treatment-emergent resistance was detected during BIC/FTC/TAF treatment. Safety outcomes were similar between arms during the randomized phase, and most AEs were Grade 1 or 2 in severity through Week 144. One AE of HCC led to discontinuation of BIC/FTC/TAF treatment.2-4

In a phase 4 study in adults with HIV and HBV who switched to BIC/FTC/TAF (N=28), 82% of participants had both HIV RNA <50 c/mL and HBV DNA <29 IU/mL at Week 24. Each of the 10 TRAEs were mild in severity, and no AEs led to treatment discontinuation.5

In registrational trials of BIC/FTC/TAF in ARV-naïve and virologically suppressed adults, a small number of participants with HIV and HBV (n=16) were included. Most participants (≥85%) achieved or maintained HIV and HBV suppression.6 BIC/FTC/TAF was well tolerated in the overall participant population, with ≤2% discontinuing due to AEs.7,8

BIC/FTC/TAF in Participants With HIV and HBV in Phase 3 and 4 Studies

ALLIANCE: Phase 3, Randomized, Double-Blind Study

Study design and demographics

ALLIANCE was a phase 3 study that evaluated BIC/FTC/TAF vs DTG + FTC/TDF as initial treatment in adults with HIV and HBV (Figure 1).2 The co‑primary endpoints were the proportions of participants at Week 48 with HIV-1 RNA <50 c/mL (FDA Snapshot algorithm) and HBV DNA <29 IU/mL (M=F analysis). Most of the participants in both arms were male and from Thailand, China, or Malaysia (Table 1). At the end of 96 weeks, participants could enroll in a 48-week OLE, during which all participants received open-label BIC/FTC/TAF. A total of 121 participants who received BIC/FTC/TAF in the randomized phase continued onto the OLE phase; 109 of these participants received BIC/FTC/TAF for ≥144 weeks.3 A total of 89 participants who received DTG/FTC/TDF in the randomized phase continued onto the OLE.4

Figure 1. ALLIANCE: Study Design2

Abbreviations: CG=Cockcroft-Gault; TFV=tenofovir.

aParticipants who had an ALT level <ULN among those who had ALT levels ≥ULN at baseline. ALT ULN was based on AASLD 2018 criteria: females: 25 U/L; males: 35 U/L.

Table 1. ALLIANCE: Baseline Demographics and Disease Characteristics2

aOther GTs (not listed) consisted of GTs of F and mixed. Data were missing for 9 and 13 participants from the BIC/FTC/TAF and DTG + FTC/TDF arms, respectively, during the randomized phase.

Efficacy results

Randomized phase: BIC/FTC/TAF vs DTG + FTC/TDF

At Week 48 (M=F analysis), in the full analysis set (all randomly assigned participants who received ≥1 dose of study drug and had ≥1 on-treatment HIV-1 RNA or HBV DNA assessment after baseline), BIC/FTC/TAF was noninferior to DTG + FTC/TDF in the achievement of HIV‑1 RNA <50 c/mL (95% [113/119] and 91% [111/122], respectively; Δ4.1%; P=0.21) and was superior in the achievement of HBV DNA <29 IU/mL (63% [75/119] and 43.4% [53/122]; Δ16.6%; P=0.0023). At Week 96 (M=F analysis), in the full analysis set, the rates of HIV-1 RNA <50 c/mL were 87% (104/119) with BIC/FTC/TAF and 88% (107/122) with DTG + FTC/TDF (P=0.94); the rates of HBV DNA <29 IU/mL were 75% (89/119) and 70% (86/122), respectively (P=0.64). The mean change in log10 HBV DNA level in both arms had a similar and gradual decline up to Week 96, with a statistically significant difference (P<0.05) in favor of BIC/FTC/TAF compared with DTG + FTC/TDF at Week 12. Treatment adherence was high for both arms through Week 96: BIC/FTC/TAF, 98.5%; DTG + FTC/TDF, 98.3%.2

At Week 96, the mean change (SD) in CD4 count from baseline was 261 (161.6) cells/mcL in the BIC/FTC/TAF arm and 229 (174) cells/mcL in the DTG + FTC/TDF arm (P=0.19). Participants who received BIC/FTC/TAF had significantly higher rates (P<0.05) of HBeAg loss and seroconversion at Week 96 than did participants who received DTG + FTC/TDF. Rates of HBsAg loss and seroconversion were numerically higher in participants who received BIC/FTC/TAF than in those who received DTG + FTC/TDF (P=0.066 and P=0.44, respectively). A greater proportion of participants who received BIC/FTC/TAF vs DTG + FTC/TDF achieved ALT normalization through Week 96 (P<0.05 at Weeks 12, 24, 60, and 72).2

A univariate subgroup analysis compared HBV treatment outcomes at Week 96 between BIC/FTC/TAF and DTG + FTC/TDF. In comparison with treatment with DTG + FTC/TDF, treatment with BIC/FTC/TAF was associated with the following: significantly higher rates of HBeAg loss/seroconversion and numerically higher rates of HBsAg loss and ALT normalization across most subgroups analyzed, including Asian participants; study drug adherence ≥95%; age <30 years; baseline HBV DNA <8 log10 IU/mL; baseline HIV-1 RNA ≤100,000 c/mL; HBV GTs B/C; baseline CD4 count ≥200 cells/mcL; abnormal ALT level at baseline or Week 12; HBV DNA <29 IU/mL at Week 48; and no treatment-emergent Grade ≥3 elevations in ALT level by Week 12.9

Results through Week 144 in participants who received BIC/FTC/TAF in both study phases3

Through Week 144 in the OLE, among participants who continued BIC/FTC/TAF during the randomized phase, rates of HIV-1 RNA and HBV DNA suppression remained high
(Figure 2), and rates of ALT normalization and HBeAg and HBsAg loss/seroconversion were maintained (Figure 3).

Figure 2. ALLIANCE: HIV-1 and HBV Suppression With BIC/FTC/TAF Through Week 144 (M=E)3

Note: Analysis was performed on the full analysis set (N=119) of participants who received BIC/FTC/TAF in both study phases; the denominators were the number of participants without missing data at each time point.

Figure 3. ALLIANCE: HBV Outcomes With BIC/FTC/TAF Through Week 144 (M=Ea)3

aHBeAg and HBsAg loss/seroconversion were assessed in the full analysis set (N=90 for HBeAg; N=119 for HBsAg) of participants who received BIC/FTC/TAF in both study phases. Denominators were the number of participants without missing data at Week 144.

bAmong participants with ALT level >ULN at baseline, this was defined as a reduction in ALT level to ≤ULN.

cParticipants who experienced a loss of serum HBeAg/HBsAg and whose baseline HBeAb/HBsAb was negative or missing.

dParticipants who had a loss of serum HBeAg/HBsAg and whose serum HBeAb/HBsAb changed from negative or missing at baseline to positive at a post-baseline study visit.

OLE phase results through Week 144 in participants who switched to BIC/FTC/TAF4

Among the 89 participants who switched from DTG + FTC/TDF to BIC/FTC/TAF at Week 96, rates of HIV-1 RNA and HBV DNA suppression were maintained through Week 144 (48 weeks of BIC/FTC/TAF treatment) in the OLE (Figure 4).

Figure 4. ALLIANCE: HIV-1 and HBV Suppression Through Week 144 in the OLE Among Participants Who Switched to BIC/FTC/TAF at Week 96 (M=E)4

Note: Analysis was performed on full analysis set (N=89) of participants who switched to BIC/FTC/TAF from DTG + FTC/TDF; the denominators were the number of participants without missing data at each time point.

Of the 27 participants with abnormal ALT levels at the time of switching to BIC/FTC/TAF (Week 96), approximately half had achieved ALT normalization within 12 weeks of BIC/FTC/TAF treatment (51.9% [14/27]) and this was maintained through 48 weeks of treatment (Week 144: 13/25; 52%). HBV-related outcomes at Week 144 are summarized in Table 2.

Table 2. ALLIANCE: HBV-Related Outcomes at Week 144 in the OLE Among Participants Who Switched to BIC/FTC/TAF at Week 964

Note: HBeAg/HBsAg loss/seroconversion analyses were performed in the serologically available full analysis set, which included participants who were HBeAg/HBsAg positive and HBeAb/HBsAb negative or with missing data at baseline (HBeAg, n=52; HBsAg, n=77).

aParticipants who changed from positive HBeAg/HBsAg at baseline to negative at a post-baseline visit and whose baseline HBeAb/HBsAb was negative or missing.

bParticipants who had a loss of serum HBeAg/HBsAg and whose serum HBeAb/HBsAb changed from negative or missing at baseline to positive at a post-baseline study visit.

Resistance results

Through Week 96, no HIV-1 treatment‑emergent resistance was detected in the BIC/FTC/TAF arm. One participant in the DTG + FTC/TDF arm with known nonadherence developed K70E and M184V/I mutations. No HBV amino acid substitutions associated with TAF or TDF resistance were detected through Week 48.2

Resistance analyses using the last-observation-carried-forward method were conducted through Week 144 in participants who met the criteria for post-baseline resistance testing and who did not achieve virological resuppression (HIV-1 RNA <50 c/mL). The criteria for post‑baseline resistance testing were as follows: virologic failure (HIV-1 RNA ≥50 c/mL at last on-treatment visit; confirmed HIV-1 RNA ≥50 c/mL after achieving HIV-1 RNA <50 c/mL; or confirmed >1 log10 increase from nadir HIV-1 RNA) plus HIV-1 RNA ≥200 c/mL at confirmation visit or HIV-1 RNA ≥200 c/mL at the end of the randomized phase, end of study, or at the last on-treatment visit. Through Week 144, rates of HIV-1 RNA <50 c/mL were high regardless of the presence of primary RAMs at baseline. At the end of the randomized phase (Week 96), 7 participants (5.7%) in the DTG + FTC/TDF arm met the criteria for the resistance analysis. Through Week 144, 6 participants (5%) who received BIC/FTC/TAF throughout the study and 1 participant (1.1%) who switched to BIC/FTC/TAF met the criteria for the resistance analysis. No treatment‑emergent primary RAMs were detected, and no participant developed resistance to study drugs.10

Safety results

Through Week 96, most AEs were Grade 1 or 2 in severity, rates of drug-related AEs were similar between the BIC/FTC/TAF and DTG + FTC/TDF arms (29% and 28%, respectively), and the rate of hepatic AEs was 24% in both arms. The most common (≥5% of participants in either arm) TRAEs in the BIC/FTC/TAF and DTG + FTC/TDF arms were weight increase (8% vs 10%) and ALT increase (2% vs 7%). One AE led to discontinuation in the BIC/FTC/TAF arm (HCC on Day 1115). One SAE (cryptococcal meningitis) was reported as drug related (attributed to immune reconstitution inflammatory syndrome) in the BIC/FTC/TAF arm.2

Through Week 144, among participants who received BIC/FTC/TAF in both study phases, most TEAEs were Grade 1 or 2 in severity. The most common drug-related TEAEs were weight increased (7%), and abnormal weight gain, ALT increased, dyslipidemia, and headache (each, 3%). The most common (≥5% of participants) Grade 3/4 laboratory abnormalities included increased ALT and AST levels (>5 × ULN) in 23% and 13% of participants, respectively; increased fasting LDL levels (9%); and increased amylase levels (8%). Seven participants (6%) had confirmed ALT flares (treatment-emergent ALT elevations at ≥2 post-baseline study visits); the flares occurred during the first 3 months in 6 participants. All events were deemed to be not related to treatment, nonserious, and nearly all resolved in <3 months; 1 participant had an ALT flare for 116 days.3

Among participants who switched to BIC/FTC/TAF, drug-related TEAEs occurred in 19% of participants during the OLE (through Week 144), with weight gain (9%) and increased LDL cholesterol level (3%) being the most common. Grade 3/4 drug-related AEs occurred in 3 participants (3%) and consisted of abnormal weight gain (n=2) and hyperlipidemia (n=1). Fasting hypercholesterolemia was the only Grade 3/4 laboratory abnormality that occurred in >1 participant (n=3; 3%). No AEs led to discontinuation of BIC/FTC/TAF after participants switched from DTG + FTC/TDF. Small median increases in eGFR (+6.6 mL/min) and total and LDL cholesterol levels (+17 mg/dL and +19 mg/dL, respectively) were observed from OLE baseline (Week 96) to Week 144, and 3 participants (3.4%) initiated lipid-lowering medications. Other metabolic parameters remained stable after participants switched.4

BEST-HBV: Phase 4, Open-Label, Single-Arm Study5

A phase 4 study evaluated the efficacy and safety of switching to BIC/FTC/TAF in adults with HIV and HBV. The primary endpoints were the proportion of participants who achieved HIV-1 RNA <50 c/mL by FDA Snapshot algorithm and HBV DNA <29 IU/mL by M=F analysis at Week 24. Most participants were male (86%), were Black or African American (89%), and had HIV-1 RNA <50 U/mL (71%) and HBV DNA <29 IU/mL (79%) at baseline.

Figure 3. BEST-HBV: Primary Efficacy Endpoints5

Of the 35 AEs reported, 10 were TRAEs (all mild in severity). Nausea was the most common TRAE (n=2; 7%). No participant experienced SAEs, discontinued BIC/FTC/TAF due to AEs, or experienced flares of hepatitis.

Phase 3 Registrational Studies: Studies 1490 and 1878

Two registrational studies (Study 1490 and Study 1878) allowed participants with HIV and HBV to be included. Sixteen participants (<3%) with HIV and HBV were randomly assigned to receive BIC/FTC/TAF in these clinical trials.6

Of the 320 ARV-naïve adults randomly assigned to receive BIC/FTC/TAF in Study 1490, 8 had HIV and HBV at screening. At Week 144, 5 of these participants had HBV DNA <29 IU/mL and HIV-1 RNA <50 c/mL. The other 3 participants had missing HBV DNA data at Week 144. No hepatic AEs, Grade 3 or 4 AEs, or treatment interruptions or discontinuations due to AEs were reported in these participants with HIV/HBV co-infection.7

Of the 290 virologically suppressed adults randomly assigned to receive BIC/FTC/TAF in Study 1878, 8 had HIV and HBV at screening, and all had HBV DNA <29 IU/mL at baseline. At Week 48, all 8 participants maintained HBV DNA <29 IU/mL and HIV-1 RNA <50 c/mL. The participants were HBsAg+ at baseline and Week 48.6 Safety outcomes in participants with HIV and HBV were not analyzed separately. In the overall study population, BIC/FTC/TAF was well tolerated, with 1% discontinuing due to AEs and most TRAEs being mild or moderate in severity.8

References

1. Enclosed, Gilead Sciences Inc. BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use. US Prescribing Information. Foster City, CA.
2. Avihingsanon A, Lu H, Leong CL, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 and hepatitis B coinfection (ALLIANCE): a double-blind, multicentre, randomised controlled, phase 3 non-inferiority trial [Main Article + Supplementary Appendix]. The Lancet HIV. 2023:1-13.
3. Avihingsanon A, Leong CL, H. C-C, et al. Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) in Treatment-Naïve People With Both HIV-1 and Hepatitis B: 3-Year Outcomes From ALLIANCE [Poster 373]. Paper presented at: HIV Glasgow; November 10–13, 2024; Glasgow, UK.
4. Avihingsanon A, Leong CL, Hung C, et al. ALLIANCE Open-Label Extension: Switch to B/F/TAF in People With Both HIV-1 and HBV [Poster 666]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 9-12, 2025; San Francisco, CA.
5. Kwakwa H, Bran J, Ruff J, Choe S, Chua JV. Efficacy, Safety, and Tolerability Bictegravir/Emtricitabine/Tenofovir Alafenamide in Adults HIV-HBV Coinfection (BEST-HBV Study) Interim Week 24 Results [Poster]. Paper presented at: IDWeek; 19-23 October, 2022; Washington, DC.
6. Rockstroh JK, Sax PE, Daar ES, et al. High HBV and HIV Suppression With Treatment of HIV/HBV Coinfection in B/F/TAF Studies [Poster 618]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 04-07 March, 2018; Boston, MA.
7. 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.
8. 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.
9. Avihingsanon A, Lu H, Leong CL, et al. Factors Associated With HBV Response to B/F/TAF Versus DTG + F/TDF at Week 96 in People With HIV-1 and HBV [Poster 732]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO.
10. D’Antoni ML, Boopathy AV, Andreatta K, et al. HIV-1 Resistance Analysis of Treatment-Naïve People With HIV and HBV Receiving B/F/TAF or DTG + F/TDF. [Poster #735]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 9–12, 2025; San Francisco.

Abbreviations

AASLD=American Association for the Study of Liver Diseases
AE=adverse event
ARV=antiretroviral
BIC=bictegravir
c/mL=copies/mL
CD4=clusters of differentiation 4
DTG=dolutegravir
FTC=emtricitabine
GT=genotype
HBeAb=hepatitis B envelope antibody
HBeAg=hepatitis B envelope antigen
HBsAb=hepatitis B surface antibody
HBsAg=hepatitis B surface antigen
HCC=hepatocellular carcinoma
M=E=missing equals excluded
M=F=missing equals failure
OLE=open-label extension
RAM=resistance-associated mutation
SAE=serious adverse event
TAF=tenofovir alafenamide
TDF=tenofovir disoproxil fumarate
TEAE=treatment-emergent adverse event
TRAE=treatment-related adverse event
ULN=upper limit of normal

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.

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