Biktarvy® (BIC/FTC/TAF)

Coadministration With Rifamycins

This document is in response to your request for information regarding the coadministration of Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide [BIC/FTC/TAF]) with rifamycins, specifically rifampin or rifampicin (RIF) and rifapentine (RPT).

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

Coadministration of BIC/FTC/TAF with RIF is contraindicated due to the effect of RIF on the BIC component. Coadministration with rifabutin or RPT is not recommended.

BIC is a substrate of CYP3A and UGT1A1. A drug that is a strong inducer of CYP3A and also an inducer of UGT1A1 can substantially decrease the plasma concentrations of BIC. TAF is a substrate of P-gp. Coadministration of drugs that induce P-gp activity is expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF. A decrease in the plasma concentrations of BIC or TAF may lead to loss of therapeutic effect of BIC/FTC/TAF and development of resistance.

Coadministration of RIF, a strong inducer of CYP3A and P-gp and inducer of UGT1A1, with BIC/FTC/TAF is contraindicated due to decreased BIC plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to BIC/FTC/TAF. Coadministration of BIC/FTC/TAF with rifabutin or RPT is expected to decrease BIC and TAF concentrations.

Clinical Studies of BIC/FTC/TAF With Rifamycins

In a phase 2b, open-label, randomized controlled study, adults with HIV and TB who received BIC/FTC/TAF twice daily concomitantly with a RIF-based treatment regimen for TB had a high rate (95%) of viral load suppression at Week 24. Most AEs were Grade 1 or 2.2

In a multicenter, retrospective cohort study in adults with HIV on RPT‑based treatment regimens for LTBI, ≥96.5% of participants in the BIC/FTC/TAF groups maintained HIV-1 RNA <200 c/mL within 12 months of LTBI treatment. Most AEs were Grade 1 or 2.3

In a phase 1, open-label study, BIC/FTC/TAF twice daily in combination with daily RIF resulted in 60%, 14%, and 20% reductions in BIC, TAF, and TFV AUC0-24h, respectively, compared with BIC/FTC/TAF daily.4,5

In a phase 1, open-label study, coadministration of RIF with FTC/TAF decreased intracellular TFV-DP concentrations by 36% compared with FTC/TAF alone.6

In a phase 1, open-label study, Cτ of BIC decreased up to 83% after weekly RPT administration versus BIC/FTC/TAF alone, and the Cτ never returned to steady state between RPT doses. The effects of weekly RPT on the PK of FTC, TAF, TFV, and TFV-DP compared with BIC/FTC/TAF alone were not considered clinically significant.7

Clinical Studies of BIC/FTC/TAF Use With Rifamycins

CAPRISA 093 INSIGHT: BIC/FTC/TAF Twice Daily With RIF

Study design2,8

A phase 2b, open-label, non-comparative, randomized controlled study evaluated the efficacy, safety, and PK of BIC/FTC/TAF 50/200/25 mg twice daily in adults (n=80) with HIV and TB who received a RIF-based treatment regimen for TB. In the non-comparative control arm, participants (n=42) received treatment with DTG/3TC/TDF once daily + DTG 50 mg at night. Participants in both arms received concomitant treatment with a RIF‑based TB treatment for 24 weeks, remained on their respective ARV regimen for an additional 2 weeks after TB treatment was stopped, then continued the once-daily dosing of their ARV regimen (BIC/FTC/TAF or DTG/3TC/TDF) until Week 48.

Results2

Virologic suppression (HIV-1 RNA <50 c/mL) at Week 24 (primary endpoint) was similar between the BIC/FTC/TAF (95%; 95% CI: 87–98%) and DTG/3TC/TDF (95%; 95% CI: 81–‍99%) arms. No treatment failures (VL >400 c/mL at Week 24 or Week 48) were reported.

All participants reported an AE. The majority were Grade 1 or 2. There were no treatment discontinuations, withdrawals, or drug switches due to AEs. SAEs were reported in 9 participants (11%) in the BIC/FTC/TAF arm and 3 (7%) in the DTG/3TC/TDF arm. Grade 3 and 4 AEs were reported in 30 participants (38%) and 6 (8%), respectively, in the BIC/FTC/TAF arm and in 15 participants (36%) and 6 (14%) in the DTG/3TC/TDF arm.

BIC Cτ levels were reduced during TB treatment (Weeks 4 and 12 geometric mean [CV%], 0.397 mg/L [73.4%]) compared with after TB treatment (Week 32 geometric mean [CV%], 2.29 mg/L [45.1%]) but mostly remained above the inhibitory quotient of 0.162 mg/L.

PK substudy9

A nested PK substudy was conducted in adults who received BIC/FTC/TAF (N=43) with and without RIF. Plasma and DBS were collected pre-dose and through 12 hours post-dose at Weeks 4 and 12 (during RIF‑based TB treatment) and through 24 to 25 hours post-dose at Week 32 (after TB treatment had been completed).

During the BIC/FTC/TAF twice-daily + RIF dosing period, exposure values for plasma TFV and TFV-DP exposures were higher than when BIC/FTC/TAF was administered once daily
(Table 1).

Table 1. CAPRISA 093 INSIGHT PK Substudy:
Plasma TFV and Intracellular TFV-DP PK Parameters9

an=40. bn=39. cn=41

Note: AUC0–24h for BIC/FTC/TAF twice daily + RIF was calculated by multiplying the extrapolated AUC0–12h by 2.

BIC/FTC/TAF With RPT-Based Regimens for LTBI3

A multicenter, retrospective cohort study was conducted in 479 PWH who were given 3 months of weekly RPT plus isoniazid (3HP) or 1 month of daily RPT plus isoniazid (1HP) in combination with ART. The primary outcome was the virologic response (HIV-1 RNA <200 c/mL) rate in the ITT and PP populations. A total of 142 patients received 1HP and BIC/FTC/TAF (1HP/BIC group) and 38 received 3HP and BIC/FTC/TAF (3HP/BIC group). Overall, 97.9% of patients achieved HIV-1 RNA <200 c/mL before LTBI treatment.

In the ITT analysis, 96.5% of patients (137/142) in the 1HP/BIC group and 100% (38/38) in the 3HP/BIC group maintained HIV-1 RNA <200 c/mL within 12 months after completing LTBI treatment. Completion rates were 95.8% and 97.4% in the 1HP/BIC and 3HP/BIC groups, respectively. In the PP analysis, 131/131 patients in the 1HP/BIC group and 37/37 in the 3HP/BIC group maintained HIV-1 RNA <200 c/mL within 12 months after LTBI treatment completion.

Most AEs were Grade 1 or 2. Grade 3 AEs were reported in 16 patients (7.8%) and 7 (2.6%) in the 1HP and 3HP groups, respectively. One Grade 4 hepatotoxicity event related to acute HCV was reported in the 1HP group. Discontinuations due to AEs occurred in 13/205 patients (6.3%) and 21/274 (7.7%) in the 1HP and 3HP groups, respectively.

PK of BIC and TAF Twice Daily in Combination With RIF4,5

Study design

A phase 1, open-label, parallel-design, single-center study evaluated the safety, tolerability, and PK of BIC/FTC/TAF 50/200/25 mg once daily (Cohort 1; n=26) vs BIC/FTC/TAF 50/200/25 mg twice daily plus RIF 600 mg once daily (Cohort 2; n=26) in healthy volunteers.

Results

Daily BIC exposure measured by AUC0–24h was expected to be 60% lower in Cohort 2 than in Cohort 1 (Table 2). Mean BIC Cτ was reduced by 80% in Cohort 2 vs Cohort 1. After this ~80% reduction is accounted for, individuals who receive BIC/FTC/TAF twice daily in combination with RIF once daily may fall below the paEC95 of BIC (162 ng/mL).4 In Cohort 2, AUC0–24h was expected to be reduced by <15% for TAF, ~20% for TFV, and ~24% for intracellular PBMC-associated TFV-DP vs Cohort 1.5 The study authors concluded that BIC/FTC/TAF STR should not be used in combination with RIF.

Table 2. PK of BIC, TAF, and TFV (Custudio et al)4,5

All healthy volunteers completed the study. Treatment-emergent AEs occurred in 31% in Cohort 1 and 39% in Cohort 2. All AEs were mild or moderate and resolved during the study. No Grade 3 or 4 AEs and no laboratory abnormalities were observed.

PK of Daily BIC/FTC/TAF With Weekly RPT7

Study design

A phase 1, open-label, multiple-dose study was conducted in 30 HIV‑negative, healthy volunteers to determine how RPT affects the PK, safety, and tolerability of BIC/FTC/TAF. BIC/FTC/TAF was given on Days 1 through 8 and Days 15 through 30, with a washout period on Days 9 through 14. RPT was dosed once weekly starting on Day 15; it was given with BIC/FTC/TAF on Days 15 and 22 (co-dosed) and 12 hours before BIC/FTC/TAF on Day 29 (staggered).

Results

Compared with BIC/FTC/TAF alone, RPT given with BIC/FTC/TAF reduced the Cτ of BIC by 35% to 83%. Cτ did not return to steady state between RPT doses. After the ~83% reduction in BIC Cτ was accounted for, individuals who receive BIC/FTC/TAF daily + RPT once weekly may fall below the paEC95 of BIC (162 ng/mL). Thus, study investigators did not recommend BIC/FTC/TAF to be used in combination with once-weekly dosing of RPT.

There was a greater decline in BIC Cτ with staggered dosing in comparison to that observed when co-dosed (Table 3). The effects of RPT on the PK of FTC, TAF, TFV, and TFV-DP compared with BIC/FTC/TAF given alone were not considered to be clinically significant.

Table 3. BIC Plasma PK Parameter Estimates (Arora et al)7

Most AEs were Grade 1. One Grade 3 AE of neck pain considered unrelated to study drugs was reported. Treatment-emergent AEs occurred at a higher frequency in those who received BIC/FTC/TAF + RPT (48%) vs BIC/FTC/TAF alone (27%). No SAEs and no clinically significant or Grade ≥3 laboratory abnormalities were reported.

PK of FTC/TAF Administered in Combination With RIF6

Study design

A phase 1, open-label, single‑center study was conducted in 23 HIV-negative, healthy volunteers to assess the PK, safety, and tolerability of FTC/TAF, FTC/TAF + RIF, and TDF. Healthy volunteers received FTC/TAF 200/25 mg once daily for 28 days, given with a standard meal containing 20 g of fat content. For the next 28 days (Days 29–56), participants received RIF 600 mg daily, given 30 minutes before a standard meal, followed by FTC/TAF 200/25 mg. On Day 57, participants discontinued FTC/TAF + RIF and began receiving TDF 300 mg monotherapy daily, given with a standard meal on Days 57 to 84.

Results

Compared with FTC/TAF, FTC/TAF + RIF decreased the plasma TAF Cmax by 50% and the TAF AUC0–24h by 55%; intracellular TFV-DP Cmax decreased by 38%, and AUC0–24h decreased by 36%. However, intracellular TFV-DP concentrations were 4‑fold higher with FTC/TAF + RIF than with TDF monotherapy (Table 4). RIF coadministration did not alter plasma FTC or intracellular FTC‑triphosphate concentrations.

Table 4. Summary of PK Parameters (Cerrone et al)6

FTC/TAF, FTC/TAF + RIF, and TDF monotherapy were well tolerated. Two AEs (both Grade 3) were reported, and no Grade 4 AEs were observed. There were 2 discontinuations: 1 case of transient ALT increase, deemed unlikely to be TAF-related by the study investigators, and 1 case of Grade 2 gastrointestinal symptoms, deemed RIF‑related by the study investigators.

References

1. Enclosed, Gilead Sciences Inc. BIKTARVY® (bictegravir, emtricitabine, and tenofovir

alafenamide) tablets, for oral use. U.S. Prescribing Information. Foster City, CA.

2. Naidoo A. Efficacy, Safety, and PK of BIC/FTC/TAF in Adults With HIV and Tuberculosis on Rifampicin at Week 24 [Oral Abstract Session-14]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO.
3. Lin KY, Sun HY, Yang CJ, et al. Treatment responses to integrase strand-transfer inhibitor-containing antiretroviral regimens in combination with short-course rifapentine-based regimens for latent tuberculosis infection among people with HIV. Clin Infect Dis. 2023:1-9.
4. Custodio JM, West SK, Vu A, et al. Pharmacokinetics of Bictegravir Administered Twice Daily In Combination With Rifampin [Presentation 34]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 04-07 March, 2018; Boston, MA.
5. Custodio J, West SK, Lutz J, et al. Twice Daily Administration of Tenofovir Alafenamide in Combination with Rifampin: Potential for Tenofovir Alafenamide Use in HIV-TB Coinfection [Presentation]. Paper presented at: European AIDS Clinical Society (EACS); 25-27 October, 2017; Milan, Italy.
6. Cerrone M, Alfarisi O, Neary M, et al. Rifampicin Effect on Intracellular and Plasma Pharmacokinetics of Tenofovir Alafenamide. J Antimicrob Chemother. 2019;74(6):1670-1678.
7. Arora P, Collins SE, Martin H, et al. Drug Interactions With Once-Daily B/F/TAF in Combination With Once-Weekly Rifapentine [Poster 1401]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual.
8. Naidoo A, Dooley KE, Naidoo K, et al. INSTIs for the management of HIV-associated TB (INSIGHT study): a phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of bictegravir, emtricitabine and tenofovir alafenamide fumarate for the treatment of HIV-1 infection in patients with drug-susceptible tuberculosis on a rifampicin-based treatment regimen: a phase 2b open-label randomised controlled trial. BMJ Open. 2022;12(11):1-9.
9. Osuala EC, Nkuhairwe IN, Letsoalo MP, et al. Pharmacokinetics of Twice-Daily TAF in Adults with HIV-Associated TB on BIC/FTC/TAF and RIFAMPICIN [Poster #647]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 9-12, 2025; San Francisco.

Abbreviations

3TC=lamivudine
AE=adverse event
ARV=antiretroviral
ART=antiretroviral therapy
AUC0–12/24h=area under the concentration-time curve from time 0 to 12/24 hours
BIC=bictegravir
c/mL=copies/mL
CAPRISA=Centre for the AIDS Programme of Research in South Africa
CD4=cluster of differentiation 4
Cmax=maximum concentration
Cτ=trough concentration
CV=coefficient of variation
DBS=dried blood spots
DTG=dolutegravir
FTC=emtricitabine
GLSM=geometric least squares mean
GMR=geometric mean ratio
LTBI=latent tuberculosis infection
P-gp=permeability glycoprotein
paEC95=protein-adjusted 95% effective concentration
PBMC=peripheral blood mononuclear cells
PK=pharmacokinetic(s)
PP=per protocol
RIF=rifampin or rifampicin
RPT=rifapentine
SAE=serious adverse event
STR=single-tablet regimen
TAF=tenofovir alafenamide
TB=tuberculosis
TDF=tenofovir disoproxil fumarate
TFV=tenofovir
TFV-DP=tenofovir diphosphate


 

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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