Biktarvy® (BIC/FTC/TAF)

Use in Severe Renal Impairment and Hemodialysis

This document is in response to your request for information regarding Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide [BIC/FTC/TAF]) and its use in patients with severe renal impairment, including hemodialysis (HD).

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

BIC/FTC/TAF is not recommended in individuals with: severe renal impairment (estimated CrCl of 15 to <30 mL/min); or ESRD (estimated CrCl <15 mL/min) who are not receiving chronic HD; or no ARV treatment history and ESRD who are receiving chronic HD.

Clinical Data on BIC/FTC/TAF Use in Severe Renal Impairment and HD

In participants with eGFR <15 mL/min on HD who switched from E/C/F/TAF to BIC/FTC/TAF in the OLE period of a phase 3b study (Study 1825)2:

• All participants who switched to BIC/FTC/TAF (n=10) maintained HIV‑1 RNA <50 c/mL at Week 48 (M=E analysis). Most AEs were Grade 1 or 2 in severity.
• Mean BIC concentrations were lower in PWH on HD than PWH not on HD, but BIC trough levels were 4- to 7-fold higher than the BIC paEC95 in phase 3 studies.

In a phase 1 study, BIC AUC∞ was approximately 27% lower in participants with an eGFR of 15 to 29 mL/min than in healthy volunteers with normal renal function. No correlation was observed between the AUC∞ or Cmax and eGFRCG. Overall, BIC was well tolerated.3

In a case series of 6 patients on HD who switched to BIC/FTC/TAF-containing regimens, all patients achieved or maintained virologic suppression, and no patients reported AEs.4

Clinical Data on BIC/FTC/TAF Use in Severe Renal Impairment and HD

Study GS-US-292-1825: BIC/FTC/TAF in PWH With ESRD on Chronic HD2

Study design and demographics

A phase 3b, open-label, multicenter, single-arm study was conducted to evaluate the safety, tolerability, PK, and efficacy of E/C/F/TAF in virologically suppressed PWH with ESRD (eGFR <15 mL/min) on chronic HD for ≥6 months. Participants switched from their current ARV regimen to E/C/F/TAF, administered as one tablet once daily, and received treatment for 96 weeks. Following regulatory approval of BIC/FTC/TAF by the FDA, the study protocol was amended to allow eligible US participants to switch to BIC/FTC/TAF in the OLE phase (N=10).

During the OLE, BIC/FTC/TAF safety was assessed by AEs and laboratory abnormalities; efficacy was assessed by the proportion of participants who were virologically suppressed (HIV‑1 RNA <50 c/mL) according to M=E analysis, and PK sampling was conducted at Weeks 4, 24, and 48.

The median (range) age of participants who switched to BIC/FTC/TAF was 55 (34–63) years. The median (IQR) eGFRCG at BIC/FTC/TAF start was 11.6 (7.8–14.6) mL/min, and the median (range) time on HD was 4 (2–16) years.

Virologic outcomes at Week 48

BIC/FTC/TAF maintained HIV-1 RNA <50 c/mL in all 10 participants (100%) according to M=E analysis. No participants met the criteria for resistance testing. The median (IQR) change in CD4 count from baseline to Week 48 (n=9) was ‑121 (‑144 to -21) cells/mcL.

The median (range) duration of exposure to BIC/FTC/TAF was 48 (47–52) weeks. Four participants had missing data at Week 96 of the E/C/F/TAF phase but were virologically suppressed at baseline of the OLE phase with BIC/FTC/TAF. One of these participants continued E/C/F/TAF through Week 108 and switched to BIC/FTC/TAF at Week 120.

PK results at Week 48

Mean BIC concentrations were lower in participants on HD than in those who were not on HD. Trough concentrations for BIC stayed 4- to 7‑fold higher than the paEC95 against wild‑type virus that was established from phase 3 studies.

While participants were on E/C/F/TAF, FTC and TFV exposures were higher in participants on HD than historical data from PWH with normal or mild/moderately impaired renal function. TFV levels were lower than historical data when using dose‑adjusted TDF in participants on HD. FTC levels were consistent with historical data observed in participants on HD. When compared with the ranges of historical data for PWH with normal renal function, TAF exposures were consistent (Table 1).

Table 1. Study 1825: TAF and FTC PK Results During E/C/F/TAF Treatment2

Abbreviations: AUC=area under the curve; AUClast=area under the curve up to last measurable concentration; AUCτ=area under the curve over the dosing interval.

aIntensive PK analysis in phase 2 trial (Study 102) in PWH.

Safety results at Week 48

Safety profiles were consistent with historical data observed in participants on HD. Most AEs reported were Grade 1 or 2 (Table 2). None of the Grade ≥3 or serious AEs were considered study-drug related. No deaths or AE leading to discontinuation occurred.

Table 2. Study 1825: Summary of AEs and Laboratory Abnormalities2

aOne participant reported multiple Grade 3 AEs that were not considered treatment-related, including cardiac failure, abdominal wall hematoma, pneumonia, vascular access site hemorrhage, spinal stenosis, hypertensive emergency, and hypertensive urgency.

bOne participant reported nausea (Grade 2) and malaise (Grade 1).

cIncluded the following: increased amylase (n=2), increased creatinine (n=1), γ-glutamyltransferase (n=1), and serum potassium (hyperkalemia; n=1).

At Weeks 24 and 48, there were no clinically relevant changes from baseline in median fasting values for TC, LDL, HDL, TG, or the TC:HDL ratio. No participant initiated lipid‑lowering medications during the study.

HIV treatment satisfaction at Week 48

As measured by the HIV Treatment Satisfaction Questionnaire, 78% of participants (7/9) felt “very satisfied” with their current treatment after they switched to BIC/FTC/TAF. As measured by pill count, the median adherence at Week 48 was 89%.

Study of BIC in Participants With Severe Renal Impairment

Study design and demographics

A phase 1, open-label, single-dose, parallel-design study assessed the PK profile, safety, and tolerability of BIC in participants with severe renal impairment (CrClCG, 15–‍29 mL/min). Participants with chronic stable renal impairment not on dialysis (n=10) and healthy volunteers with CrClCG ≥90 mL/min (n=8) were eligible to participate in this study. At screening, all were required to have BMI values of 18 to 40 kg/m2. Participants with severe renal impairment were matched to healthy volunteers with normal renal function based on gender, age, and BMI. Participants and healthy volunteers received a moderate‑fat breakfast followed by a single dose of BIC 75 mg (not commercially available). PK assessments were conducted during the 144‑hour period after dose administration. Safety was assessed throughout the study and during the follow-up period.3,5

The mean (range) age was 62 (22–75) years in the severe renal impairment group and 56 (22–67) years in the normal renal function group. The mean (range) CrClCG was 24 (22–‍26) mL/min in the severe renal impairment group and 107 (90–131) mL/min in the normal renal function group.3

PK results3

The BIC AUC∞ was approximately 27% lower in participants with severe renal impairment than in healthy volunteers with normal renal function (Table 3). No correlation was observed between the AUC∞ or Cmax and eGFRCG.

Table 3. Summary of BIC PK Parameters3

Abbreviations: Fu=unbound fraction; GLSM=geometric least squares mean; Q=quartile; t1/2=terminal half-life.

Safety3

Overall, BIC was well tolerated, and all AEs were Grade 1 in severity. There were 2 AEs, 1 drug-related AE, and no serious AEs in each study group. There were 10 laboratory abnormalities in the severe renal impairment group (Grade 1/2/3: 2/4/4) and 4 in the normal renal function group (Grade 1/2/3: 2/2/0).

Case Series

There are limitations in the interpretation of case reports. Case reports cannot be generalized. Unlike controlled clinical trial, causality cannot be inferred based on uncontrolled observational data. In addition, incidence or prevalence cannot be estimated due to the lack of a representative population sample. Other limitations of case reports include the retrospective design and publication bias.6

BIC/FTC/TAF in patients on HD4

A retrospective, single-center case series identified 6 patients on HD who switched to BIC/FTC/TAF-containing regimens between January 2018 and October 2022. Patient demographics, laboratory parameters, ART regimens, and patient-reported QoL measures were obtained from medical records. (Table 4).

After switching to BIC/FTC/TAF, all patients achieved or maintained virologic suppression and no patients reported AEs. Patient 1 reported increased QoL post-switch.

Table 4. Case Series: Summary of Patients on HD Who Switched to BIC/FTC/TAF‑Containing Regimens4

Abbreviations: 2 ×/d=two times per day; 3 ×/d=three times per day; 3TC=lamivudine; AA=African American; ABC=abacavir; ATV=atazanavir; COBI=cobicistat; DDI=drug-drug interaction; DOR=doravirine; DTG=dolutegravir; EVG=elvitegravir; F=female; GI=gastrointestinal; INSTI-R=integrase strand transfer inhibitor resistance; M=male; NNRTI‑R=non-nucleos(t)ide reverse transcriptase inhibitor resistance; NRTI‑R=nucleos(t)ide reverse transcriptase inhibitor resistance; RPV=rilpivirine; RTV=ritonavir; ZDV=zidovudine.

aPatient 2 was admitted for a GI bleed and required initiation of proton pump inhibitor treatment, which is contraindicated with concomitant RPV.

bPatient 3 was receiving amlodipine and metoprolol tartrate, each of which had the potential to interact with COBI. The patient was also receiving calcium acetate supplementation, which interacts with EVG. There was also a potential for resistance to EVG.

cPatient 4 had a history of NRTI-R (M41L and M184V mutations), NNRTI-R (K103R, V179D, and G190A mutations). There was also an increased cardiovascular risk with ABC.

dPatient 5 had variable adherence to her ARV regimen, and self-discontinued ABC and TDF 2 months prior to the switch. She also had a history of NRTI-R (M184V), NNRTI-R (K103N), and INSTI-R (Q148 and G190S), and severe GI symptoms with protease inhibitors.

ePatient 6 had low-level viremia and occasionally had an undetectable viral load, no resistance, and no concerns for DDIs (calcium supplement dosing was separated from DTG). The patient was required to have an undetectable viral load prior to being considered for a kidney transplant.

fPatient 6 had two consecutive undetectable viral load measurements about 2.5 years after the regimen switch.

References

1. Enclosed, Gilead Sciences Inc. BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use. US Prescribing Information. Foster City, CA.

2. Eron JJ, Wilkin A, Ramgopal M, et al. A Daily Single-Tablet Regimen of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppress Adults Living With HIV and End-stage Renal Disease on Chronic Hemodialysis, [Poster 1002]. Paper presented at: IDWeek; October 21-25, 2020; Virtual.

3. Zhang H, Shao Y, Garner W, et al. The Effect of Hepatic or Renal Impairment on Bictegravir Pharmacokinetics [Poster 27]. Paper presented at: 18th International Workshop on Clinical Pharmacology of Antiviral Therapy; 14-16 June, 2017; Chicago, IL.

4. Sidman EF, Ondrush NM. Utilization of bictegravir/emtricitabine/tenofovir alafenamide in patients with end-stage renal disease on hemodialysis. Am J Health Syst Pharm. 2023;80(9):e92-e97.

5. ClinicalTrials.gov. Pharmacokinetics of Bictegravir in Adults With Normal and Impaired Renal Function. ClinicalTrials.gov Identifier: NCT02400307. Available at: https://clinicaltrials.gov/ct2/show/NCT02400307?term=NCT02400307. Accessed: 10 February 2021. Last Updated: 11 October. 2019.

6. Nissen T, Wynn R. The Clinical Case Report: A Review of Its Merits and Limitations. BMC Res Notes. 2014;7:264. https://www.ncbi.nlm.nih.gov/pubmed/24758689

Abbreviations

AE=adverse event
ARV=antiretroviral
AUC∞=area under the curve to time infinity
BIC=bictegravir
c/mL=copies/mL
Cmax=peak concentration
CG=Cockcroft–Gault equation
CV=coefficient of variation
E/C/F/TAF=elvitegravir/
cobicistat/emtricitabine/
tenofovir alafenamide
ESRD=end-stage renal disease
FTC=emtricitabine
HD=hemodialysis
M=E=missing=excluded
OLE=open‑label extension
paEC95=protein-adjusted 95% effective concentration
PK=pharmacokinetic(s)
PWH=people with HIV-1
QoL=quality of life
TAF=tenofovir alafenamide
TC=total cholesterol
TDF=tenofovir disoproxil fumarate
TFV=tenofovir
TG=triglycerides

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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