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. 2024 Oct 6;26(2):302–307. doi: 10.1111/hiv.13721

Bictegravir/emtricitabine/tenofovir alafenamide in adults with HIV‐1 and end‐stage kidney disease on chronic haemodialysis

Joseph J Eron 1, Moti Ramgopal 2, Olayemi Osiyemi 3, Mehri Mckellar 4, Jihad Slim 5, Edwin DeJesus 6, Priyanka Arora 7, Christiana Blair 7, Jason T Hindman 7,✉, Aimee Wilkin 8
PMCID: PMC11786611  PMID: 39370144

Abstract

Introduction

Treatment for people with HIV‐1 and end‐stage kidney disease (ESKD) on haemodialysis (HD) has previously required complex dose‐adjusted regimens, with limited data on the use of a single‐tablet regimen in this population. Our aim was to assess the efficacy and safety of once‐daily bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) and to evaluate the pharmacokinetics of bictegravir (BIC) in adults with HIV‐1 and ESKD on HD.

Methods

We performed an open‐label extension (OLE) of an open‐label, multicentre, single‐group phase 3b study (NCT02600819) of adults with ESKD on HD and HIV‐1 with virological suppression. Participants switched to elvitegravir/cobicistat/F/TAF (E/C/F/TAF) 150/150/200/10 mg for 96 weeks, following which a subgroup of US participants entered an OLE phase in which they switched to B/F/TAF 50/200/25 mg for 48 weeks, returning for study visits at weeks 4 and 12, and every 12 weeks thereafter. Study assessments included virological response, safety and pharmacokinetic analysis of BIC.

Results

Ten participants entered the OLE (median age, 55 years). Virological suppression (HIV‐1 RNA <50 copies/mL) was maintained in all participants over 48 weeks of B/F/TAF treatment. B/F/TAF was well tolerated, with no treatment discontinuations. Mean BIC trough concentrations were lower than those previously reported for people with HIV‐1 with normal kidney function, but remained four‐ to seven‐fold higher than the established protein‐adjusted 95% effective concentration against wild‐type HIV‐1.

Conclusion

These findings support the use of the once‐daily B/F/TAF single‐tablet regimen for people with HIV‐1 and ESKD on HD. This regimen offers a convenient treatment option for this population as it reduces the need for dose adjustment, eases pill burden and avoids potential drug–drug interactions associated with alternatives that may impact individuals on multiple medications or awaiting transplantation.

Keywords: B/F/TAF, end‐stage kidney disease, haemodialysis, HIV‐1, pharmacokinetics, safety

INTRODUCTION

Improvements in HIV‐1 treatment have resulted in an ageing population at increased risk of age‐related comorbidities including kidney disease [1, 2, 3]. People with HIV‐1 are at risk of kidney disease from several causes, including medication‐associated nephrotoxicity, HIV‐associated nephropathy and non‐HIV‐associated conditions such as diabetes and hypertension [4]. However, treatment for people with HIV‐1 and end‐stage kidney disease (ESKD) on haemodialysis (HD) has previously required complex dose‐adjusted regimens, with limited data on single‐tablet regimens (STRs) [5, 6, 7].

Phase 3 studies have demonstrated favourable renal/bone safety with tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in people with HIV‐1 [8]. TAF and TDF are prodrugs of the active metabolite tenofovir (TFV), but TAF achieves higher levels of intracellular TFV‐diphosphate in HIV target cells at lower doses compared with TDF; this enables effective treatment with ~90% lower systemic TFV exposure in people with normal kidney function [9].

We conducted a phase 3b study showing that a daily STR of elvitegravir/cobicistat/emtricitabine (FTC)/TAF (E/C/F/TAF) 150/150/200/10 mg was well tolerated and maintained high rates of virological suppression in participants with HIV‐1 and ESKD on chronic HD [7]. Both FTC and TFV are renally eliminated, and increased exposures have been observed in adults with kidney impairment [10]. As expected, daily E/C/F/TAF in this study resulted in higher FTC and TFV exposures relative to individuals with HIV‐1 with healthy renal function [7]. The overall adverse event profile was consistent with that expected for the study population (medically complex with ESKD) [7].

The study protocol was subsequently amended to allow eligible US participants to enrol in an open‐label extension (OLE) with bictegravir (BIC)/F/TAF (B/F/TAF) 50/200/25 mg after week 96 to assess the efficacy and safety of B/F/TAF, and the pharmacokinetics (PK) of BIC, in adults with HIV‐1 and ESKD on HD.

We present the results of the OLE after 48 weeks of B/F/TAF treatment. To our knowledge, this was the first clinical trial to evaluate B/F/TAF in adults with HIV‐1 and ESKD on HD.

METHODS

Study design and participants

Study GS‐US‐292‐1825 (NCT02600819) was a phase 3b, open‐label, multicentre, single‐group study in Europe and the US. Detailed eligibility criteria and methods were described previously [7]. Participants were ≥18 years old with HIV‐1 and ESKD [estimated glomerular filtration rate calculated using the Cockcroft–Gault equation (eGFRCG) <15 mL/min] on chronic HD for ≥6 months before screening, and required to be virologically suppressed (HIV‐1 RNA <50 copies/mL) on a stable antiretroviral treatment regimen for ≥6 consecutive months before screening, with a CD4 cell count ≥200 cells/μL and no documented HIV‐1 resistance to E/C/F/TAF components. In the main study, participants received E/C/F/TAF 150/150/200/10 mg STR once daily for ≥96 weeks.

The protocol was amended to include an OLE phase in which US participants remaining in the study after 96 weeks had an option to discontinue E/C/F/TAF and switch to B/F/TAF 50/200/25 mg STR (oral, daily, without regard to food) and after HD, for 48 weeks. Participants returned for visits at weeks 4, 12 and every 12 weeks thereafter.

This study was conducted in accordance with the Declaration of Helsinki and approved by central or site‐specific review boards/ethics committees. All participants provided written informed consent.

Outcomes

Plasma trough concentrations (Ctrough) of BIC were determined on HD days at weeks 4, 24 and 48. A sparse‐timed blood sample was to be collected from all participants within 10 min prior to HD initiation; pre‐dose (≤30 min prior to study drug administration) blood samples were also collected at these visits. Based on established BIC PK, only samples collected within 20–28 h after the previous dose were included for trough PK assessment (if participants had multiple values at the same time, the within‐person mean was calculated before calculating the group mean). Virological response was evaluated by the proportion of participants with HIV‐1 RNA <50 copies/mL by visit, and the change from baseline in CD4 cell count and percentage by visit. Safety was assessed by recording adverse events (AEs), coded using the Medical Dictionary for Regulatory Activities version 22.0, and by haematological analysis and serum chemistry tests. Adherence to B/F/TAF was calculated by pill count. The HIV Treatment Satisfaction Questionnaire, status version (HIV‐TSQs) and 36‐Item Short Form Survey (SF‐36) were administered at weeks 4, 24 and 48.

Statistical analysis

Descriptive statistics summarized changes from baseline in CD4 count and percentage, safety and laboratory data (including lipid panel and glucose under fasting conditions), and PK data. HIV‐1 virological response was evaluated using a ‘missing = excluded’ (M = E) approach.

RESULTS

Demographics and disease characteristics at OLE baseline

Of 55 participants enrolled in the main study, 10 entered the B/F/TAF OLE phase (Figure S1). One continued E/C/F/TAF beyond week 108 and switched to B/F/TAF at week 120. All 10 received one or more dose of B/F/TAF and were included in the B/F/TAF plasma PK analysis, full analysis and safety analysis sets. The OLE participants were predominantly male at birth and black, with median age 55 years and median (range) baseline CD4 count of 563 (385–827) cells/μL (Table S1). At enrolment, participants had received HD for a median (range) of 4 (2–16) years. The median (range) duration of exposure to B/F/TAF on study was 48 (47–52) weeks.

Virological outcomes

At week 48 of the OLE, 100% (10/10) of participants (95% confidence interval: 69.2–100%) maintained virological suppression, with all measured HIV‐1 RNA values <50 copies/mL throughout the study. CD4 counts (Figure S2) and percentages remained relatively stable through week 48. The median (range) change from baseline to week 48 (n = 9) in CD4 count was −121 (−296–45) cells/μL and 1.5% (−5.2–8.8%) for CD4 percentage.

Safety

All participants had one or more AE during the OLE; most were grade 1/2 in severity, including one participant with study drug‐related grade 2 nausea and grade 1 malaise. None led to discontinuation of study drug (Table S2). One participant had multiple grade 3 AEs and three participants had serious AEs; none were considered related to the study drug. No deaths were reported.

There were no clinically relevant changes in median values for haematology or clinical chemistry parameters from baseline through 48 weeks. Median serum values for amylase, blood urea nitrogen, lipase, parathyroid hormone, creatinine and phosphate were outside the normal reference range (at baseline/post‐baseline), as is characteristic of ESKD [11, 12]; otherwise, median values were generally within the relevant reference ranges. Fifty percent of participants had at least one grade ≥3 laboratory anomaly (Table S2).

Pharmacokinetics

In a small subset of participants with evaluable data collected at trough, mean (range) (percentage coefficient of variation) BIC Ctrough values were 919 ng/mL (293.5–1810 ng/mL) (83.1%), 674 ng/mL (288–1060) (81.0%) and 1097 ng/mL (632–1510) (40.2%) at weeks 4 (n = 5), 24 (n = 2) and 48 (n = 3), respectively. Ctrough values for BIC were lower compared with the historical mean (percentage coefficient of variation) value of 2610 ng/mL (35.2%) observed in a larger pool of adults with HIV‐1 with normal kidney function or mild‐to‐moderate kidney impairment (n = 1193) [13]. However, BIC Ctrough remained four‐ to seven‐fold higher than the protein‐adjusted 95% effective concentration (paEC95) of 162 ng/mL against wild‐type HIV‐1 for BIC (Figure 1) [13].

FIGURE 1.

FIGURE 1

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Concentration of bictegravir (BIC) [bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) plasma pharmacokinetics (PK) analysis set]. aMean of sparse timed PK and trough/pre‐dose values where both samples were collected at the same time. bUS Food and Drug Administration. Office of clinical pharmacology review–BIKTARVY [14]. paEC95, protein‐adjusted 95% effective concentration; SD, standard deviation.

Treatment adherence and patient‐reported outcomes

Median (range) treatment adherence through week 48 was 88.5% (76.1–99.1%). At week 48, all participants were satisfied or very satisfied with every aspect of their treatment (HIV‐TSQs; Figure 2). Treatment satisfaction score remained stable through week 48, with median (range) baseline (n = 10) and week 48 (n = 9) scores of 58 (52–60) and 59 (51–60), respectively. SF‐36 mental and physical component summary scores remained relatively stable through week 48 (Table S3).

FIGURE 2.

FIGURE 2

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HIV treatment satisfaction at week 48 [HIV Treatment Satisfaction Questionnaire, status version (HIV‐TSQs); bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) safety analysis set]. aFor question 2: well controlled and very well controlled; for question 5: convenient and very convenient; for question 6: flexible and very flexible; for question 9: ‘Yes, I would recommend the treatment’ and ‘Yes, I would definitely recommend the treatment’. The survey was completed by 9 of 10 participants at week 48.

DISCUSSION

The mean BIC Ctrough values observed during B/F/TAF treatment in people with HIV‐1 and ESKD on chronic HD here were lower than those reported in people with HIV‐1 with normal kidney function; however, they remained four‐ to seven‐fold higher than the established paEC95 against wild‐type HIV‐1 [13]. This is consistent with the efficacy observed here, with all participants maintaining virological suppression over 48 weeks of the OLE. CD4 counts/percentages remained relatively stable through week 48; differences in median values are unlikely to be clinically meaningful given that virological suppression was maintained and are probably explained by variability due to the limited number of participants. B/F/TAF was well tolerated, with no treatment discontinuations. While all participants experienced one or more AE during the OLE, with one participant experiencing multiple grade 3 AEs and three participants experiencing serious AEs, this is to be expected given the high rate of comorbidities in a population with ESKD. No grade ≥3 AEs or serious AEs were considered related to study drug.

Given that BIC is primarily metabolized through the liver [14], BIC exposures were expected to be similar in the study population compared with people with HIV‐1 with normal kidney function; however, BIC exposure data in the current study were from a limited number of participants (n ≤ 5 per analysis window) and the observed BIC trough concentrations, for example, had large ranges (from <300 to >1800 ng/mL) across visits. It is possible that non‐adherence to study drug may have contributed to some of the lower individual BIC exposures observed. A larger sample size would likely have given more precise estimates.

In the phase 1b study for BIC, the lowest dose (5 mg once daily) resulted in a BIC Ctrough of 1.4‐fold of the paEC95 (225 ng/mL), which is lower than in the current study, yet led to a robust reduction in mean (SD) plasma HIV‐1 viral load of ~1.45 (0.10) log10 copies/mL through day 11 [15]. Considering that all participants maintained virological suppression through week 48 of the OLE, the lower BIC Ctrough levels in the current study compared with people with HIV‐1 with normal kidney function are not likely to be clinically relevant.

Exposures of FTC, TAF and TFV were not measured during the OLE, but were measured as components of E/C/F/TAF as part of the larger main study of E/C/F/TAF and reported previously [7].

Based on these study results, B/F/TAF was approved in Europe and the US for people with HIV and eGFR <15 mL/min on chronic HD [14, 16], and is recommended in the US Department of Health and Human Services guidelines for people with HIV and eGFR <30 mL/min on chronic HD [17]. B/F/TAF offers an alternative to E/C/F/TAF for individuals with ESKD on chronic HD and receiving multiple non‐HIV medications or awaiting transplantation, due to the potential for drug–drug interactions with cobicistat in these individuals.

This study focused on a specific population of individuals with HIV‐1 and ESKD on chronic HD, for whom limited clinical data exist. Limitations include the exclusion of people on peritoneal dialysis and results cannot be extrapolated to this group. Given that participants included in the OLE had successfully completed at least 96 weeks of treatment of E/C/F/TAF in the main study, results may also not be generalizable to all people with HIV‐1 and ESKD on HD. Additionally, the number of participants was small (n = 10) and only a subset had evaluable PK data at each time point. The study had no control group, potentially leading to a reduced ability to distinguish background and study drug‐related AEs. These limitations reflect the challenges associated with studies in this population.

CONCLUSION

These findings support the use of once‐daily B/F/TAF STR for people with HIV‐1 and ESKD on chronic HD. This offers a convenient option for treatment of HIV‐1 in this population, reducing the need for dose adjustment, easing pill burden and limiting the risk of potential drug–drug interactions.

AUTHOR CONTRIBUTIONS

CB designed the study; JJE, MR, OO, MM, JS, ED and AW obtained the data; all authors were involved in data analysis or interpretation, and reviewed, critically revised and approved the content of the manuscript.

FUNDING INFORMATION

This study was funded by Gilead Sciences, Inc.

Supporting information

Data S1. Supporting information.

HIV-26-302-s001.docx (122.3KB, docx)

ACKNOWLEDGEMENTS

We thank all participants and their families, participating sites, investigators and Gilead Sciences study staff, including Polina German for clinical pharmacology support for the main study and Christoph C. Carter, Diana M. Brainard, Sean E. Collins and Hal Martin for clinical research support for the open‐label extension. This work was supported by Gilead Sciences, Inc. (Foster City, CA, USA). Medical writing support including development of a draft outline, and subsequent drafts in consultation with the authors, collating author comments, copyediting, fact checking and referencing was provided by Anne Errichelli, DPhil, and Victoria Warwick, PhD, at Aspire Scientific (Bollington, UK) and funded by Gilead Sciences, Inc.

Eron JJ, Ramgopal M, Osiyemi O, et al. Bictegravir/emtricitabine/tenofovir alafenamide in adults with HIV‐1 and end‐stage kidney disease on chronic haemodialysis. HIV Med. 2025;26(2):302‐307. doi: 10.1111/hiv.13721

DATA AVAILABILITY STATEMENT

Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation with qualified external researchers based on submitted curriculum vitae and reflecting non‐conflict of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Sciences' discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1. Supporting information.

HIV-26-302-s001.docx (122.3KB, docx)

Data Availability Statement

Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation with qualified external researchers based on submitted curriculum vitae and reflecting non‐conflict of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Sciences' discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com.

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