Efficacy and Safety of Switching to Daily Bictegravir Plus Lenacapavir From a Complex HIV Treatment Regimen: A Randomized, Open-Label, Multicenter Phase 2 Study (ARTISTRY-1)

Abstract

Once-daily single-tablet regimens (STRs) are the global standard for human immunodeficiency virus (HIV) treatment [1] and have been shown to further improve clinical outcomes and quality of life (QoL) compared with more complex regimens [2, 3]. However, many people with HIV (PWH) in the United States are prescribed complex treatment regimens [4] for reasons including drug resistance, intolerance, toxicity, drug-drug interactions, or contraindications to existing STRs [1, 5, 6]. These regimens have a higher pill burden, which can affect QoL and may be associated with lower levels of treatment adherence compared with STRs [2, 3, 7–10].

Current guidelines recommend treatment optimization to maintain viral suppression without putting future treatments at risk [1, 11]. However, this can be challenging in PWH with virologic suppression and for whom antiretroviral therapy (ART) was not effective. Approaches that reduce the number or dosing frequency of antiretroviral drugs or avoid the use of pharmacokinetic boosters—which have a high potential for interactions with other medications—are therefore warranted [1, 11].

A fixed-dose combination of bictegravir (BIC) and lenacapavir (LEN) could be a viable alternative in PWH with virologic suppression who do not meet the label indication criteria for treatment with currently available STRs. BIC is an integrase strand transfer inhibitor with a high barrier to resistance [12] that is approved for the treatment of HIV infection as a component of the fixed-dose combination of BIC/emtricitabine/tenofovir alafenamide. LEN is a first-in-class capsid inhibitor without documented de novo resistance in the absence of prior exposure, which can be administered subcutaneously or orally [13, 14] and has no clinically relevant interactions with most other antiretroviral drugs, including BIC.

ARTISTRY-1 is a phase 2/3 study evaluating the efficacy and safety of switching from complex ART regimens to BIC and LEN among virologically suppressed PWH. ARTISTRY-1 is the first study evaluating once-daily LEN in this clinical setting; previous LEN studies included treatment-naïve participants [13] or viremic (viral load ≥400 copies/mL for ≥8 weeks before screening) participants with multidrug-resistant HIV-1 [14]. Here, we report data from the phase 2 dose-finding part of the study evaluating the efficacy and safety of switching to BIC + LEN versus continuing on a complex ART regimen through 24 weeks.

METHODS

Study Design and Participants

ARTISTRY-1 (GS-US-621-6289; NCT05502341) is an ongoing operationally seamless, randomized, open-label, multicenter, active-controlled phase 2/3 study. In the phase 2 part of the study, participants were from Australia, Canada, the Dominican Republic, Puerto Rico, and the United States. Eligible participants were ≥18 years old, had virologic suppression (plasma HIV-1 RNA <50 copies/mL) for ≥6 months before screening, and had been on a stable complex ART regimen for ≥6 months because of previous viral resistance, intolerance, or contraindication to existing STRs. Reasons for being on a complex ART regimen were documented for each participant at baseline based on available clinical information and at investigator discretion. A complex ART regimen was defined as one containing a boosted protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor plus ≥1 other third agent from a class other than nucleos(t)ide reverse transcriptase inhibitors, a regimen of ≥2 pills per day or one requiring dosing more than once daily, or one containing a parenteral agent or agents as well as oral agents (thus excluding a complete long-acting injectable regimen).

Participants were required to have a Cockcroft-Gault estimated glomerular filtration rate of ≥15 mL/min, not be on renal replacement therapy, and have no documented or suspected resistance to BIC. Participants assigned female at birth and of childbearing potential who engaged in heterosexual intercourse were required to use contraception. Those with prior exposure to LEN or chronic hepatitis B virus infection were excluded (complete exclusion criteria are listed in the Supplementary Methods).

In the phase 2 dose-finding part of the study, participants were randomized 2:2:1 to receive BIC 75 mg + LEN 25 mg or BIC 75 mg + LEN 50 mg or to continue with their complex ART regimen for ≥24 weeks (until the last participant completed the week 24 visit). Randomization was performed using an interactive response technology system at the time of consent. Single-agent BIC and LEN tablets were coadministered once daily as separate tablets orally, regardless of food intake. Participants in the BIC + LEN groups received an observed oral loading dose of LEN 600 mg on days 1 and 2 to achieve a rapid peak plasma concentration of the drug, in addition to the daily doses of BIC + LEN starting on day 1.

This study was conducted in accordance with the Declaration of Helsinki and was approved by central or site-specific institutional review boards or independent ethics committees. Site-specific institutional review board/independent ethics committee numbers are provided in the Supplementary Methods. All participants provided written informed consent.

Outcomes and Assessments

Outcomes

In the phase 2 part of the study, the primary end point was the proportion of participants with HIV-1 RNA ≥50 copies/mL at week 24, as determined by the US Food and Drug Administration (FDA) Snapshot algorithm [15]. Key secondary end points included the proportion of participants with HIV-1 RNA <50 copies/mL at week 24 (FDA Snapshot algorithm), the change in CD4 cell count from baseline at week 24, and the proportion of participants with adverse events (AEs) up to week 24. Other efficacy evaluations included virologic suppression throughout 24 weeks.

Assessments

After the day 1 visit, participants completed study visits on day 2 (to confirm intake of oral loading dose for participants on BIC + LEN) and at weeks 4, 12, and 24 and every 12 weeks thereafter. HIV-1 RNA viral load was assessed using whole-blood samples collected on day 1 and at weeks 4, 12, and 24 and every 12 weeks thereafter. Participants were considered to have virologic rebound if at any visit after the day 1 visit they had HIV-1 RNA ≥50 copies/mL subsequently confirmed at the following scheduled or unscheduled visit or if they had HIV-1 RNA ≥50 copies/mL at study drug discontinuation. HIV-1 resistance testing was performed in the case of confirmed virologic rebound with HIV-1 RNA ≥200 copies/mL. Adherence to BIC + LEN through the 24-week visit was measured based on pill count.

Statistical Analysis

All efficacy data and available cumulative safety data through week 24 are included in the analyses. Efficacy end points were analyzed for the full analysis set, which included all randomized participants who received any dose of the study drugs. Participants were grouped according to the treatment to which they had been randomized. Safety end points were analyzed using the safety analysis set, which included all randomized participants who received any dose of the study drugs.

For analyses relating to the proportions of participants with HIV-1 RNA ≥50 or <50 copies/mL at week 24, 2-sided 95% confidence intervals (CIs) for the difference between each of the BIC + LEN groups and the complex ART regimen group were constructed based on an unconditional exact method using 2 inverted 1-sided tests [16]. P values for these comparisons were based on the Fisher exact test.

CD4 cell counts were summarized using observed, on-treatment data for participants in the full analysis set. Changes from baseline in CD4 cell counts for each treatment group at week 24 were compared using an analysis-of-covariance model, including baseline CD4 cell count as a covariate and treatment as a fixed effect. Differences (including 95% CIs) in least squares mean changes from baseline for CD4 cell count were provided (ie, differences between each of the BIC + LEN groups and the complex ART regimen group). In the phase 2 part of this study, all statistical tests were 2 sided and evaluated at the significance level of .05, with no multiplicity adjustment.

RESULTS

Participants and Treatments

The first participant was screened on 16 August 2022. In total, 162 participants were screened, and 128 were randomized (Figure 1). Fifty-one participants received BIC 75 mg + LEN 25 mg, 52 received BIC 75 mg + LEN 50 mg, and 25 continued on a complex ART regimen. All 128 participants were included in the full and safety analysis sets. The last participant had the final week 24 visit on 13 July 2023. Overall, 18.8% of participants were female at birth, 30.5% were Black, and 15.9% were Hispanic or Latine; their median age (range) was 60 (26–79) years (Table 1).

Figure 1.

Participant disposition. One participant on bictegravir (BIC) 75 mg + lenacapavir (LEN) 50 mg discontinued the study drugs because of an adverse event, but the corresponding record was not entered in the database at the time of database finalization. Among the 33 patients who did not meet eligibility criteria, the most common reasons were (1) antiretroviral therapy (ART) regimen did not fit the complexity definition per protocol; (2) HIV-1 RNA viral load ≥50 copies/mL; and (3) exclusionary serologies that indicated chronic hepatitis B infection according to protocol.

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The median duration of HIV treatment (interquartile range [IQR]) was 27.0 (19.9–32.0) years, with a median of 6.0 (3.0–11.0) prior ARTs (Table 1). The most common reason for receiving a complex ART regimen was a history of resistance (81.3% of participants), followed by intolerance to components of STRs (29.7%), and contraindication to STRs (9.4%). Participants were receiving a broad range of complex ART regimens at baseline (Figure 2), the most common being a PI + integrase strand transfer inhibitor, either alone (18.8%) or with a nucleos(t)ide reverse transcriptase inhibitor (27.3%) or nonnucleoside reverse transcriptase inhibitor (17.2%). In total, 100 participants (78.1%) were on a stable baseline regimen that included a PI. At baseline, participants were on a median (range) of 2 (1–5) ARTs and were taking a median of 3 (2–9) pills per day, with 43.0%, 18.8%, 10.9%, and 27.3% of participants taking 2, 3, 4, or ≥5 pills per day, respectively (Table 1). Fifty-three participants (41.4%) were taking a baseline regimen that included twice-daily antiretroviral agents.

Figure 2.

Diversity of complex antiretroviral therapy regimens (safety analysis set). The most common regimens are shown in italics for the top regimen categories; this is not an exhaustive list. Percentages do not sum to 100% due to rounding. Abbreviations: AI, attachment inhibitor; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; ETR, etravirine; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; MVC, maraviroc; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor; PI, protease inhibitor; RPV, rilpivirine; TAF, tenofovir alafenamide.

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Baseline characteristics and demographics were generally similar across groups. Two participants in the BIC 75-mg + LEN 50-mg group had screening HIV-1 RNA <50 copies/mL, but day 1 and baseline HIV-1 RNA measurements of 86 and 90 copies/mL, respectively. These participants had been on a complex ART regimen for >46 and >10 months, respectively. Adherence to BIC + LEN through the week 24 visit was high in both groups, with median (IQR) on-treatment adherence of 99.4% (98.2%–100.0%) in the BIC 75-mg + LEN 25-mg group and 99.7% (98.8%–100.0%) in the BIC 75-mg + LEN 50-mg group.

Virologic Outcomes

At week 24, HIV-1 RNA was ≥50 copies/mL in 0 of 51 participants in the BIC 75-mg + LEN 25-mg group, 1 of 52 (1.9%) in the BIC 75-mg + LEN 50-mg group, and 0 of 25 in the complex ART regimen group (primary end point; FDA Snapshot algorithm; Figure 3). One participant receiving BIC 75 mg + LEN 50 mg had HIV-1 RNA ≥50 copies/mL (178 copies/mL) at week 24 that later (by week 36) decreased to <50 copies/mL without a change in regimen. No HIV-1 genotyping/phenotyping was performed, as no participants met the protocol-defined threshold of HIV-1 RNA >200 copies/mL.

Figure 3.

Virologic outcome at week 24 (US Food and Drug Administration Snapshot algorithm; full analysis set). The differences (Δ) in percentage (95% CI) in bictegravir (BIC) + lenacapavir (LEN) compared with complex antiretroviral therapy (ART) regimen were calculated based on an unconditional exact method using 2 inverted 1-sided tests. P values were based on the Fisher exact test. Two participants in the BIC 75-mg + LEN 25-mg group had no virologic data in the week 24 window as both had discontinued the study drugs before the week 24 visit, 1 due to an adverse event (AE; grade 1 nausea) and 1 for other reasons. One participant in the BIC 75-mg + LEN 50-mg group had no virologic data in the week 24 window because they discontinued the study drugs before the week 24 visit due to an AE (grade 3 vomiting). Abbreviations: CI, confidence interval; HIV-1, human immunodeficiency virus.

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At week 24, 49 of 51 participants (96.1%), 50 of 52 (96.2%), and 25 of 25 (100.0%) maintained virologic suppression in the BIC 75-mg + LEN 25-mg, BIC 75-mg + LEN 50-mg, and complex ART regimen groups, respectively. One participant receiving BIC 75 mg + LEN 25 mg and another receiving BIC 75 mg + LEN 50 mg had no virologic data in the week 24 window as both had discontinued the study drugs because of an AE determined by the investigator to be related to the study drugs (grade 1 nausea and grade 3 vomiting, respectively), while 1 participant receiving BIC 75 mg + LEN 25 mg discontinued the study drugs for other reasons. All 3 participants had a final available HIV-1 RNA measurement of <50 copies/mL (at weeks 4, 12, and 4, respectively). Virologic suppression (<50 copies/mL [missing = excluded analysis]) was maintained at week 24 for 49 of 49 participants (100.0%), 50 of 51 (98.0%), and 25 of 25 (100.0%) in the BIC 75-mg + LEN 25-mg, BIC 75-mg + LEN 50-mg, and complex ART regimen groups, respectively.

CD4 cell counts and percentages remained stable through week 24. The median (IQR) change from baseline in CD4 cell count was 18 (−39 to 70), −16 (−80 to 93), and 42 (−36 to 90) cells/µL in the BIC 75-mg + LEN 25-mg, BIC 75-mg + LEN 50-mg, and complex ART regimen groups, respectively. The difference in least squares mean change from baseline for CD4 cell count (compared with a complex ART regimen) was 0 (95% CI, −71 to 70) for BIC 75 mg + LEN 25 mg and −13 (−84 to 58) for BIC 75 mg + LEN 50 mg. The median (IQR) percentage changes in CD4 cell counts were −0.1% (−2.2% to 1.3%), −0.6% (−2.4% to 2.0%), and 0.2% (−1.2% to 1.6%), respectively.

Safety

Through week 24, 39 (76.5%), 33 (63.5%), and 17 (68.0%) participants experienced ≥1 AE in the BIC 75-mg + LEN 25-mg, BIC 75-mg + LEN 50-mg, and complex ART regimen groups, respectively (Table 2); 4 (7.8%), 2 (3.8%), and 1 (4.0%), respectively, experienced a grade ≥3 AE, 1 of which was considered related to the study drugs (worsening of vomiting in a participant with a history of vomiting and diabetes mellitus).

Two (3.9%), 1 (1.9%), and 2 (8.0%) participants in the BIC 75-mg + LEN 25-mg, BIC 75-mg + LEN 50-mg, and complex ART regimen groups, respectively, had experienced a serious AE (SAE) by week 24, all considered unrelated to the study drugs, with no SAEs leading to study discontinuation. After week 24, within the FDA Snapshot algorithm analysis window, 1 additional unrelated SAE was reported for each BIC/LEN group (1 case each of anxiety and coronary artery disease).

By week 24, 1 participant in the BIC 75-mg + LEN 25-mg group had discontinued treatment due to grade 1 nausea on day 1, whereas 1 participant in the BIC 75-mg + LEN 50-mg group with a history of diabetes mellitus and a 3-year history of recurrent episodes of nausea and vomiting had discontinued treatment due to grade 3 worsening of vomiting; both AEs were considered related to the study drugs. One death in the BIC 75-mg + LEN 50-mg group occurred after week 24; this was due to coronary artery disease and was unrelated to the study drugs.

AEs with a frequency of ≥5% in any treatment group by Preferred Term by week 24 were coronavirus disease 2019, diarrhea, hypertension, constipation, cough, and nasopharyngitis. All were grade 1 or 2, apart from 1 occurrence of grade 3 diarrhea (unrelated to the study drugs). New or worsening hypertension events were reported in 4 participants (7.7%) in the BIC 75-mg + LEN 50-mg group (2 of whom had a history of hypertension) and 1 (4.0%) in the complex ART regimen group. All were assessed as unrelated to the study drugs or complex ART regimen.

At week 24, median changes from baseline in blood pressure and body weight were small and not clinically significant (Supplementary Table 1). Grade 3 or 4 laboratory abnormalities occurred in 6 (11.8%), 12 (23.1%), and 8 (32.0%) participants in the BIC 75-mg + LEN 25-mg, BIC 75-mg + LEN 50-mg, and complex ART regimen groups, respectively, through week 24. The most common are listed in Supplementary Table 2. All laboratory abnormalities through week 24 were either consistent with participants’ medical history or transient.

DISCUSSION

This is the first randomized study evaluating the efficacy and safety of a once-daily combination of BIC and LEN in virologically suppressed PWH and the first to evaluate once-daily LEN in those receiving complex ART treatment regimens. BIC + LEN was highly effective in maintaining virologic suppression over 24 weeks in participants switching from a complex regimen. BIC 75 mg + LEN 25 mg and BIC 75 mg + LEN 50 mg were well tolerated and had similar safety profiles, supporting a switch to BIC + LEN in PWH with virologic suppression.

Participants were treatment-experienced, virologically suppressed PWH who were receiving a multitablet and/or multidrug complex regimen. The study population was relatively diverse: 19% were female, and 30% were Black. As expected, based on the requirement to be on a complex ART regimen, participants had a relatively long duration of HIV treatment (median, 27 years) and included a substantial proportion (41%) taking a twice-daily baseline regimen, as well as those with prior exposure to a high number of ARTs (median, 6). Since rates of drug resistance typically increase with treatment duration [17], it is unsurprising that >80% of participants reported a history of antiretroviral resistance, with a further 29.7% reporting intolerance to components of STRs and 9.4% reporting contraindications to STRs. Consequently, this population is likely to face particular challenges related to the complexity of their treatment, including decreased adherence and poorer QoL [2, 3, 7, 10].

Both long-term safety and convenience are important considerations when optimizing ART. Many participants were receiving complex ART regimens that included a boosted PI, which may be associated with metabolic complications and an increased incidence of drug interactions [18]. A fixed-dose treatment regimen combining BIC and LEN, both of which have a comparatively low potential for drug interactions, could simplify treatment for PWH who are on complex ART regimens, without compromising virologic suppression or overall health [19, 20]. Notably, the median age was 60 years; correspondingly, most participants had ≥1 comorbidity known to be associated with older age (including dyslipidemia and diabetes). Furthermore, the study enrolled individuals with an estimated glomerular filtration rate ≥15 mL/min, making the BIC + LEN combination a potential regimen for aging PWH with chronic kidney disease.

Based on these phase 2 data, a BIC 75-mg/LEN 50-mg STR regimen will be assessed in phase 3 of the ARTISTRY-1 study. A small, once-daily, fixed-dose combination BIC/LEN tablet could offer a new option for individuals for whom resistance and/or intolerability to other antiretroviral agents have made currently available STRs unsuitable, potentially leading to greater adherence and improved QoL.

Study limitations include: the open-label design, limited number of participants, and limited follow-up time; the lack of assessment of whether participants preferred BIC + LEN to their previous ART regimen; and the fact that adherence was measured by pill count. Additional long-term evidence of the efficacy and safety of switching to BIC and LEN is needed, together with studies on treatment adherence and QoL.

In conclusion, in this phase 2 dose-finding study, the combination of BIC + LEN was highly effective in maintaining virologic suppression, as expected for a population without BIC resistance or prior LEN exposure. Treatment was well tolerated, with similar safety profiles observed in the 2 BIC + LEN treatment groups. These data support the evaluation of a fixed-dose STR combination of BIC and LEN to optimize treatment in virologically suppressed PWH receiving complex ART regimens, which may offer additional benefits for this population.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The authors thank all participants and their families, participating sites, investigators, and study staff involved in the study. They also thank Hal Martin for clinical research support. 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 Joanna Nikitorowicz-Buniak, PhD, and Anna Chapman-Barnes, PhD, at Aspire Scientific Limited (Bollington, UK) and was funded by Gilead Sciences, Inc. (Foster City, California).

Author Contributions. K. M., J. Slim, M. R., M. H., M. B., J. Santana, and S. S. M. contributed to data collection; I. M., Y. G., P. A., J. M. M. R., and P. S. contributed to study design and data analysis or interpretation; and J. M. B. contributed to study design. All authors contributed to drafting or revising of the manuscript, provided approval of the final manuscript for submission, and agree to be accountable for all aspects of the work.

Financial support. This work was supported by Gilead Sciences, Inc.

Data sharing statement. Gilead Sciences, Inc., shares anonymized individual patient data on 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 [email protected].

Potential conflicts of interest. K. M. has received speaker honoraria from and has participated on a data safety monitoring board or advisory board with Epividian, Gilead Sciences, Inc., Janssen Therapeutics, Merck, and ViiV Healthcare. J. Slim has received speaker honoraria from Gilead Sciences, Inc., Janssen Therapeutics, Merck, and ViiV Healthcare. M. R. has received consulting fees from AbbVie, Gilead Sciences, Inc., Merck, and ViiV Healthcare and speaker honoraria from AbbVie, Gilead Sciences, Inc., and ViiV Healthcare. M. H. has received speaker honoraria and travel support from and has participated on a data safety monitoring board or advisory board with Gilead Sciences, Inc., Merck, and ViiV Healthcare. M. B. has participated on advisory boards with and has received travel support and speaker honoraria from Gilead Sciences, Inc., and ViiV Healthcare. J. Santana has received speaker honoraria from AbbVie, consulting fees from AbbVie Global Consulting, and research funding from Chem Bio Diagnostics and Moderna Vaccine Therapeutics. I. M., Y. G., P. A., J. M. M. R., P. S., and J. M. B. are employees and shareholders of Gilead Sciences, Inc. S. S. M. has received speaker honoraria from Gilead Sciences, Inc.; has participated in advisory boards with and received consulting fees from Gilead Sciences, Inc., Janssen Therapeutics, Theratechnologies Inc., and ViiV Healthcare; and has received travel support from Gilead Sciences, Inc., Janssen Therapeutics, and ViiV Healthcare.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

Author notes