Lenacapavir-Containing Antiretroviral Therapy in the OPERA Cohort: Patterns of Use and Treatment Outcomes

Abstract

Lenacapavir (LEN), a twice-yearly injectable long-acting capsid inhibitor used in combination with an optimized background regimen, is indicated for heavily treatment-experienced adults with multi-drug-resistant HIV-1 infection. From the US Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, 116 adults with HIV with ≥1 set of LEN injections were included [baseline viral load (VL) <200 copies/mL = 74; ≥200 copies/mL = 42]. Many (56%) simplified their regimen at LEN initiation and/or later, and 31% maintained all the antiretrovirals (ARVs) from their prior regimen throughout LEN use. Among those with a baseline VL <200 copies/mL, the cumulative probability (Kaplan–Meier) of maintaining suppression to <200 copies/mL was 92% [95% confidence interval (CI): 80, 96]. Among those with a baseline VL ≥200 copies/mL, the cumulative probability of achieving suppression was 73% (95% CI: 59, 86). Among 78 individuals who received ≥2 sets of LEN injections, 82% received all sets of injections on time or early (≤28 weeks after the prior set) and 18% received ≥1 set late (>28 weeks after the prior set). The median delay was 11 days past the injection window (interquartile range: 4, 118). At study end, 91% remained on a LEN-containing regimen. In this cohort representative of routine clinical care in the United States, factors other than virologic control may be driving the decision to start LEN (e.g., safety, tolerability, resistance, simplification). Most people experienced favorable virologic outcomes and good adherence to LEN, which may serve as an effective option for those who could benefit from a long-acting injectable agent from a novel ARV class.

Keywords

adherence effectiveness heavily treatment experienced HIV lenacapavir

Introduction

People with HIV are considered to be heavily treatment experienced (HTE) when they have limited treatment options due to resistance, intolerance or safety concerns, and often require highly tailored regimens with less common antiretroviral (ARV) combinations.^1–8 Even with the availability of many classes of ARVs, HTE individuals may struggle to achieve or maintain virologic suppression due to numerous factors such as viral resistance, drug toxicity, poor adherence, excessive pill burden, poor tolerability, or drug–drug interactions.^2–5 Poor virologic outcomes, low CD4 cell counts indicative of an impaired immune system, and increased risks of death and AIDS defining events (ADE) have been reported among HTE individuals with multi-drug resistance.^7,9–18 HTE regimens may be challenging to manage due to potentially limited effectiveness in the setting of pre-existing resistance, complex dosing requirements, or undesirable toxicity, safety, or tolerability profiles.^7,19–24 Moreover, higher pill burden and demanding dosing schedules may lead to suboptimal ART adherence among HTE individuals.^25,26

Lenacapavir (LEN) is the first capsid inhibitor to be approved by the Food and Drug Administration (FDA; 22DEC2022) as a twice-yearly injectable.²⁷ LEN interferes with several stages of the HIV life cycle: nuclear uptake of pre-integration complexes, virion production, and capsid core formation.²⁸ When used in the management of HTE people with HIV in the United States, LEN in combination with other ARVs selected by the provider [i.e., optimized background regimen (OBR)] is indicated for individuals with multi-drug-resistant HIV-1 infection who are failing their current ARV regimen due to resistance, intolerance, or safety considerations.²⁹ LEN is initiated with a combination of injections and oral doses. A set of two maintenance LEN injections is then administered every 26 weeks, within a 2-week window before or after the due date.²⁹ It was approved by the FDA on the basis of the efficacy evidence from 72 HTE participants in the CAPELLA trial.^30–34 An indirect treatment comparison analysis found that after adjusting for viral load (VL), CD4 cell count, number of previous ARVs, and overall susceptibility score, the odds of viral suppression were 6 to 13 times higher with LEN + OBR (individual participant trial data), compared with ibalizumab (IBA) + OBR, fostemsavir (FTR) + OBR, or OBR alone (aggregated data from published studies).³⁵

The objectives of this study were to characterize people with HIV who started LEN injections during real-world, routine clinical care in the United States and to describe their patterns of LEN and OBR use, as well as their virologic and immunologic outcomes on LEN-containing regimens over the first 2 years since FDA approval.

Methods

Study population

This study utilized data from the Observational Pharmaco-Epidemiology Research & Analysis (OPERA^®) cohort, an electronic health record (EHR) database of prospectively collected health information from routine clinical care in the United States. At the time of this study, the OPERA cohort included 157,120 people with HIV from 103 clinics across 22 states and 1 territory, which represents approximately 14% of the people with HIV in the United States.

The OPERA database complies with all Health Insurance Portability and Accountability Act (HIPAA), Health Information Technology for Economic and Clinical Health (HITECH), and Health Information Trust Alliance (HITRUST) requirements, which expand upon the ethical principles detailed in the 1964 Declaration of Helsinki. The OPERA database received annual institutional review board (IRB) approval by Advarra IRB including a waiver of informed consent and authorization for use of protected health information.

For this study, all ART-experienced adults (aged ≥18 years) with HIV-1 who received their first set of LEN injections between December 22, 2022, and September 30, 2024, were included. Person-time was censored at the first of (1) loss to follow-up (12 months after the last clinical contact), (2) study end (December 31, 2024), (3) LEN discontinuation, or (4) death.

Measurements

A set of LEN injections was defined as 2× 1.5 mL injections administered on the same day, as noted in the EHR. The prior regimen was defined as the combination of ARVs documented 16 days prior to the first set of LEN injections, accounting for possible changes in ARVs occurring on Day 1 of the initiation sequence if the option to start injections on Day 15 was selected. The initial OBR was defined as the ARVs prescribed in combination with LEN on the same day as the first set of LEN injections. ARV changes from prior regimen to initial OBR or from initial OBR to subsequent OBR were categorized as a continuation, a simplification, or another type of change. A continuation occurred if all ARVs remained the same, excluding the addition of LEN. A simplification consisted of changes resulting in fewer ARV agents [including LEN, excluding pharmacokinetic (PK) boosting agents], fewer ARV classes (including LEN, excluding PK boosting agents), and/or fewer pills per day (excluding oral LEN at initiation). Other changes were those resulting in the same or a larger number of ARV agents, ARV classes, or pills per day. Subsequent changes after the initial OBR were not described individually but summarized across all changes (ever/never).

Achievement of virologic suppression was defined as the first follow-up VL <200 copies/mL among people with a VL ≥200 copies/mL at LEN start. Maintenance of virologic suppression was defined as all follow-up VLs <200 copies/mL among people with a VL <200 copies/mL at LEN start. A sensitivity analysis was conducted using a stricter virologic suppression threshold of <50 copies/mL, both at initiation and during follow-up.

Achievement of a CD4 cell count ≥200 cells/μL was defined as the first follow-up CD4 cell count ≥200 cells/μL among people with a CD4 cell count <200 cells/μL at LEN start. Maintenance of CD4 cell count ≥200 cells/μL was defined as all follow-up CD4 cell counts ≥200 cells/μL among people with a CD4 cell count ≥200 cells/μL at LEN start. Change in CD4 cell count over time since the first set of injections was estimated among people with a CD4 cell count measurement within 4 weeks before or after the second or third set of injections.

A set of injection was considered (1) early if received within <24 weeks after the prior set of injections, (2) on time if received within ≥24 to ≤28 weeks after the prior set of injections, and (3) late if received >28 weeks after the prior set of injections, thus requiring a reinitiation from Day 1 as per the label.²⁹ Discontinuation was considered to have occurred if no additional LEN injections were observed, with >28 weeks of follow-up between the last observed injection set and study end.

Statistical analyses

Population characteristics at the time of the first set of LEN injections, as well as changes in ARVs, were characterized for the entire study population using descriptive statistics. Virologic and immunologic effectiveness was assessed among those with any follow-up measurements of VL and CD4 cell count, respectively. Kaplan–Meier methods were used to assess the cumulative probability of achieving or maintaining virologic and immunologic outcomes. Patterns of adherence to the injection schedule were described among people with ≥2 sets of LEN injections, using descriptive statistics.

Results

Study population

A total of 116 adults with HIV received ≥1 set of LEN injections between December 22, 2022, and September 30, 2024. They were followed for a median of 58 weeks [interquartile range (IQR): 37, 78] after the first set of injections, and 36% had received only the first set of injections by study end (December 31, 2024). All had an LEN prescription prior to the first set of injections, suggesting that oral dosing was received.

Characteristics of LEN users are described in Table 1. The median age at LEN injection initiation was 54 years, and 75% were aged ≥42 years. Most had commercial insurance and/or Medicaid coverage. Most had been living with HIV for a long time, with half having been diagnosed ≥16 years before starting LEN; half had experienced at least one AIDS-defining event in the past, and 36% had uncontrolled HIV infection with a VL ≥200 copies/mL at LEN initiation, including 28% with a VL ≥1000 copies/mL.

Table 1.

Demographic and Clinical Characteristics at the First Set of Lenacapavir Injections

	Individuals with ≥1 set of LEN injectionsN = 116
Median age (IQR)	54 (42, 61)
Female sex, n (%)	26 (22)
Race, n (%)
Black	57 (49)
White	53 (46)
Mixed/other/unknown	6 (5)
Hispanic ethnicity, n (%)	15 (13)
Payer type,^a n (%)
Commercial Insurance	69 (59)
Medicaid	57 (49)
Medicare	43 (37)
Ryan White/ADAP	11 (9)
No payer data available	≤5^b
Years since HIV diagnosis, median (IQR)	16 (5, 25)
History of AIDS-defined events, n (%)	60 (52)
VACS index, median (IQR)	32 (18, 48)
CD4 cell count, n (%)
<200 cells/µL	27 (23)
≥200 to <500 cells/µL	46 (40)
≥500 cells/µL	43 (37)
Viral load, n (%)
<50 copies/mL	53 (46)
≥50 to <200 copies/mL	21 (18)
≥200 to <1000 copies/mL	10 (9)
≥1000 copies/mL	32 (28)

Payer categories are not mutually exclusive.

HIPAA regulations require the masking of cells with one to five individuals.

ADAP, AIDS Drug Assistance Program; IQR, interquartile range; LEN, lenacapavir; VACS, Veterans Aging Cohort Study; N, number.

Regimen characteristics before and during LEN use

At the time of LEN initiation, the median duration of the prior regimen was 49 weeks (IQR: 10, 121), and most (77%) were previously on a regimen including ≥2 anchor agents (i.e., integrase strand transfer inhibitors, protease inhibitors, non-nucleoside reverse transcriptase inhibitors, entry inhibitors). Both before and at LEN initiation, ART regimens were highly individualized, with a lot of variation in ARV combinations (Table 2). Most individuals maintained the same ARV agents from the prior regimen when they added LEN or maintained the same OBR after LEN start (Table 3). The baseline VL distribution was comparable between individuals who maintained their prior ARVs, those who simplified the regimen, and those who had other types of changes at the start of LEN. Among those who maintained their prior regimen when they started LEN, 49% experienced changes in their background regimen later during LEN use (simplification: 35%, other change: 14%). Overall, 36 individuals (31%) maintained the same ARVs from their prior regimen throughout their LEN use. A total of 65 individuals (56%) simplified their regimen either at LEN initiation (18%), later during LEN use (34%), or both (4%).

Table 2.

Characteristics of the Prior Antiretroviral Therapy Regimen and of the Optimized Background Regimen at the First Set of Lenacapavir Injections

	Prior regimenN = 116	OBR at LEN startN = 116
ARV class (excluding LEN), n (%)^a
Nucleoside reverse transcriptase inhibitor	73 (63)	61 (52)
Integrase strand transfer inhibitor	95 (82)	97 (84)
Non-nucleoside reverse transcriptase inhibitor	49 (42)	50 (43)
Protease inhibitor	53 (46)	40 (34)
Entry inhibitor	39 (34)	41 (35)
Number of anchor agents (excluding LEN)
1, n (%)	27 (23)	31 (27)
2, n (%)	59 (51)	59 (51)
≥3, n (%)	30 (26)	26 (22)
ARV combination (excluding LEN), n (%)
Cabotegravir + rilpivirine	18 (16)	26 (22)
Bictegravir/emtricitabine/tenofovir alafenamide	14 (12)	20 (17)
Any other (≤5 individuals per combination)	84 (72)	70 (60)
Duration of prior regimen, median weeks (IQR)	49 (10, 121)	NA

Not mutually exclusive.

ARV, antiretroviral; IQR, interquartile range; LEN, lenacapavir; N, number; NA, not applicable; OBR, optimized background regimen.

Table 3.

Changes in Antiretrovirals at Lenacapavir Initiation and During Lenacapavir Use

	OBR at LEN startN = 116	OBR(s) after LEN start^aN = 116
Continuation of regimen, n (%)	70 (61)	60 (52)
Simplification of regimen, n (%)^b	25 (22)	44 (38)
Fewer ARV agents (including LEN), n (%)	10 (40)	43 (98)
Fewer ARV classes (including LEN, excluding pharmacokinetic booster), n (%)	7 (28)	34 (77)
Fewer pills/days (excluding oral LEN at initiation), n (%)	24 (96)	38 (86)
Change of regimen without simplification, n (%)^c	20 (17)	12 (10)

Individuals with multiple changes are represented once in the table, with all changes considered (ever/never); median of 1 change per person (IQR: 1, 2).

Types of simplification are not mutually exclusive.

Change resulting in the same or a larger number of ARV agents, ARV classes, and pills/day.

ARV, antiretroviral; LEN, lenacapavir; N, number; OBR, optimized background regimen.

Virologic and immunologic outcomes

Among 69 individuals with a VL <200 copies/mL at LEN initiation and at least one follow-up VL measurement, the 12-month cumulative probability of maintaining virologic suppression at <200 copies/mL throughout follow-up was high at 92% (95% CI: 80, 96) (Fig. 1). Among 49 individuals with a baseline VL <50 copies/mL, 13 (26%) lost suppression at a median of 3.9 months after initiation (IQR: 2.5, 8.5), with a 12-month cumulative probability of maintaining suppression at <50 copies/mL of 78% (95% CI: 63, 88). Of note, 10 of the individuals who lost suppression (77%) had low-level viremia, as their VL remained <200 copies/mL.

FIG. 1.

Maintenance of virologic suppression among LEN users with a baseline viral load (VL) <200 copies/mL and ≥1 follow-up VL measurement (N = 69). CI, confidence interval; c/mL, copies/milliliters; IQR, interquartile range; LEN, lenacapavir. Excluding five individuals without any VL measurement during follow-up.

Among 39 individuals with a VL ≥200 copies/mL at LEN initiation and at least one follow-up VL measurement, the 12-month cumulative probability of achieving virologic suppression at <200 copies/mL was 76% (95% CI: 62, 88) (Fig. 2). Among 59 individuals with a baseline VL ≥50 copies/mL, 39 (66%) achieved suppression at <50 copies/mL at a median of 2.8 months after initiation (IQR: 1.0, 4.6), with a 12-month cumulative probability of 74% (95% CI: 59, 86).

FIG. 2.

Achievement of virologic suppression among LEN users with a baseline viral load (VL) ≥200 copies/mL and ≥1 follow-up VL measurement (N = 39). CI, confidence interval; c/mL, copies/milliliters; IQR, interquartile range; LEN, lenacapavir. Excluding three individuals without any VL measurement during follow-up.

Out of 106 individuals with ≥1 follow-up CD4 cell count, the proportion with a CD4 cell count ≥200 cells/μL increased from 75% at LEN initiation to 87% at their last measurement, a median of 20 weeks after the first set of LEN injections (IQR: 10, 27). Among individuals with a CD4 cell count <200 cells/μL at LEN start, the median change in CD4 cell count was +83 cells/μL (IQR: +27, +128) by the second set of injections, if available. Most individuals with a CD4 cell count ≥200 cells/μL at LEN start maintained a level at ≥200 cells/μL throughout follow-up, with a median change in CD4 cell count of +27 cells/μL (IQR: −63, +86) by the second set of injections, if available (Table 4).

Table 4.

Immunological Outcomes Among Individuals with ≥1 Follow-Up CD4 Cell Count

	Individuals with ≥1 follow-up CD4 cell countN = 106
CD4 cell count <200 cells/µL at LEN initiation, n (%)	26 (25)
Any follow-up CD4 ≥200 cells/µL, n (%)	12 (46)
12-month cumulative probability of achieving a CD4 ≥200 cells/µL, % (95% CI)	45 (26, 70)
Received a second set of injections and CD4 measured within ±4 weeks of injections, n (%)	9 (35)
Change from first to second set of injections, median cells/µL (IQR)	+83 (+27, +128)
CD4 cell count ≥200 cells/µL at LEN initiation, n (%)	80 (75)
All follow-up CD4 ≥200 cells/µL, n (%)	78 (98)
12-month cumulative probability of maintaining a CD4 ≥200 cells/µL, % (95% CI)	96 (86, 99)
Received a second set of injections and CD4 measured within ±4 weeks of injections, n (%)	42 (52)
Change from first to second set of injections, median cells/µL (IQR)	+27 (−63, +86)
Received a third set of injections and CD4 measured within ±4 weeks of injections, n (%)	20 (25)
Change from first to third set of injections, median cells/µL (IQR)	+37 (−65, +163)
Last measured follow-up CD4 ≥200 cells/µL, n (%)	92 (87)
Weeks from first set of injections to last CD4 measurement, median (IQR)	20 (10, 27)

CI, confidence interval; IQR, interquartile range; LEN, lenacapavir; N, number.

Injection adherence and persistence

Adherence and persistence were assessed among 78 individuals who received at least one set of maintenance injections during the study period. Most individuals (82%) received all sets of maintenance injection on time or early (Table 5). Most individuals (91%) remained on LEN at study end, while 9% were considered to have discontinued because no additional injection was observed, with >28 weeks of follow-up left after the last set of injections received (Table 5).

Table 5.

Persistence and Adherence to Lenacapavir Injections Schedule Among Individuals with ≥2 Sets of Lenacapavir Injections

	Individuals with maintenance injectionsN = 78
Total sets of maintenance injections, N	144
Number of sets of maintenance injections per person, median (IQR)	2 (1, 3)
Individuals who received all sets of maintenance injections on time,^a n (%)	61 (78)
Individuals who received any sets of maintenance injections early,^b n (%)	≤5^e
Days between the early set of injections and the start of the injection window, median (IQR)	10 (4, 14)
Individuals who received any set of maintenance injections late,^c n (%)	14 (18)
Days between the end of the injection window and the delayed set of injections, median (IQR)	11 (4, 118)
On LEN at study end, n (%)	71 (91)
Discontinuation,^d n (%)	7 (9)
Days between the end of the injection window and the end of follow-up, median (IQR)	111 (103, 196)

On time: ≥24 to ≤28 weeks after the prior set of injections.

Early: <24 weeks after the prior set of injections.

Late: >28 weeks after the prior set of injections.

HIPAA regulations require the masking of cells with one to five individuals.

Discontinuation: no further injections, with >28 weeks of follow-up after the last set of injections.

IQR, interquartile range; LEN, lenacapavir; N, number.

A total of 144 sets of maintenance injections were received during the study period across all individuals with maintenance injections. Of those, most sets of injections were received on time or early (n = 128; 89%); the latter were received a median of 10 days early (IQR: 4, 14). Finally, out of the 144 total sets of injections across all individuals, 16 (11%) sets of injections were received late, with a median delay of 11 days (IQR: 4, 118) past the end of the injection window during which it should have been received. Of those, 13 (81%) did not get a new prescription for oral LEN dosing, suggesting they did not receive another initiation dose.

Discussion

In this large cohort representative of routine HIV care in the United States, 116 individuals received at least one set of LEN injections, most of whom (64%) had well-controlled HIV at the time of initiation. Similarly, the proportion of people who started LEN while virologically suppressed ranged from 42% to 71% in four other cohorts with sample sizes ranging from 33 to 94 individuals.^36–39 As LEN is indicated for individuals who are failing their current regimen due to resistance, intolerance, or safety concerns,²⁹ this finding suggests that factors other than virologic control were driving the decision to start LEN, such as concerns about safety, tolerability, underlying resistance, or regimen simplification. Indeed, reasons for LEN initiation in a French cohort included not only multi-drug resistance (64%), poor oral ART tolerability (19%), drug–drug interaction avoidance (19%), and unexplained low-level viremia (6%) but also other reasons such as adherence challenges with oral ART (35%), somatic incapacity in taking oral ART (12%), and patient-requested ART simplification (27%).³⁷ Interestingly, LEN use resulted in ART simplification among 56% of the OPERA population, who experienced a reduction in the number of ARV agents, ARV classes, or pills/day at LEN initiation or during LEN use. A reduction in the number of pills per day was also observed in another US cohort.³⁹

LEN + OBR appeared to be effective in OPERA, with a 12-month cumulative probability of achieving virologic suppression (baseline VL ≥200 copies/mL) or maintaining virologic suppression (baseline VL <200 copies/mL) of 76% and 92%, respectively. In addition, 87% of the population with follow-up CD4 measurement(s) achieved a CD4 cell count ≥200 cells/μL at the last measurement. The efficacy of LEN + OBR has previously been demonstrated in the phase 2/3 CAPELLA trial, which included 72 adults with multi-drug-resistant HIV-1 on a failing regimen (i.e., VL ≥400 copies/mL for ≥8 weeks). Over 80% had a VL <50 copies/mL at weeks 26, 52, 104, and 156, and the proportion of individuals with a CD4 cell count ≥200 cells/μL increased from 36% at baseline to 64% at week 52 and 77% at week 156.^30–34

Observational studies of HIV treatment with LEN are limited, but they have also demonstrated the effectiveness of LEN-containing regimens. A retrospective study of 13 centers in France included 94 HTE individuals with drug resistance mutations to at least one ARV from two major drug classes who were followed for a median of 13 months (IQR: 8, 18).³⁸ Of the 49 with a baseline VL <50 copies/mL, 94% had a VL <50 copies/mL at last follow-up visit, and 6% experienced virologic failure (i.e., two consecutive VL ≥50 copies/mL). Of the 45 with a baseline VL ≥50 copies/mL, 64% achieved a VL <50 copies/mL at last visit, 9% experienced virologic failure, and 27% had virological non-response (i.e., <1 log₁₀ copies/mL decrease in VL or failure to achieve a VL <50 copies/mL at week 24). A US retrospective cohort included 70 HTE individuals initiating LEN from 6 centers in Chicago and Pittsburgh who were followed for a median of 12 months (IQR: 6, 19).³⁹ At LEN initiation, 32 had a VL <200 copies, all of whom remained suppressed throughout follow-up. Among the 38 with a baseline VL ≥200 copies/mL, 82% achieved suppression. Another study included 33 individuals who received LEN through the French Compassionate Use Program.³⁶ Of the 14 who started LEN with a VL <50 copies/mL, 86% maintained a VL <50 copies/mL at week 26, and 93% had a VL <50 copies/mL at last follow-up visit. Of the 19 who started LEN with a VL ≥50 copies/mL, 53% achieved a VL <50 copies/mL at week 26 and 74% at last follow-up visit. The proportion with a CD4 cell count >200 cells/μL increased from 60% at baseline to 68% at week 26, with a median increase of 86 cells/μL (IQR: 10, 197). Finally, a study using data from the PRESTIGIO registry⁴⁰ followed 10 individuals with four-class resistance on an LEN-containing regimen with a median baseline VL of 2884 copies/mL and a median baseline CD4 cell count of 287 cells/μL. Over a median of 30 months (IQR: 19, 34), 90% achieved a VL <200 copies/mL and a median CD4 cell count increase of 5 cells/μL (IQR: −48, 101). Results from the CAPELLA trial and from observational studies are generally consistent with the OPERA findings, showing favorable virologic and immunologic outcomes among individuals receiving LEN + OBR.

In OPERA, among 78 individuals who received ≥2 sets of LEN injections, 86% of injection sets were received on time, although delays tended to be relatively short, with a median of 11 days late. This contrasts with the CAPELLA trial, in which 98% of injections were received within a 14-day window of the scheduled doses.³⁴ However, adherence in a clinical trial is expected to be higher than in the real world, where fewer resources can be deployed to ensure receipt of the injections during the appropriate window. To the best of our knowledge, only one other real-world study has reported data on injection schedule adherence. Among 73 individuals in France, the second set of LEN injections was on time in 81%, early in 15% (median 22.4 weeks after the first set; IQR: 21.0, 23.4), and late in 4% (median 28.4 weeks after the first set; IQR: 28.1, 30.0).³⁷ Interestingly, a simulation study has suggested that LEN concentrations could remain more than four times higher than the in vitro protein-adjusted 95% effective concentration for up to 14 days beyond the injection window, corresponding to 30 weeks since the last set of injections.⁴¹ With a median delay of 11 days in OPERA, the LEN concentration was likely to be above this threshold for at least 50% of late injections.

Over a median follow-up of 58 weeks, 91% of people who started LEN in OPERA were still on LEN at study end. This is comparable to the 93% who remained on LEN after 52 weeks in the CAPELLA trial,³² as well as most observational studies to date (87–95%),^37–39 with the exception of the PRESTIGIO registry, in which only 80% remained on LEN at study end.⁴⁰

This study has several strengths. OPERA is a large, diverse cohort representative of HIV care in the United States. With over 157 thousand people with HIV at the time of the study, this represents approximately 14% of people living with diagnosed HIV infection in the United States.⁴² As a result, this study included 116 individuals receiving LEN injection, making it the largest study of LEN for HIV treatment so far, including trials and observational studies. The assessment of real-world use of LEN in the United States through EHR data from routine clinical care uncovered interesting patterns in terms of user characteristics and OBR selection, providing insight into how LEN is being prescribed in the real world.

However, this study is not without limitations. Because only EHR data were utilized, only information recorded in the EHR by a provider for routine clinical care was available. It was therefore impossible to assess which initiation sequence was selected (first set of injections on Day 1 vs. Day 15). This is why prior regimens were assessed 16 days before the first set of injections, to ensure that the OBR was not captured if the second option was selected. The use of oral bridging to cover injection delays could not be assessed due to inconsistent recordkeeping. In addition, the genotyping and resistance to any ARVs before, during, or after LEN use could not be assessed, as resistance testing is infrequent in routine clinical care, and results are not always accessible in the EHR. Moreover, commercial tests for LEN-specific mutations are not currently available. Finally, reasons for LEN initiation and background regimen selection could not be assessed due to their incomplete documentation in the EHR.

In conclusion, in this cohort representative of routine clinical care in the United States, a high proportion of individuals started LEN while virologically suppressed, unlike participants in the CAPELLA trial. This, combined with the fact that many experienced regimen simplifications with LEN use, suggests that factors other than virologic control may be driving the decision to start LEN. Given the favorable virologic and immunologic outcomes observed, as well as the high adherence to the injection schedule in this real-world setting, LEN + OBR may serve as an effective long-acting injectable option for treatment-experienced people with HIV.

Authors’ Contributions

L.B. and J.S.F. share the responsibility for the design of this study. K.M., R.K.H., P.C.L., M.G.S., M.B.W., J.S.F., and jG.P.F. contributed to the acquisition of data. L.B. is responsible for all the analyses. All authors have contributed to the interpretation of results, have critically reviewed and approved the article, and have participated sufficiently in the work to take public responsibility for its content.

Footnotes

Acknowledgments

This research would not be possible without the generosity of people living with HIV and their OPERA caregivers. Additionally, the authors are grateful for the following individuals: Kelly Oh (SAS programming), Kristine Ferguson (QA), Bernie Stooks (data architecture), Lisa Lutzi and Nicole Shaw (Data management/quality), and Judy Johnson and Quateka Cochran (Clinical data categorization).

Author Disclosure Statement

K.M. has received research grants from Gilead Sciences, Merck, Janssen, and GSK/ViiV Healthcare; honoraria for speakers’ bureau and advisory boards from Gilead Sciences, Merck, Janssen, and GSK/ViiV Healthcare; and advisory board participation with Epividian. L.B., J.S.F., and G.P.F. are employed by Epividian, Inc.; Epividian has had research funded by AIDS Healthcare Foundation, EMD Serono, Gilead Sciences, Janssen Scientific Affairs, LLC, Merck & Co., Theratechnologies Inc., and ViiV Healthcare. R.K.H. has received research grants from Gilead Sciences and ViiV Healthcare; speaker honoraria from ViiV Healthcare, Merck, and Gilead Sciences, and advisory board participation with ViiV Healthcare, Gilead Sciences, and Epividian. P.C.L. is a member of the Epidemiology and Clinical Advisory Board for Epividian. M.G.S. is on the speakers’ bureau for ViiV Healthcare and Gilead Sciences, and on the advisory board for ViiV Healthcare. M.B.W. has served as a principal investigator on ViiV Healthcare clinical trials but did not receive personal compensation for this work, which went directly to the AIDS Healthcare Foundation. M.B.W. is also a member of the Epidemiology and Clinical Advisory Board for Epividian. K.D. is employed by Gilead Sciences and holds stock in Gilead Sciences.

Funding Information

This work and publication fees were supported by Gilead Sciences. Epividian Inc. has put in place safeguards to ensure the integrity of its studies. For every study, analyses are conducted in accordance with the protocol approved by members of the Epidemiology and Clinical Advisory Board, who do not receive any financial compensation for their participation in the study. It is Epividian’s policy to publish the results of all studies, regardless of the results, for full transparency.

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