Long-Acting Cabotegravir Injections Are More Acceptable Than Long-Acting Lenacapavir Injections After One Dose: Results From the CLARITY Randomized Crossover Study

Abstract

Introduction

Injection site reactions (ISRs) are a key consideration when selecting long-acting injectables (LAIs), and are central to healthcare provider (HCP) and patient shared decision-making. We evaluated the acceptability of ISR profiles alongside participant and HCP-reported preferences for long-acting cabotegravir (CAB LA) and lenacapavir (LEN LA).

Methods

CLARITY (NCT06970223) is an open-label, randomized, crossover study. Adults without HIV received single-dose CAB LA (intramuscular) and LEN LA (subcutaneous) on Days 1 and 15 (randomized so either CAB LA or LEN LA was the first injection). The primary endpoint was the proportion of participants reporting “very acceptable or totally acceptable” local reactions and pain 7 days post-injection using the Perception of Injection (PIN) questionnaire. Secondary endpoints included characterization of the ISR profile. Exploratory endpoints included participant and HCP preferences and participant perspectives using questionnaires and interviews.

Results

Overall, 61 participants received CAB LA and 62 received LEN LA. A higher proportion of participants reported local reactions and pain as “totally or very acceptable” with CAB LA injections versus LEN LA [69% (42/61) vs. 48% (29/60); odds ratio, 3.4 (95% CI, 1.25 to 9.22); P < 0.019 post hoc]. CAB LA consistently showed more favorable PIN domain and individual items of assessment scores versus LEN LA. CAB LA demonstrated a favorable ISR profile versus LEN LA, including fewer visible ISR events (36 vs. 221). Ninety percent (54/60) of participants preferred CAB LA, whereas 10% (6/60) preferred LEN LA; 86% (6/7) of HCPs preferred CAB LA and 14% (1/7) preferred LEN LA. Participants reported less pain during CAB LA versus LEN LA injections.

Conclusion

CAB LA was more acceptable than LEN LA, had a more favorable ISR profile, and was preferred by a majority of participants and HCPs. These findings highlight differences in the injection experience that can inform shared decision-making when choosing LAIs.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03703-3.

Key Summary Points

Why carry out this study?

The injection site reaction (ISR) profile of long-acting injectables (LAIs) is an important factor influencing the preferences and lived experiences of individuals using these medicines.

Before this study, no direct comparisons were conducted comparing injection experiences or ISR profiles between long-acting cabotegravir (CAB LA) and lenacapavir (LEN LA).

The CLARITY study (NCT06970223) was designed to address this evidence gap by evaluating the acceptability of local reactions and pain, ISR profiles, treatment preferences, and participant perspectives following single doses of intramuscular CAB LA and subcutaneous LEN LA.

What was learned from this study? CAB LA demonstrated significantly greater injection acceptability than LEN LA, with more participants and healthcare providers preferring CAB LA over LEN LA after a single dose of each LAI.

CAB LA was associated with a more favorable ISR profile versus LEN LA, including an approximately fourfold lower rate of ISR events per dose, fewer visible ISRs, fewer grade ≥ 2 ISRs, and a lower proportion of participants with non-pain ISRs.

Introduction

Innovative therapeutic strategies are needed to drive further progress toward ending the HIV epidemic [1–4]. Long-acting injectables (LAIs) represent an important advancement for HIV-1 treatment and prevention by offering alternatives to daily dosing [3]. LAIs help address challenges associated with daily oral pills, including adherence anxiety, the burden of daily dosing, persistent reminders of HIV status, and stigma related to taking pills, which can ultimately compromise long-term persistence [3, 5–8]. Across studies, LAIs have been associated with higher participant preference compared with daily oral medicines in treatment and prevention settings [5, 9, 10].

The integrase strand transfer inhibitor, long-acting cabotegravir (CAB LA) administered intramuscularly (IM) as 1 injection every 2 months is the first LAI indicated for pre-exposure prophylaxis (PrEP) [11, 12]. In clinical trials, CAB LA demonstrated superior efficacy versus daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), and has shown high rates of effectiveness in real-world studies [13–16]. The capsid inhibitor, long-acting lenacapavir (LEN LA) administered subcutaneously (SC) as 2 injections every 6 months, demonstrated superior efficacy to daily oral TDF/FTC in clinical trials, and is approved as another LAI PrEP option [17–20]. Findings from an indirect treatment comparison indicate that CAB LA and LEN LA offer similar and high efficacy in reducing HIV acquisition risk compared with no PrEP and oral TDF/FTC [21].

Long-acting injectables also offer an innovative approach for HIV treatment. The first and only complete long-acting regimen, cabotegravir plus rilpivirine (CAB + RPV LA), is approved in the suppressed switch setting [22, 23]. Long-acting LEN is approved in combination with other antiretrovirals for people with multidrug-resistant HIV that are heavily treatment-experienced [24], a population with limited treatment options in which the ISR profile is weighed against the critical need to achieve virologic suppression. Novel long-acting combinations are under investigation including CAB (with or without rilpivirine) paired with LEN [25–27], supporting a critical need to understand ISR profiles of both agents.

As new LAI options with unique attributes continue to evolve and diversify, people with HIV and individuals who could benefit from PrEP, as well as their healthcare providers (HCPs), will be presented with several unique, effective options that differ in dosing intervals, route of administration, drug interactions, and tolerability profiles [28, 29]. The clinician–patient discussion around LAI choice must therefore broaden to encompass considerations beyond safety and efficacy including practical and patient-centric elements of LAIs [28, 29]. Proactively facilitating evidence-based discussions may enhance patient engagement and support medication adherence [30, 31]. Evidence is therefore needed to understand if there are distinct and differentiating injection site reaction (ISR) profiles and injection experiences among current LAIs.

Injection site reactions are localized adverse events (AEs) occurring at the site of injection that may include pain, swelling, induration, nodules, and erythema [32]. Several drug-related factors can influence the ISR profile, including formulation, injection volume and site, and the number of injections per dose [33]. Concerns regarding injection-related reactions may reduce acceptance of and adherence to LAIs among individuals who could otherwise benefit from them, and may also influence HCP recommendations in clinical practice [28, 32, 33]. Importantly, the initial injection experience and subsequent tolerability may be a key determinant of LAI persistence. [34]

The CLARITY study (NCT06970223) was designed to evaluate the acceptability of CAB LA and LEN LA, provide a detailed characterization of their ISR profiles, and assess preferences and lived experiences with these LAIs among people without HIV and HCPs. Here, we report outcomes through Day 22. CLARITY aims to inform clinical discussions and support shared, evidence-based decision-making for LAI medicines.

Methods

Study Design

CLARITY (NCT06970223) is a phase 1, randomized, open-label, crossover study conducted at a single US center evaluating the acceptability and tolerability of a single dose each of CAB LA (1 injection delivered IM in the gluteus medius) and LEN LA (2 injections delivered SC in the abdomen) [35]. This analysis focuses on observations up to Day 22; the CLARITY study evaluates key secondary endpoints through Day 190 (Supplementary Fig. 1). Additionally, participants are followed until their ISRs resolve or until Week 54, after which they are referred to local care for clinical management. Participants receiving LAIs were adults without HIV with bodyweight ≥ 50 kg and body mass index of 18–32 kg/m² at screening. Participants did not have a specific requirement for increased HIV risk or eligibility for PrEP; similarly, clinical recommendations from the Centers for Disease Control and Prevention are to prescribe PrEP to individuals who ask for it, independent of HIV risk factors [36]. Key exclusion criteria included any important comorbidities/infections, substance use, or abnormalities in diagnostic tests that would preclude participation in the study (Supplementary Methods).

Healthcare providers were eligible for inclusion in interviews and to complete Medication Preference Questionnaires if they were responsible for or involved in any aspect of offering and administering CAB LA and LEN LA at the study site.

Ethics

The study was conducted in accordance with legal and regulatory requirements and the principles in the Declaration of Helsinki and the Council for International Organizations of Medical Sciences international ethical guidelines. An institutional review board reviewed and approved the study protocol and other relevant documents (Advarra IRB: Pro00085558, approved March 19, 2025), and all participants provided written informed consent before study enrollment.

Injection Procedures

Participants were randomized 1:1 to receive either (1) a single dose of CAB LA on Day 1 followed by a single dose of LEN LA on Day 15 or (2) a single dose of LEN LA on Day 1 followed by a single dose of CAB LA on Day 15 (Supplementary Fig. 1). To promote standardization in injection techniques, investigators were trained using manufacturer-provided guidelines and videos, as well as instructions from the approved CAB LA and LEN LA package inserts before study initiation. Long-acting CAB (600 mg) was administered as one 3-mL IM injection in the gluteus medius, while LEN LA (927 mg) was administered as two 1.5-mL SC injections in the abdomen, consistent with the prescribing information [11, 19]. To minimize interference with ISR findings, participants were asked not to take analgesics (including topical anesthesia or ice packs) on the day of injection and for 48 h post-injection.

Endpoints

The primary endpoint was the proportion of participants reporting local reactions and pain as “very acceptable or totally acceptable” 7 days after each injection of CAB LA or LEN LA. Responses were based on the acceptability domain of the Perception of Injection (PIN) questionnaire.

Secondary endpoints included participant-reported domain and individual item scores of the PIN questionnaire 7 days after each injection. Additional secondary endpoints included characterization of ISRs (specifically their incidence, duration, and severity) and the incidence and severity of non-ISR AEs. Participant-reported intensity of post-injection site pain, assessed using the Numeric Rating Scale (NRS), was also evaluated as a secondary endpoint.

Exploratory endpoints included participant and HCP preferences between the 2 LAIs and the reasons for those preferences, assessed via questionnaires. A separate exploratory endpoint examined perceptions of feasibility, acceptability, and appropriateness of LAIs using a mixed-methods approach combining implementation science questionnaires and semi-structured interviews. Select data from the implementation science questionnaires and semi-structured interviews are presented here.

Procedures

All questionnaire assessments were self-administered electronically.

PIN Questionnaire

Experiences with injections were assessed 7 days after each injection using the 21-item PIN questionnaire (adapted from the validated Sanofi Pasteur Vaccinees’ Perception of Injection questionnaire) [37, 38]. Participant responses were scored on a 5-point Likert scale, with 1 representing the least favorable perception of injection and 5 the most favorable. Assessments used in this study are listed in Supplementary Table 1.

Safety Assessments

Healthcare providers assessed ISRs in detail and reviewed AEs at every study visit after dosing using Division of AIDS (DAIDS) grading criteria (version 2.1, July 2017) [39]. ISRs were graded in severity from 1 to 4 per DAIDS grading criteria and included pain, erythema, swelling, induration, nodule, pigmentation changes, pruritus, warmth, cellulitis, and rash. Further details on safety monitoring are provided in the Supplementary Methods.

Intensity of ISR Pain

The NRS was used to assess post-injection pain intensity. The NRS is a visual analogue scale ranging from 0 (no pain) to 10 (extreme pain) that captures the maximum level of pain experienced following injection. The NRS was self-administered at clinic visits at a similar number of days after each LAI dose. For the first LAI dose, assessments were conducted on Day 1 (within 30–60 min post-LAI administration) and on Days 2, 5, and 8. For the second LAI dose, assessments were conducted on Day 15 (within 30–60 min post-LAI administration) and on Days 16, 19, and 22.

Participant-Reported Preferences

Participant preference was assessed using a 2-item Medication Preference Questionnaire comparing preference and rationale for preference between CAB LA and LEN LA. This questionnaire was administered on Day 22 after participants had experience with both CAB LA and LEN LA. Healthcare providers also completed Medication Preference Questionnaires on both Days 8 and 22 (7 days after each LAI dose). Participants and HCPs could select more than 1 reason for their preference. Data from Day 22 (after HCPs had experience with both LAIs) are presented here.

Perceptions of LAI Feasibility, Acceptability, and Appropriateness

Perceptions of CAB LA and LEN LA appropriateness, acceptability, and feasibility were assessed via bespoke electronic questionnaires and interviews conducted on Days 8 and 22. A subset of participants and healthcare providers engaged in semi-structured interviews conducted by trained moderators with experience conducting in-trial interviews to understand lived experiences with each LAI. Each interview allowed for a window such that the Day 8 interview could occur between Days 8 and 13 and the Day 22 interview between Days 22 and 27.

Interview questions included the following themes: willingness to use CAB LA or LEN LA in the future when weighed in the context of preventing HIV acquisition, LAI recommendations to others, preference for LAIs, experience with ISRs, and impact of ISRs on daily life (details in Supplementary Methods). Interviews were up to 60 min long and conducted via a tele-conferencing platform.

Statistics

All randomized participants who received ≥ 1 LAI dose were included in the primary and secondary analyses. The subset of participants who also completed interviews were included in analyses of the semi-structured interviews.

Summary statistics were used to report the dimension score of acceptability of local reactions and pain assessed within the 21-item PIN questionnaire and the proportion of participants reporting “totally or very acceptable” local reactions and pain 7 days after each injection. Secondary endpoints were analyzed using descriptive statistics for continuous variables, and the number and proportion of participants were reported for categorical variables.

Relative risks of the proportion of participants experiencing ISRs with CAB LA versus LEN LA were calculated. A post hoc Bayesian negative binomial model with participant-specific random effects was used to estimate posterior mean ISR rates and posterior median rate ratio of ISR events with LEN LA versus CAB LA. The event rate estimates were posterior means, with 95% credible intervals (CrIs) based on 2.5 and 97.5 percentiles. To evaluate the proportion of participants with non-pain ISRs, a sensitivity analysis was conducted where injection site pain and lower abdominal pain were removed from the overall ISR category. Outputs were produced to show ISRs overall and overall excluding pain.

In a post hoc analysis of the statistical significance of the primary endpoint, McNemar's test statistic and the associated P value were calculated based on chi-square distribution using a continuity correction to compare CAB LA and LEN LA acceptability. In a separate post hoc analysis of participant preference, the proportion of participants preferring CAB LA was evaluated using an exact binomial test, with P values estimated based on a 2-sided test.

Interview results are presented both quantitatively (e.g., the proportion of participants who preferred CAB LA vs. LEN LA) and qualitatively (e.g., the reasons underlying those preferences). Rapid analysis and applied thematic analysis of interview results explored perceptions of injection implementation, acceptability, appropriateness, and feasibility. A combination of deductive and inductive coding techniques was used, and coding was completed by a primary and secondary coder with oversight from a coding lead. Key themes were supported by representative quotes and frequency tables.

Results

Participant Disposition

Of 135 participants screened, 64 were enrolled (Supplementary Fig. 2). One participant was randomized but did not receive LAI (withdrawn by participant for “other” reason). One participant received CAB LA on Day 1 but did not receive LEN LA on Day 15, and 2 participants received LEN LA on Day 1 but not CAB LA on Day 15 (as detailed in Supplementary Fig. 2). Altogether, 63 participants received LAIs, including 61 who received CAB LA (61 injections) and 62 who received LEN LA (124 injections). Seven HCPs were included to provide preferences on CAB LA versus LEN LA.

Demographics and Baseline Characteristics

Participants Receiving LAIs

CLARITY enrolled a diverse population; 29% (18/63) were Black or African American, 38% (24/63) were Hispanic or Latine, and 33% (21/63) were assigned female sex at birth. Mean [standard deviation (SD)] age was 48 (14) years and mean (SD) body mass index was 27 (3) kg/m² (Supplementary Table 2).

A total of 42 interviews were conducted with 26 participants (41% of all study participants), including 20 interviews at Day 8 and 22 at Day 22. Among these 26 participants, 31% (8/26) were assigned female sex at birth, 89% (23/26) were aged < 65 years, 23% (6/26) identified as Black or African American, and 12% (3/26) identified as Asian.

HCPs

Seven HCPs were included in assessments of LAI preference and perspectives (1 physician, 1 nurse, 1 medical assistant, 1 individual in an “other” role, and 3 HCPs who did not report their clinical role).

Participant-Reported Acceptance of Local Reactions and Pain from the PIN Questionnaire

A higher proportion of participants rated local reactions and pain at 7 days post-dose with CAB LA as “totally or very acceptable” compared with LEN LA in PIN questionnaire assessments [combined Day 8 and Day 22: CAB LA, 69% (42/61); LEN LA, 48% (29/60); Fig. 1A]. In a post hoc analysis, CAB LA was associated with significantly higher odds of being rated as “totally or very acceptable” local reactions and pain versus LEN LA (odds ratio, 3.4; 95% CI, 1.25–9.22; P < 0.019; McNemar’s test statistic, χ² = 5.5; Fig. 1B).

Fig. 1.

A The proportion of participants reporting local reactions and pain as “totally or very acceptable” using the PIN questionnaire and B odds of higher acceptability with CAB LA versus LEN LA at 7 days after each injection. C Mean PIN domain and D individual item scores at 7 days after each injection; lower scores indicate better outcomes. CAB LA long-acting cabotegravir, LEN LA long-acting lenacapavir, PIN Perception of Injection. ^aData from 7 days post-injection (from Days 8 and 22) are combined. ^bAmong participants with available data. ^cA post hoc analysis was conducted using McNemar’s test (χ² = 5.5), with the P value calculated from the chi-square distribution using a continuity correction, to compare the acceptability of CAB LA and LEN LA

Long-acting CAB was associated with more favorable acceptability domain scores versus LEN LA at 7 days post-injection, reflected by lower scores indicating better outcomes (Fig. 1C). In addition, CAB LA was associated with more favorable PIN domain scores than LEN LA across the movement, sleep and bother domains, with lower scores indicating better outcomes (Fig. 1C). Similarly, individual PIN item scores favored CAB LA (Fig. 1D). Mean scores were also lower with CAB LA compared with LEN LA for anxiety before injection, pain, satisfaction, anxiety after injection, and willingness to continue treatment, indicating better outcomes.

Safety Outcomes

ISRs

Overall, CAB LA was associated with a favorable ISR profile versus LEN LA (Table 1). A lower proportion of participants reported any ISR from CAB LA [85% (52/61)] compared with LEN LA [100% (62/62)]. Additionally, fewer participants experienced grade ≥ 2 ISRs with CAB LA [30% (18/61)] versus LEN LA [56% (35/62)]. The proportion of participants reporting ISR pain were similar for both CAB LA 80% (49/61) and LEN LA 82% (51/62). Seven percent (4/61) of participants had a maximum grade 3 ISR with CAB LA, all of which were injection site pain. For LEN LA, 8% (5/62) of participants had maximum grade 3 ISRs overall, including 1 with injection site erythema and 5 with injection site swelling. No participants experienced a serious ISR or withdrew due to an ISR.

Table 1.

Summary of ISR safety

ISR	CAB LA (n = 61, 61 injections)a	LEN LA (n = 62, 124 injections)a
Participant-level summary of ISR frequency, n (%)b
Any ISR	52 (85)	62 (100)
Maximum grade 1	34 (56)	27 (44)
Maximum grade 2	14 (23)	30 (48)
Maximum grade 3	4 (7)c	5 (8)d
Maximum grade 4	0	0
Leading to study withdrawal	0	0
Related to treatment	52 (85)	62 (100)
ISRs of interest
Injection site pain	49 (80)	51 (82)
Injection site induration	11 (18)	54 (87)
Injection site nodule	20 (33)	46 (74)
Injection site erythema	7 (11)	35 (57)
Injection site swelling	21 (34)	36 (58)
Injection site hyperpigmentation	0	15 (24)
Additional ISRs
Injection site warmth	11 (18)	28 (45)
Leakagee	0	17 (27)
Injection site pruritis	3 (5)	12 (19)
Injection site bruising	0	6 (10)
Lower abdominal pain	0	1 (2)
Summary of ISR events, n
ISR events overall	123	538
ISR events of interest
Injection site pain	50	101
Injection site induration	11	94
Injection site nodule	20	92
Injection site erythema	7	52
Injection site swelling	21	67
Injection site hyperpigmentation	0	26
Visible ISR eventsf	36	221

CAB LA long-acting cabotegravir, ISR injection site reaction, LEN LA long-acting lenacapavir

^aOne participant received CAB LA at Day 1 but did not receive LEN LA at Day 15; 2 participants received LEN LA at Day 1 but did not receive CAB LA at Day 15

^bDenominator for percentages are the number of participants in the study

^cFour participants experienced maximum grade 3 injection site pain

^dOne participant experienced maximum grade 3 injection site erythema and 5 participants experienced maximum grade 3 injection site swelling

^eRefers to leakage from the injection site

^fDefined as having any erythema, hyperpigmentation and/or visible nodule, induration, or swelling

Fewer total ISR events were observed with CAB LA (123 events) than with LEN LA (538 events), with a total of 61 CAB LA (1 injection per dose) and 124 LEN LA (2 injections per dose) administered. Participants experienced fewer unique ISRs per CAB LA dose, with a median (range) of 2.0 (1–6), compared with a median (range) of 9.0 (1–18) per LEN LA dose. The estimated mean ISR event rate per injection for CAB LA was 2.020 (95% CrI: 1.643, 2.440), while for LEN LA the per injection rate was 4.367 (95% CrI: 3.877, 4.914) in a post hoc negative binomial model analysis. The rate ratio for LEN LA versus CAB LA was estimated at 2.165 (95% CrI: 1.786, 2.644) per individual injection. The posterior probability that the ISR event rate per LEN LA injection was higher than CAB LA exceeded 0.999, indicating very strong evidence of a higher ISR event rate with LEN LA. Given that LEN LA requires 2 injections per dose, this equates to a ratio of 4.33 ISRs per LEN LA dose for each ISR event per CAB LA dose based on the negative binomial model, an approximately fourfold increase with LEN LA versus CAB LA. The number of visible ISR events (defined as having any erythema, or hyperpigmentation and/or visible nodule, induration, or swelling) were lower with CAB LA (n = 36) versus LEN LA (n = 221).

Relative Risk Analysis of ISRs and Non-pain ISR Safety Profile

Long-acting CAB was associated with lower relative risks for ISRs versus LEN LA, including non-pain ISRs such as swelling, nodules, pruritus, induration, and erythema (Fig. 2). In a sensitivity analysis, CAB LA was associated with a more favorable non-pain ISR safety profile than LEN LA, with fewer non-pain ISRs overall [49% (30/61) vs. 100% (62/62), respectively; Fig. 3A]. Across specific ISRs, CAB LA was consistently associated with lower proportion of non-pain ISRs, including induration [18% (11/61) vs. 87% (54/62)], nodules [33% (20/61) vs. 74% (46/62)], erythema [11% (7/61) vs. 57% (35/62)], swelling [34% (21/61) vs. 58% (36/62)], and hyperpigmentation [0% (0/61) vs. 24% (15/62)].

Fig. 2.

Relative risk of ISRs with CAB LA (n = 61) versus LEN LA (n = 62). CAB LA long-acting cabotegravir, ISR injection site reaction, LEN LA long-acting lenacapavir. ^aRelative risk was calculated for ISR events experienced during CAB LA and LEN LA dosing and defined as the ratio of the participant-level risk of ISRs with CAB LA to the participant-level risk with LEN LA

Fig. 3.

A Proportion of participants with non-pain ISRs up to Day 22 in a sensitivity analysis and B representative images of CAB LA and LEN LA injection sites in 1 participant. CAB LA long-acting cabotegravir, ISR injection site reaction, LEN LA long-acting lenacapavir. ^aInjection site pain and lower abdominal pain ISRs were excluded from the sensitivity analysis. ^bLeakage refers to leakage from the injection site

Intensity of Post-Injection Site Pain

Using the pain NRS (0–10 scale with lower scores indicating less pain), participants reported more favorable pain scores with CAB LA than LEN LA on the day of injection, with mean (SD) scores of 1.0 (1.6) versus 3.3 (2.6; Supplementary Fig. 3), as well as lower mean peak pain scores (2.4 vs. 3.3). Pain NRS scores were similar between the 2 LAIs on post-injection Days 2, 5, and 8.

Non-ISR Safety

No serious AEs or discontinuations due to drug-related AEs were reported across LAIs. The most common non-ISR drug-related AEs were gastrointestinal disorders (CAB LA, n = 1; LEN LA, n = 6), all of which were grade 1. Grade ≥ 2 non-ISR, drug-related AEs were uncommon and included grade 3 neuralgia in 1 participant (CAB LA) and grade 2 rash in 1 participant (CAB LA). One participant discontinued LEN LA because of a migraine that was considered unrelated to the LAI.

Preferences and Perspectives from Medication Preference Questionnaires

LAI Preferences

A total of 60 participants completed the Medication Preference Questionnaire at Day 22, after they had experience with both LAIs. Ninety percent (54/60) of participants preferred CAB LA, whereas 10% (6/60) preferred LEN LA (Fig. 4A); this preference for CAB LA was statistically significant in a post hoc analysis (90%; 95% CI, 79%-96%; P < 0.001; Fig. 4B).

Fig. 4.

A Proportion of participants reporting preference for CAB LA or LEN LA, B proportion of participants preferring CAB LA over LEN LA in post hoc analysis, and C reasons for preferring CAB LA or LEN LA (more than 1 reason could be chosen by a participant) at Day 22, after receiving both CAB LA and LEN LA. CAB LA long-acting cabotegravir, LEN LA long-acting lenacapavir. ^aParticipants provided preferences on Day 22, after receiving both CAB LA and LEN LA

Among the 54 participants who preferred CAB LA, the 3 most common reasons were less pain during (74% [40/54)] the injection, less pain after (61% [33/54)] the injection, and the duration of swelling and nodules (57% [31/54)]. Among the 6 participants who preferred LEN, the 3 most common reasons were less pain or soreness after injection administration (83% [5/6)], duration of swelling and nodules (50% [3/6)], and the size of the injection nodules or swelling (50% [3/6)]. Details on reasons for participant preference are presented in Fig. 4C.

HCP Preferences

Among the 7 HCPs who completed the Medication Preference Questionnaire, a majority preferred CAB LA (86% [6/7)], whereas 1 preferred LEN LA (14%; Fig. 5A). The 4 most common reasons HCPs preferred CAB LA were fewer participant-reported side effects (83% [5/6)], less severe participant-reported side effects (67% [4/6)], less pain experienced by participants during injection (67% [4/6)], and less pain or soreness experienced by participants after injection administration (67% [4/6)]. Reasons for CAB LA preference are presented in Fig. 5B. One HCP preferred LEN LA due to ease of injection preparation.

Fig. 5.

A HCP-reported preference for LAIs at Day 22 and B reasons for CAB LA preference among HCPs (more than 1 reason could be chosen by a participant). Healthcare providers provided their preferences on Day 22, after participants had experience with both CAB LA and LEN LA. One HCP reported a preference for LEN LA due to ease of injection preparation. CAB LA long-acting cabotegravir, HCP healthcare provider, LAI long-acting injectable, LEN LA long-acting lenacapavir

Impact of ISRs on Body Image and Self-Consciousness from Implementation Science Questionnaires

Among the 57 participants completing questionnaires, more participants reported body image concerns with LEN LA versus CAB LA. Across Days 8 and 22, 25% (14/57) of participants agreed or strongly agreed that ISRs from LEN LA negatively affected how they felt about their body, compared with 11% (6/57) with CAB LA. Similarly, 51% (29/57) of participants agreed or strongly agreed that they felt self-conscious about visible ISRs with LEN LA versus 21% (12/57) with CAB LA.

Participant-Reported Perspectives from Semi-Structured Interviews

Willingness to Use Each LAI and Recommendations for Future Choice

A total of 26 participants completed interviews, yielding 42 interviews in total: 22 following CAB LA administration and 20 following LEN LA administration. Nearly all participants [96% (21/22)] indicated that they were willing to use CAB LA in the future, and 75% (15/20) reported that they would use LEN LA, based on interviews conducted on Days 8 and 22 (Fig. 6A). Willingness to use LAIs was largely driven by the perception that potential side effects were preferable to the risk of acquiring HIV-1 (Fig. 6B). The single participant who indicated they would not use CAB LA cited concerns about side effects (Table 2 shows relevant quotes from participant interviews). Among the 25% (5/20) who reported they would not use LEN LA in the future, reasons included intolerance of ISRs and concerns about a foreign substance remaining in the body for a long period of time.

Fig. 6.

A Participants’ perspective on whether they would take CAB LA or LEN LA in the future from Day 8 and 22 interviews and B example reasons for future willingness to use CAB LA and LEN LA. C Participants’ recommendations of CAB LA or LEN LA for others from Day 8 and 22 interviews and D example reasons for recommending CAB LA or LEN LA to others. CAB LA long-acting cabotegravir, LAI long-acting injectable, LEN LA long-acting lenacapavir. ^aParticipants were asked to reflect on their experiences with each LAI and consider their willingness to continue receiving CAB LA and LEN LA after the study has ended. ^bParticipants were asked whether they would recommend the injection they were currently receiving to others

Table 2.

Quotes from participant interviews

Topic	Quotes
Reasons for future unwillingness to use CAB LA or LEN LA	“No, because of my experience with it so far, in as much as it was a relatively dependent injection, and there’ve been essentially negative after effects from it.”—Participant referencing CAB LA “It just hurts too much. I don’t think that I would… I would not want nodules on me in dealing with this on a day-to-day basis. No way. No.”—Participant referencing LEN LA “I’ve had too many issues with it. I have a foreign thing in my body that’s going to be here for a long time, and it is not leaving no time soon. No, no, no, and no.”—Participant referencing LEN LA
Reasons for recommending CAB LA or LEN LA to othersa	“It’s in a more private area and there was no reaction. The best main benefit is there was no reaction. The second benefit was if there had been a reaction, it was a private area.”—Participant referencing CAB LA “If they’re high risk, I don’t…I feel like ethically I’d have to say yes. Then I would give the caveat of, “By the way, that first injection day is going to suck.”—Participant referencing LEN LA
Reasons for recommending CAB LA over LEN LA	“Because it’s a lot easier. You get along with your day no matter what lifestyle or what job you do, it’s like so easy and so fast. It would benefit anybody that’s going through that situation”—Participant referencing CAB LA “If I received the frontal and what I felt at that initial time, the second time I go into it for the next 6 months, will I feel that very same effect or will it be slightly worse? You don’t know unless you were to do it more times in the frontal. Now if I get it into my buttocks, I think I have a better chance of having the same type of feeling of pretty much nothing at all.” – Participant referencing LEN LA “The abdomen injections I feel would affect me for the majority of those 6 months, I feel the buttock injection would only affect me for the first week. When we get it every 2 months with minimal side effects sounds better than 2 months of hard nodules that make me self-conscious and make me not be able to work twice a year.” – Participant referencing CAB LA
Advice participants would give to someone who is considering the injection in the buttock (CAB LA) vs. the injection in the abdomen (LEN LA)	“I would tell them from a personal experience that the glute one is more manageable. It’s less painful. The effects of it, it has little to none effects at all on your body.”—Participant referencing CAB LA “You’re gonna be good in your butt, but the stomach going to hurt.”—Participant referencing CAB LA “I would state as the conversation that we had just right now with what I just stated with the positioning and the injections, the male yeah, it’s fine for you. But until they find another body part for the female, this is not going to work.”—Participant referencing CAB LA “My advice is thoroughly discuss it beforehand with your doctor and ask as many questions as you can… For me personally, is just the mental aspect in preparing yourself for the injections and what to expect afterwards.”—Participant referencing LEN LA “Just be mindful that everyone’s reaction is different and that you might have some pain and discomfort, but it could be worse, so just prepare for it.”—Participant referencing CAB LA “The long lasting side effects that I experienced with myself, is long. Especially the nodules are lasting longer than what I expected.” – Participant referencing LEN LA
Reasons for shifting preference from CAB LA to LEN LA after considering dosing frequency	“I would probably take the abdomen one because it has a longer lasting. There’s the six months versus the two months. The 2 months, you’re going to have to get three shots…Yeah would just endure the discomfort and take the abdomen one.” – Participant referencing LEN LA “In that case, I’d probably go with the shots in the abdomen because there are fewer shots one can take. At the end of the day, even though I tolerate the shots really well, apparently, I prefer to have as few shots as possible if I’m going to get the same results.”—Participant referencing LEN LA
Description of any pain or discomfort experienced during and after injection	“They’re puncturing the skin, so there’s going to be a little discomfort.”—Participant referencing CAB LA “I’d say within 24 h, some mild tenderness, which went away after 24 h.”—Participant referencing CAB LA “Probably within 5 to 6 h after receiving the shot. Not only did I feel the pain, I had a fever in my butt. I had a full-blown fever going on down there. Yeah. It was hot, it was swollen.”—Participant referencing CAB LA “It’s just the needle put in the body and not… It’s a little bit pain, but not… Just a very few seconds I feel it, and after that, okay. It’s not a big deal.”—Participant referencing LEN LA “I felt fine, just relaxed and as I said it was easy.”—Participant referencing LEN LA “As soon as she pulled the needle out, I had very strong pain, burning pain. It was very uncomfortable pain.”—Participant referencing LEN LA “The only thing in the moment I could think about was how much it hurt. I couldn’t think about anything else, because it was very, very painful.”—Participant referencing LEN LA “It was horrible… I would say the burning, stinging and pain was constant for the first 12 h.”—Participant referencing LEN LA

CAB LA long-acting cabotegravir, LAI long-acting injectable, LEN LA long-acting lenacapavir

^aAdditional reasons are presented in Fig. 6

When asked whether participants would recommend the injection they were currently receiving to others, nearly all participants recommended CAB LA [96% (21/22)], whereas 55% (11/20) recommended LEN LA across the Day 8 and 22 interviews (Fig. 6C). Reasons for recommending CAB LA included comfort, less pain, and minimal impact on lifestyle or physical appearance (Fig. 6D; Table 2). Long-acting LEN was recommended by some participants because they felt that the clinical benefits of LEN LA outweighed concerns regarding the ISR profile.

When asked which LAI participants would recommend to others during the Day 22 interview, most participants selected CAB LA [91% (20/22)] over LEN LA [9% (2/22)]. The primary reasons these participants recommended CAB LA over LEN LA were the favorable ISR profile and minimal impact on their lifestyle (Table 2).

In addition to describing why they would recommend each LAI, participants were also asked what advice they would give to someone who is considering each LAI after having received both injections (Table 2). For individuals considering CAB LA injections, participants recommended being prepared for some post-injection pain and discomfort. Participants emphasized the need to be prepared for potential side effects such as pain and discomfort, swelling, and visible lumps for individuals considering LEN LA injections.

Participant Preference for LAI and Impact of Considering Dosing Frequency on Preference

In the interviews, a high proportion of participants preferred CAB LA [86% (19/22)] over LEN LA [14% (3/22); Fig. 7A] on Day 22 (after they received both LAIs), consistent with the outcomes from the Medication Preference Questionnaire reported above. When participants were asked to consider dosing frequency of LAIs (every 2 months vs. every 6 months), 23% (5/22) switched their preference from CAB LA to LEN LA, and 77% (17/22) did not change their preference (Fig. 7B). This shift in preference resulted in 59% (13/22) of participants preferring CAB LA and 36% (8/22) preferring LEN LA after dosing frequency was considered (Fig. 7C). The 5 participants who changed preference to LEN LA primarily reported the convenience of less frequent dosing as the reason for the change (Table 2).

Fig. 7.

A Participants’ preferences for CAB LA or LEN LA after receiving both LAIs at Day 22, before being asked to consider dosing frequency; B the proportion of participants who shifted their preference for CAB LA or LEN LA or did not change their preference when asked to consider dosing frequency; and C the proportion of participants that preferred CAB LA or LEN LA after being asked to consider dosing frequency of CAB LA or LEN LA. After participants had received both LAIs, they were asked about their preferences for CAB LA or LEN LA based on their experiences throughout the study (data shown in A). Participants were then asked to consider how dosing frequency might influence their preference for HIV-1 prevention, with CAB LA being administered every 2 months and LEN LA administered every 6 months (data shown in C). CAB LA long-acting cabotegravir, LAI long-acting injectable, LEN LA long-acting lenacapavir, Q2M every 2 months, Q6M every 6 months

Pain or Discomfort During and After Injections

Pain was predominantly reported after CAB LA injections [77% (17/22)] rather than during injections [27% (6/22)] across interviews on Days 8 and 22. For LEN LA, 95% (19/20) of participants reported pain or discomfort both during and after the injections.

Participants receiving CAB LA reported no to minimal pain during the injection and described it as “discomfort,” such as when the needle was going into the skin (Table 2). Participants indicated that experience of discomfort did not negatively impact their perception of CAB LA. Participants generally reported a greater range of pain and discomfort with LEN LA, from no pain at all to more intense sensations such as “burning pain” or sharp jabs.

Impact of ISRs on Daily Life

Across interviews on Days 8 and 22, participants reported lesser impact of ISRs on daily life after CAB LA than after LEN LA (Supplementary Table 3). After CAB LA injections, the most commonly reported impacts on daily life (reported by ≥ 25% of participants) were changed to daily activities [41% (9/22)] and impact on exercise [27% (6/22)]. The most commonly reported impacts on daily life after LEN LA injections were change to daily activities [70% (14/20)], impact on exercise [50% (10/20)], covering up the injection site [40% (8/20)], impact on body perception [35% (7/20)], impact on sexual activity [30% (6/20)], and impact on sleep [25% (5/20)].

Discussion

Long-acting injectables offer several advantages over daily oral medicines, including improved convenience, confidentiality, and freedom from reminders of daily dosing [3, 5]. As options for highly effective LAIs continue to expand, understanding the experiences of people who could benefit from PrEP, people with HIV, and their HCPs is increasingly important to inform LAI choice. Findings from CLARITY demonstrated that local reactions and pain from a single dose of CAB LA were significantly more acceptable than those associated with a single dose of LEN LA, as assessed by the PIN questionnaire. Long-acting CAB was associated with a more favorable ISR profile than LEN LA, with an approximately fourfold lower rate of ISR events per dose, fewer visible ISR events, fewer participants experiencing non-pain ISRs, and less injection-day pain.

Findings from the Medication Preference Questionnaires (n = 60 participants) revealed that experiences with ISRs influenced participant and HCP preferences, with a majority of participants and HCPs preferring CAB LA over LEN LA. This was consistent with the more favorable ISR profile observed with CAB LA. There was also consistency between the Medication Preference Questionnaires and interview outcomes (n = 26 participants), with a higher proportion of participants recommending CAB LA to others and expressing a willingness to continue CAB LA compared with LEN LA in interviews. More participants who received LEN LA reported that ISRs negatively affected their body image and more participants reported self-consciousness related to visible ISRs, compared with CAB LA. Participants also reported lesser impact of ISRs on daily life after CAB LA than after LEN LA. It is important to note that, when participants were asked to consider dosing frequency, a subset shifted their preference to LEN LA, underscoring dosing interval as another attribute influencing choice of LAI [40]. Altogether, these findings highlight differences in the injection experience that can inform shared decision-making when choosing LAIs.

Prior studies have shown high acceptability and preference for LAIs over daily oral pills across diverse populations [40–46]. In the open-label extension of HPTN-083, 96% of cisgender men and transgender women who have sex with men chose CAB LA over daily oral TDF/FTC [44]. Likewise, in the open-label extension of HPTN 084, 78% of cisgender women preferred CAB LA over daily oral TDF/FTC [45]. In the PURPOSE 1 and 2 trials, a majority of participants preferred twice-yearly LEN LA over oral PrEP [43, 46]. High acceptability scores were reported among adult males using CAB LA through Month 6 of the PILLAR study [41]. In the phase 4 EBONI study, more than 95% of Black women reported positive experiences with CAB LA and indicated they would recommend it to others [42]. CLARITY expands on these findings by directly comparing CAB LA and LEN LA acceptability and preferences. Prior to the CLARITY study, no direct comparative data were available evaluating ISR profiles and injection experiences between CAB LA and LEN LA. CLARITY addresses this evidence gap by directly comparing ISR profiles, injection experiences, and preferences in participants who received both CAB LA and LEN LA.

These results also have implications for the use of CAB LA and LEN LA among people with HIV. As the combination of CAB LA and LEN LA for treatment continues to be investigated [25–27], findings from CLARITY provide insight into how the injection experience may shape preferences and choices among people with HIV and their healthcare providers. However, the CLARITY study population differs from people receiving LAIs for treatment, where selection of LAIs is primarily driven by the need to maintain virologic suppression. As a result, acceptance of and perspectives on distinct injection site reaction profiles may differ.

CLARITY has several strengths, including the direct comparison between 2 LAIs in the same participants. The randomized crossover design reduced potential bias by minimizing potential sequence effects and allowed for within-participant comparisons and assessments of preferences consistent with US Food and Drug Administration recommendations [47]. Another strength is the use of the validated PIN questionnaire, which has established use in HIV research and related contexts [38, 48].

CLARITY also has limitations. Participants received only a single dose of each LAI, which does not reflect clinical practice where individuals would receive maintenance injections. Although CLARITY was designed to evaluate a single dose of each CAB LA and LEN LA, the initial injection experience can be the catalyst for continuation or subsequently discontinuation of LAIs [33, 34]. Because both medicines are long-acting, attribution of systemic AEs to a specific LAI was difficult to assess as participants received both study medications. Furthermore, the single-center design of the study limits the generalizability of its results, and HCP preferences may be influenced by local practices or institutional leadership. Although we did not consider an individual’s risk for HIV, Centers for Disease Control and Prevention guidelines recommend informing all sexually active individuals about PrEP and prescribing PrEP to anyone who asks for it, including those without HIV risk factors [36]. Finally, this analysis includes data through Day 22; the study is ongoing and longer-term follow-up data will provide additional information on ISR incidence, duration, and participant experience.

Conclusion

We show that CAB LA injections were more acceptable than LEN LA and were associated with a more favorable ISR profile. Participants reported less impact of CAB LA injections on daily activities and their perceptions of body image and self-consciousness. These differences contributed to participant and to HCP preferences, with a majority of both favoring CAB LA over LEN LA (90% of participants and 86% of HCPs). These findings demonstrate that the injection experience can influence the preferences and choices of individuals who can benefit from PrEP, people with HIV, and their HCPs when selecting an LAI.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Conceptualization: Dainielle Fox, Richard Grove, Nanlesta Pilgrim, Piotr Budnik, Jean van Wyk, Kimberley Brown; Data curation: Emilie Elliot, Justine Boles, Dainielle Fox, Kehui Wang, Richard Grove, Kimberley Brown; Formal analysis: Emilie Elliot, Justine Boles, Dainielle Fox, Suryakant Somvanshi, Richard Grove, Kimberley Brown; Funding acquisition: Dainielle Fox, Kimberley Brown; Investigation: Emilie Elliot, Justine Boles, Dainielle Fox, Apinya Vutikullird, Amber Mottola, Kim Fletcher, Kehui Wang, Suryakant Somvanshi, Richard Grove, Katie Strano, Nanlesta Pilgrim, Laure Dupont-Benjamin, Piotr Budnik, Kimberley Brown; Methodology: Dainielle Fox, Suryakant Somvanshi, Richard Grove, Nanlesta Pilgrim, Laure Dupont-Benjamin, Jean van Wyk, Piotr Budnik, Kimberley Brown; Project administration: Emilie Elliot, Justine Boles, Dainielle Fox, Kim Fletcher, Rebecca Borsi, Kimberley Brown; Resources: Emilie Elliot, Justine Boles, Dainielle Fox, Kim Fletcher, Piotr Budnik, Kimberley Brown; Software: Justine Boles, Dainielle Fox, Kim Fletcher, Kehui Wang, Suryakant Somvanshi, Richard Grove, Kimberley Brown; Supervision: Emilie Elliot; Justine Boles, Dainielle Fox, Piotr Budnik, Jean van Wyk, Harmony P. Garges, Kimberley Brown; Validation: Emilie Elliot, Justine Boles, Dainielle Fox, Apinya Vutikullird, Amber Mottola, Kehui Wang, Suryakant Somvanshi, Richard Grove, Nanlesta Pilgrim, Jean van Wyk, Harmony P. Garges, Kimberley Brown; Visualization: Emilie Elliot, Justine Boles, Dainielle Fox, Katherine L. Nelson, Kim Fletcher, Kehui Wang, Suryakant Somvanshi, Laure Dupont-Benjamin, Rebecca Borsi, Piotr Budnik, Jean van Wyk, Kimberley Brown; Writing – original draft: Emilie Elliot, Justine Boles, Dainielle Fox, Katherine L. Nelson, Kehui Wang, Suryakant Somvanshi, Nanlesta Pilgrim, Laure Dupont-Benjamin, Piotr Budnik, Kimberley Brown. Writing – review and editing: Emilie Elliot, Justine Boles, Dainielle Fox, Katherine L. Nelson, Apinya Vutikullird, Amber Mottola, Kim Fletcher, Kehui Wang, Suryakant Somvanshi, Richard Grove, Katie Strano, Nanlesta Pilgrim, Laure Dupont-Benjamin, Rebecca Borsi, Piotr Budnik, Jean van Wyk, Harmony P. Garges, Kimberley Brown.

Funding

This study was funded by ViiV Healthcare. The journal’s Rapid Service and Open Access Fees were funded by ViiV Healthcare.

Data Availability

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Declarations

Conflict of Interest

Justine Boles, Emilie Elliot, Dainielle Fox, Nanlesta Pilgrim, Rebecca Borsi, Piotr Budnik, Jean van Wyk, and Kimberley Brown are employees of ViiV Healthcare and may hold stock in GSK. Katherine L. Nelson was an employee of ViiV Healthcare at the time of this work and may hold stock in GSK and is now an employee of and holds stock in Merck. Apinya Vutikullird has received travel support for Investigator meetings from Akero Therapeutics, AstraZeneca, Boehringer Ingelheim, 89bio, Eli Lilly, Regeneron, and Viking. Kim Fletcher, Kehui Wang, Suryakant Somvanshi, Richard Grove, and Harmony P. Garges are employees of and hold stock in GSK. Laure Dupont-Benjamin is an employee of ViiV Healthcare; owns stock in AbbVie, GSK, Haleon, and ViiV Healthcare; and has received consulting fees from the International Union Against Tuberculosis and Lung Disease. Amber Mottola and Katie Strano have nothing to disclose.

Ethical Approval

The study was conducted in accordance with legal and regulatory requirements and the principles in the Declaration of Helsinki and the Council for International Organizations of Medical Sciences international ethical guidelines. An institutional review board reviewed and approved the study protocol and other relevant documents (Advarra IRB: Pro00085558, approved March 19, 2025), and all participants provided written informed consent before study enrollment.