Acceptability and tolerability of long-acting injectable cabotegravir or rilpivirine in the first cohort of virologically suppressed adolescents living with HIV: results from the More Options for Children and Adolescents (IMPAACT 2017/MOCHA) phase I/II trial

Summary

Background

Long-acting injectable Cabotegravir (CAB-LA) and Rilpivirine (RPV-LA) have demonstrated safety, acceptability and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA Study [More Options for Children and Adolescents]; ClinicalTrials.gov Identifier: NCT03497676) was the first to use these injectable formulations in adolescents (12 to <18 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in Cohort 1 of the study.

Methods

With continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either CAB-LA or RPV-LA and 52 received at least 2 injections. This secondary analysis of participant-reported outcomes included a Face Scale assessment of pain at each injection and a Pediatric Quality of Life Inventory (PedsQL^™) at baseline and Week 16 for participants in the United States (U.S.), South Africa, Uganda, Botswana and Thailand. A subset of 11 adolescents and 11 parents/caregivers in the U.S. underwent in-depth interviews after receipt of 1 or 2 injections.

Findings

Using the 6-point Face Scale, the majority of the 29 male and 26 female participants (43/52 (83%) at Week 4 and 38/52 (73%) at Week 8) reported that the injection caused “No Hurt” or “Hurts little bit” while only a single participant (2%) rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents/caregivers in the U.S. frequently had more hesitancy than adolescents about use of LA formulations, but parental acceptance was higher after their children received injections.

Interpretation

High acceptability and tolerability of CAB-LA or RPV-LA injections suggests that these are likely to be favored treatment options for some adolescents living with HIV.

Funding

The study was funded by the National Institutes of Health and ViiV Healthcare, Inc.

Introduction

The IMPAACT 2017 Phase I/II Study of Safety, Acceptability, Tolerability and Pharmacokinetics of Oral and Long-acting Injectable Cabotegravir (CAB-LA) and Long-acting Injectable Rilpivirine (RPV-LA) in Virologically Suppressed HIV-1-Infected Children and Adolescents is titled the “MOCHA” Study in recognition of its role as the first study to provide More Options for Children and Adolescents in the form of long-acting injectable antiretroviral (LA ART) medications for the treatment of HIV-1. CAB-LA + RPV-LA is the first LA regimen recommended for the maintenance of virologic suppression in adult people living with HIV-1 (PLHIV)¹. The MOCHA study represented the first opportunity to assess the acceptability and tolerability of LA ART in children between 12 and <18 years of age. LA ART has been identified as a key area for development to advance treatment of HIV-1 in children², yet we lack data on how well these formulations will be accepted and tolerated by young PLHIV and their parents. Increased child/adolescent and parental satisfaction with HIV-1 treatment have been shown to improve adherence and long-term treatment success³. The manuscript reports the tolerability and acceptability of CAB-LA or RPV-LA among the first adolescents receiving one of these formulations while continuing their daily oral ART, as part of the study done to confirm appropriate dosing for this age group.

In adult PLHIV, once-monthly CAB-LA + RPV-LA has been found to be highly acceptable in diverse practice sites in the United States (U.S.), although adverse events (AEs) were common, with injection site reactions as the most frequently reported AEs⁴. Transitioning of dosing from monthly to every 2 months has been found to maintain efficacy in adults with the benefit of fewer injections, but higher injection volumes⁵.

Pre-implementation preferences for LA injectable ART formulations differ by the population studied, with adolescents showing both a strong interest and a variety of perceived obstacles such as possible challenges with the frequency of clinic visits required for LA ART⁶. For treatment of adolescents with chronic diseases, decision-making is complex, requiring discussion and collaboration between the adolescents, their parents and medical providers⁷. We aimed to identify acceptability and tolerability aspects unique to the participant population and to evaluate adolescent participants’ experiences with CAB-LA or RPV-LA in the first group of adolescents to access these products. The MOCHA study has two consecutive cohorts with Cohort 1 establishing dose, safety and pharmacokinetics (PK) of oral and injectable CAB-LA and RPV-LA in virologically suppressed adolescents who remain on their pre-study oral ART regimen. This manuscript describes Cohort 1 participant-reported outcomes and the experiences of a subset of parents/caregivers. The study is ongoing with Cohort 2, in which adolescents are receiving both CAB-LA and RPV-LA without oral ART.

Effective implementation of evidence-based practices remains a significant challenge and participant-reported outcomes can help guide preparation for successful implementation programs. Determinant frameworks help to elucidate the context in which a practice will be implemented and can help with planning for sustainable development of processes for implementing new interventions⁸. The work described in this manuscript was guided by the Consolidated Framework for Implementation Research (CFIR)⁹ in order to inform the future implementation of sustainable treatment programs for adolescents living with HIV-1 who can benefit from receipt of LA ART.

Methods

Study design

IMPAACT 2017 is a Phase I/II, multicenter, open-label, noncomparative dose-finding study (NCT03497676) with Cohort 1 conducted at eight U.S. and seven international sites in 4 countries (South Africa, Uganda, Botswana and Thailand). The study was approved by applicable IRBs at each participating site, with Advarra converting to serve as the single IRB for U.S. sites in November 2020. The study protocol can be found on the IMPAACT Network website: https://www.impaactnetwork.org/studies/impaact2017.

Participants

Adolescent participants had confirmed HIV-1 infection, were between ages 12 and <18 years with body weight ≥35 kg and body mass index (BMI) ≤31∙5 kg/m², and had been on stable ART with an HIV-1 viral load <50 copies/mL at a participating IMPAACT study site. For Cohort 1 of the study, reported herein, there was a target enrolment of up to 55 participants to achieve at least 15 dose-evaluable adolescents on each LA formulation. Participants on protease inhibitor-based or non-nucleoside reverse transcriptase inhibitor-based ART were assigned to receive CAB-LA (Cohort 1C) and participants on non-boosted integrase inhibitor-based ART were assigned to receive RPV-LA (Cohort 1R). Since the primary objectives of Cohort 1 were to confirm dosing of the investigational products, participants had to be willing to continue their pre-study ART during Cohort 1 but were given the option to participate in Cohort 2 where CAB + RPV-LA were given as a complete regimen to replace oral treatment. All adolescent participants and their parent/legal guardian provided written assent and consent, as applicable.

For U.S.-based participants, parents/caregivers were also eligible to enroll for in-depth interviews (IDIs). Eligibility for IDIs for both adolescents and parents/caregivers included being willing to be interviewed in English. A maximum sample size of 30 interviews was pre-determined with the goal of continuing interviews until thematic saturation was achieved. Initially, all participants who met IDI inclusion criteria were asked to participate in this component. Later in the enrollment period, the interview team purposively selected IDI participants to improve the balance of adolescent participant sex at birth, age (both older and younger adolescents), and enrollment site in the completed interviews. The eligible parent/caregiver was determined by the enrolled adolescent based on the criterion of who is most involved in supporting their medication-taking. Written consent was provided by adult participants.

Procedures

For this secondary analysis, enrolled adolescents completed questionnaires related to participant-reported outcomes as detailed further below. The study schema showing the dosing schedule and timing of quantitative and qualitative acceptability and tolerability assessments is outlined in Figure 1. Step 1 consisted of oral lead-in dosing of CAB or RPV. Participants who met safety criteria to advance to injectable study product then entered study Step 2 and received CAB-LA or RPV-LA in the gluteus medius. Participants enrolled to Protocol Version 2.0 received a total of three individual intramuscular doses of either CAB-LA or RPV-LA administered four weeks apart. The first dose was 3mL (600mg CAB-LA or 900mg RPV-LA) and the second and third doses were 2mL (400mg CAB-LA or 600mg RPV-LA); this was aligned to the monthly dosing regimen in adults. Participants enrolled to Protocol Version 3.0 received a first 3mL intramuscular dose of 600mg CAB-LA or 900 mg RPV-LA and an identical dose four weeks later,aligned with the initial doses of the every-2-month dosing regimen previously established for adults.

Figure 1:

Acceptability and tolerability data collection schedule. The pain during injection questionnaire used a face scale. PIN=perceptions of injections. PedsQL=Pediatric Quality of Life Inventory

Quantitative assessments were administered by site staff via questionnaires covering reasons for switching from daily oral ART to LA study products, participant perceptions of study injections, and quality of life. Training and written standard operating procedures helped ensure uniformity of administration across sites, including strategies for asking sensitive questions, the importance of reading items word-for-word, avoiding educating participants during data collection and reporting of open-ended responses verbatim. All participant-reported outcome questionnaires were administered to the adolescents at all enrolling sites, except for the perceptions of injection questionnaire. This questionnaire was administered only to adolescents from U.S. sites whose primary language was English or Spanish for proprietary reasons.

A Reason-for-Switch Questionnaire, was created by the study team to document participants’ reasons for wanting to try the LA study product. Adolescents were asked to select all reasons that applied to them from a list of possible motivations for trying LA ART. The final choice option was “other” with a free-text response space to collect reasons that were not identified a priori by the study team. After identifying all applicable reasons, participants specified which reason was the most important to them.

Pain during injections was assessed using the Faces Pain Scale-Revised which includes 6 visual and text options: “no hurt,” “hurts little bit,” “hurts little more,” “hurts even more,” “hurts whole lot” and “hurts worst¹⁰.” Pain and other sensations and changes in function related to receipt of study injections were assessed using the Perceptions of Injection (PIN) Questionnaire, an adapted version of the Vaccinees’ Perception of Injection (VAPI) questionnaire. The PIN evaluates acceptability and tolerability of injections and injection site reactions, scoring items across four dimensions with a 5-point Likert Scale ranging from “totally acceptable” (1) to “not at all acceptable” (5)¹¹.

A commonly used 23-item Pediatric Quality of Life Inventory, the PedsQL^TM, was used to measure physical, emotional, and social dimensions of health as well as school functioning¹².

U.S. participants were eligible to complete a single IDI any time after the first injectable dose and before the Week 12 visit. Interviews were conducted by members of the protocol team who were not at an enrollment site and were not known to any study participants. For the interviews, interviewees were in private locations in the clinic or in their own homes, depending on their preference. Example interview guides are available in the Online Supplemental information. Interviews were audio recorded through a secure audio conference administered through the Children’s Hospital of Philadelphia Information Services and PGi services ReadyConference Plus conferencing system. Recordings were securely transmitted to ADA Transcription (Mt. Holly, NJ) which provided professional transcription of the audio files. The interviewer reviewed each transcript for accuracy and completeness prior to coding.

Outcomes

For the PedsQL^™, a Total score and summary scores for physical, emotional, and social dimensions of health and for school functioning were calculated using published guidelines¹². All other questionnaire responses were reported based on number(%) responding for each item since no validated summation methods exist. Qualitative outcomes were themes arising from the IDIs, guided by the CFIR Framework.

Analysis

Questionnaire data were summarized as described above. Qualitative analysis began during data collection to allow for an iterative process through which questions and probes were refined to enhance the depth of understanding elicited. Topics arising from open-ended inquiries in early interviews were incorporated into prompts for subsequent interviews. Thematic saturation was evaluated during analysis of the transcripts by multiple investigators, based on agreement that new information ceased to arise from new interviews. Analysis used a thematic approach whereby the protocol interview team and coding assistants searched for patterns in the data to help conceptualize ideas that helped explain the presence of those patterns¹³. Analysis began with reading and rereading transcripts until content became intimately familiar¹⁴. The initial code book was designed using the CFIR framework (See Supplemental Table 1, Appendix Page 1) and emergent themes were incorporated into the code book as they arose in the transcripts. Code definitions, including inclusion and exclusion criteria were documented in the code book to improve inter-coder reliability. Coders assigned codes to sections of the text using NVivo 12 software¹⁵. All transcripts were independently double-coded and coders compared and reconciled coding results with assistance from the lead qualitative investigator in group meetings. Once transcripts were coded, principle sub-themes were identified within each code that reflected finer distinctions in the data. Matrices were used to display the data to highlight differences arising from different groups, including: adolescents versus parents/caregivers, age (older versus younger), sex, enrollment site, and whether they received CAB-LA or RPV-LA. Relationships between themes and speakers were mapped to highlight and clarify similarities and differences in perspective.

Role of the funding source

The study was sponsored and funded by the National Institutes of Health (NIH). The DAIDS provided regulatory oversight. ViiV Healthcare, Inc. and Janssen provided study products and funds to the NIH but were not involved in sponsorship or regulatory oversight. Representatives of NIH, ViiV Healthcare, Inc., and Janssen participated in study design, data interpretation, and manuscript writing.

Results

Participant characteristics are outlined in Table 1 for all included adolescents who completed study questionnaires and for the subset of adolescents who completed IDIs. Tables 2–5 summarize data from the Reasons for Switch, Faces Pain Scale, PedsQL^™ and PIN questionnaires, respectively. Most adolescents expressed that they hoped someday to take medicine that does not require daily pills and that they are interested in research of new treatments, with the former reason driving participation for most (54.7%). Despite the high motivation to have non-pill regimens, 58.2% indicated that they find it “easy” or “very easy” to take their pills every day as recommended by their doctor. Perceptions of the injections were similar across time points. Most adolescents reported either having no injection-related symptoms or being only “a little” bothered by symptoms. The number of adolescents endorsing each of the injection-related symptom queried is summarized in Table 5. Few adolescents reported being “moderately,” “very,” or “extremely” bothered by any injection-related symptoms. The symptom most commonly endorsed was pain during the injection with 26.1%, 17.4% and 13.0% being “a little,” “moderately” or “very” bothered by pain during the injection, respectively. Three (37.5%) in the CAB-LA group reported having a little or moderate bruising at the injection site while one (6.7%) in the RPV-LA group reported bruising. At least a little pain with sitting was reported in 67.5% of those in the CAB-LA group compared with 33.3% of those in the RPV-LA group. Overall, adolescents receiving RPV-LA rated their pain and reactions to the injections as more acceptable than adolescents receiving CAB-LA. However, two adolescents (one in the RPV-LA arm and one in the CAB-LA arm) rated their pain and reactions as “not at all acceptable.” PedsQL scores were similar between baseline (pre-injection) and Week 16 (Supplemental Table 2, Appendix Page 3).

Table 1:

Participant demographic characteristics for total cohort completing acceptability and tolerability assessments (a) and qualitative interview participants (b)

(a) Demographic Characteristic Total study cohort	Cohort 1Ca N=30	Cohort 1Rb N=25	TOTAL N=55 adolescents
Adolescent Ages (years)
12–13	5 (17)c	3 (12)	8 (15)
14–15	14 (47)	7 (28)	21 (38)
16–17	11 (37)	15 (60)	26 (47)
Adolescent Sex
Male	16 (53)	13 (52)	29 (53)
Female	14 (47)	12 (48)	26 (47)
Weight
< 50 kg	17 (57)	10 (40)	(49)
≥ 50 kg	13 (43)	15 (60)	(51)
Raced
Asian	9 (30)	0	9 (16)
Black	21 (70)	21 (84)	42 (76)
White	0	4 (16)	4 (7)
Enrollment Country
Botswana-based sites	0	5 (20)	5 (9)
Thailand-based sites	8 (27)	0	8 (15)
US-based sites	8 (27)	17 (68)	25 (45)
South Africa-based sites	14 (47)	3 (12)	17 (31)
Protocol Version at Enroll
V2.0e	8 (27)	15 (60)	23 (42)
V3.0f	22 (73)	10 (40)	32 (58)
(b) Demographic Characteristic Qualitative interviews	Cohort 1C N=6	Cohort 1R N=5	TOTAL N=11 adolescents
Ages
12–13	2	1	3 (27)
14–15	2	1	3 (27)
16–17	2	3	5 (45)
Sex
Male	5	1	6 (55)
Female	1	4	5 (45)
Weight
< 50 kg	3	1	4 (36)
≥ 50 kg	3	4	7 (64)
Total # of Injections at Time of Interview
1	2	0	2 (18)
2	4	5	9 (82)
Enrollment Site
Emory School of Medicine	0	3	3 (27)
Johns Hopkins University	1	2	3 (27)
Lurie Children’s Hospital	1	0	1 (9)
University of Colorado, Denver	3	0	3 (27)
University of Southern California, Los Angeles	1	0	1 (9)
	Cohort 1C N=6g	Cohort 1R N=5	TOTAL N=10 parents/caregivers
Relationship of Interviewed Parent/Caregiver to Adolescent (N=10)g
Mother	4g	4	8 (73)
Father	1	0	1 (9)
Grandmother	1	1	2 (18)

^aCohort 1C consisted of participants assigned to receive long-acting cabotegravir injections.

^bCohort 1R consisted of participants assigned to receive long-acting rilpivirine injections.

^cPercent values given in parentheses may not add up to 100 due to rounding. Percent values are omitted when the denominator is <20.

^dEthnicity was collected only for U.S.-based participants, three of whom identified as Hispanic.

^eAll participants in V2.0 were based in the U.S. since international enrollments were not allowed until V3.0.

^fTwo participants in Cohort 1R enrolled under protocol V3.0 were based in the U.S. All other V3.0 enrollees were based outside of the U.S.

^gOne mother is counted twice because she is the mother of two enrolled children. The mother was interviewed only once but spoke separately about her experiences with each of her enrolled children.

Table 2:

Quantitative Acceptability Data from Surveys Administered to Adolescents. Reasons for Switch Questionnaire

Reasons for Switch Questionnaire	Cohort 1C (N=29)a n(%)	Cohort 1R (N=24)a n(%)	TOTAL (N=53)a n(%)
Reasons for wanting to try long-acting injectable medicine b
I am interested in research of new treatments.	19 (66)	21 (88)	40 (75)
My doctor or someone else in my clinic asked me to do the study.	5 (17)	11 (46)	16 (30)
My parent or someone else in my family asked me to do the study.	2 (7)	8 (33)	10 (19)
I do not like the way my current medicine makes me feel.	6 (21)	2 (8)	8 (15)
I am worried that my current medicine might cause me problems in the future.	3 (10)	2 (8)	5 (9)
I find it difficult to take my current medication on a regular basis.	7 (24)	9 (38)	16 (30)
I hope that someday I can take medicine that does not make me have to take pills every day.	23 (79)	21 (88)	44 (83)
Some other reason.	4 (14)	1 (4)	5 (9)
Primary reason for wanting to try long-acting injectable medicine
I am interested in research of new treatments.	9 (31)	8 (33)	17 (32)
My doctor or someone else in my clinic asked me to do the study.	0	0	0
My parent or someone else in my family asked me to do the study.	1 (3)	0	1 (2)
I do not like the way my current medicine makes me feel.	1 (3)	0	1 (2)
I am worried that my current medicine might cause me problems in the future.	0	1 (4)	1 (2)
I find it difficult to take my current medication on a regular basis.	2 (77)	2 (8)	4 (8)
I hope that someday I can take medicine that does not make me have to take pills every day.	16 (55)	13 (54)	29 (55)
Some other reason.	0	0	0
How easy or difficult is it for you to take your pills every day as recommended by your doctor?
Very Easy	11 (38)	9 (38)	20 (38)
Easy	6 (21)	6 (25)	12 (23)
Neither Easy nor Difficult	11 (38)	5 (21)	16 (30)
Difficult	1 (3)	4 (17)	5 (9)
Very Difficult	0	0	0

^aTwo U.S.-based participants, one in Cohort 1C and one in Cohort 1R, prematurely discontinued treatment and did not complete questionnaires at the Week 4b visit.

^bParticipants were asked to check all reasons that apply for this question. Since participants could pick more than one reason, total of percent endorsing each option is >100%.

Table 5:

Quantitative Acceptability Data from Surveys Administered to Adolescents. Revised Perceptions of Injection (PIN) Questionnaire

Revised Perceptions of Injection (PIN) Questionnaire	Cohort 1Ca		Cohort 1Rb		TOTAL
	Week 8 n(%)	Week 16 n(%)a	Week 8 n(%)	Week 16 n(%)	Week 8 n(%)	Week 16 n(%)
Number of Participants c	0	8	2	15	2	23
Feel anxious about getting the injection before your last injection?
Not at all	-	4	1	9	1	13 (57)
A little		4	1	5	1	9 (39)
Moderately		0	0	1	0	1(4)
Very		0	0	0	0	0
Extremely		0	0	0	0	0
How bothered were you by pain during the injection?
Not at all	-	3	0	8	0	11 (48)
A little		3	1	3	1	6 (26)
Moderately		2	0	3	0	5 (22)
Very		0	1	1	1	1 (4)
Extremely		0	0	0	0	0
How bothered were you by pain in your butt (buttock)?
Not at all	-	5	2	5	2	10 (44)
A little		0	0	6	0	6 (26)
Moderately		1	0	3	0	4 (17)
Very		2	0	1	0	3 (13)
Extremely		0	0	0	0	0
How bothered were you by redness at the injection site?
Not at all	-	8	2	15	2	23 (100)
A little		0	0	0	0	0
Moderately		0	0	0	0	0
Very		0	0	0	0	0
Extremely		0	0	0	0	0
How bothered were you by swelling at the injection site?
Not at all	-	8	2	12	2	20 (87)
A little		0	0	3	0	3 (13)
Moderately		0	0	0	0	0
Very		0	0	0	0	0
Extremely		0	0	0	0	0
How bothered were you by itching at the injection site?
Not at all	-	7	2	15	2	22 (96)
A little		1	0	0	0	1 (4)
Moderately		0	0	0	0	0
Very		0	0	0	0	0
Extremely		0	0	0	0	0
How bothered were you by hardening (a bump) at the injection site?
Not at all	-	8	2	11	2	19 (83)
A little		0	0	4	0	4 (17)
Moderately		0	0	0	0	0
Very		0	0	0	0	0
Extremely		0	0	0	0	0
How bothered were you by bruising at the injection site?
Not at all	-	5	2	14	2	19 (83)
A little		2	0	1	0	3 (13)
Moderately		1	0	0	0	1 (4)
Very		0	0	0	0	0
Extremely		0	0	0	0	0
How much were you bothered when you were trying to fall asleep?
Not at all	-	5	0	10	0	15 (65)
A little		1	1	3	1	4 (17)
Moderately		1	0	1	0	2 (9)
Very		1	1	1	1	2 (9)
Extremely		0	0	0	0	0
How much were you bothered when you were rolling over or moving during sleep?
Not at all	-	5	1	8	1	13 (57)
A little		2	0	5	0	7 (30)
Moderately		0	0	1	0	1 (4)
Very		1	1	1	1	2 (9)
Extremely		0	0	0	0	0
How much were you bothered when you were walking?
Not at all	-	2	1	9	1	11 (48)
A little		4	1	2	1	6 (26)
Moderately		1	0	3	0	4 (17)
Very		0	0	1	0	1 (4)
Extremely		1	0	0	0	1 (4)
How much were you bothered when you were sitting?
Not at all	-	3	0	11	0	14 (61)
A little		4	1	2	1	6 (26)
Moderately		0	0	1	0	1 (4)
Very		1	1	1	1	2 (9)
Extremely		0	0	0	0	0
How much were you bothered when you were exercising, playing or lifting heavy objects?
Not at all	-	5	1	9	1	14 (61)
A little		1	0	3	0	4 (17)
Moderately		1	0	1	0	2 (9)
Very		1	1	1	1	2 (9)
Extremely		0	0	1	0	1 (4)
How much pain did you feel when you were trying to fall asleep?
Not at all	-	5	1	12	1	17 (74)
A little		1	1	1	1	2 (9)
Moderately		1	0	1	0	2 (9)
Very		1	0	1	0	2 (9)
Extremely		0	0	0	0	0
How much pain did you feel when you were rolling over or moving during asleep?
Not at all	-	5	1	9	1	14 (61)
A little		0	1	5	1	5 (22)
Moderately		2	0	0	0	2 (9)
Very		1	0	1	0	2 (9)
Extremely		0	0	0	0	0
How much pain did you feel when you were walking?
Not at all	-	4	2	9	2	13 (57)
A little		2	0	2	0	4 (17)
Moderately		0	0	3	0	3 (13)
Very		1	0	0	0	1 (4)
Extremely		1	0	1	0	2 (9)
How much pain did you feel when you were sitting?
Not at all	-	3	1	10	1	13 (57)
A little		4	1	2	1	6 (26)
Moderately		0	0	2	0	2 (9)
Very		1	0	0	0	1 (4)
Extremely		0	0	1	0	1 (4)
How much pain did you feel when you were exercising, playing or lifting heavy objects?
Not at all	-	4	2	9	2	13 (57)
A little		2	0	3	0	5 (22)
Moderately		0	0	2	0	2 (9)
Very		1	0	1	0	2 (9)
Extremely		1	0	0	0	1 (4)
How acceptable was/were the reaction(s) you had to the injection?
Totally acceptable	-	3	1	8	1	11 (48)
Acceptable		1	0	3	0	4 (17)
Moderately acceptable		4	1	2	1	6 (26)
A little acceptable		0	0	1	0	1 (4)
Not at all acceptable		0	0	1	0	1 (4)
How acceptable was your pain?
Totally acceptable	-	2	0	6	0	8 (35)
Acceptable		0	1	2	1	2 (9)
Moderately acceptable		5	0	6	0	11 (48)
A little acceptable		0	1	1	1	1 (4)
Not at all acceptable		1	0	0	0	1 (4)
How satisfied were you with the needle and syringe that were used to give you the injection?
Very satisfied	-	2	0	3	0	5 (22)
Satisfied		4	2	5	2	9 (39)
Neither satisfied nor dissatisfied		1	0	6	0	7 (30)
Dissatisfied		0	0	1	0	1 (4)
Very dissatisfied		1	0	0	0	1 (4)
How anxious do you feel about getting your next injection?
Not at all	-	1	1	5	1	6 (26)
A little		3	1	1	1	4 (17)
Moderately		1	0	1	0	2 (9)
Very		1	0	1	0	2 (9)
Extremely		0	0	0	0	0
Not applicable		2	0	7	0	9 (39)
If you were not involved in this study, would you want to receive your medicine as injections?
Yes, definitely	-	4	0	11	0	15 (65)
Yes, probably		4	0	1	0	5 (22)
I don’t know		0	0	1	0	1 (4)
Probably not		0	2	2	2	2 (9)
Definitely not		0	0	0	0	0
How much more likely would you be to want to receive your medicine as injections if you could receive the injections every 8 weeks instead of every 4 weeks?
Much more likely	-	7	1	11	1	18 (78)
A little bit more likely		1	1	2	1	3 (13)
Neither more likely nor less likely		0	0	2	0	2 (9)

^aCohort 1C consisted of participants assigned to receive long-acting cabotegravir injections.

^bCohort 1R consisted of participants assigned to receive long-acting rilpivirine injections.

^cPercent values given in parentheses may not add up to 100 due to rounding. Percent values are omitted when the denominator is <20. Only domestic, English and Spanish-speaking participants are included for the Perceptions of Injections Questionnaire.

While our final few interviews did not elicit any new themes, we are not confident that thematic saturation was achieved for younger adolescents. Only three 12- and 13-year-olds were eligible for IDIs. In the interviews with U.S.-based participants, the participants overwhelmingly indicated that they found the LA formulations to be desirable. However, they also highlighted practical concerns about switching from oral to injectable LA ART. The codes that were most represented in the interview data are summarized by CFIR domain in Supplemental Table 3, Appendix Page 4. Themes related to not having to remember to take pills/avoiding the stress of monitoring adolescents’ daily medication-taking and not having to worry about hiding pills from peers dominated discussions of the relative advantage of LA versus pill-based regimens. However, the ability to maintain a routine injection schedule when busy with school, extracurricular activities and work, particularly for those planning to move to college was a coexisting common concern.

When stratified by participants’ age, sex, enrollment site, and whether they received CAB-LA or RPV-LA, no consistent differences in themes emerged. However, perspectives of adolescents receiving the LA medications and their parents/caregivers differed in several key respects. Pre-study disagreements between adolescents and their consenting parents/caregivers regarding whether the adolescent should initiate LA ART were described. Key similarities and differences between adolescent and parent/caregiver perspectives are outlined below.

Both adolescents and parents/caregivers had positive assessments of their experience with the LA formulations. They agreed that adaptability is a key advantage of the LA formulations. However, parents/caregivers had many more concerns than their children regarding the strength and quality of evidence supporting the use of the LA products. For those who verbalized the most hesitancy, their trust in their healthcare providers played a key role in their ultimately agreeing to let the adolescent try the LA formulation. Parents/caregivers expressed having greater initial fear about the process of ensuring safety and practical follow-up needs. However, all interviewed parents/caregivers reported being reassured after experiencing the process with the first dose. For example, the mother of a 14-year-old male noted: “I really was scared that he wouldn’t be able to go to school, but he went to school the next day.” After experiencing what it was like for her child to receive the injection, she said: “My advice to other parents is that I think, on my own part, that the injection is better (than daily pills).”

Adolescents’ most consistent concern was about the location of the injection. Many expressed wanting a shot that could be given somewhere other than the buttocks. Nevertheless, all interviewed adolescents expressed that they would recommend LA formulations to their peers. The idea that the LA regimens would relieve them of the hassle and internalized stigma associated with daily pill-taking was seen as compelling. As one 12-year-old female summarized: “Take the shot once a month, be over with it and you can actually live a normal life instead of taking pills in front of people every day or looking at yourself like you’re not a real human or something.” However, while some saw the ability to avoid daily reminders of their HIV status (i.e., through taking pills) as a positive, a few noted that more frequent clinic visits could add to their stress related to living with HIV-1. A 14-year-old male expressed that: “Especially for that teenager who’s already not liking to be reminded that they’re HIV positive. Then actually having to go to the clinic every month would not be necessarily a positive experience for them.”

Discussion

Through both quantitative assessments asked of all adolescent participants and in-depth interviews of U.S.-based adolescents and parents/caregivers enrolled in Cohort 1 of the MOCHA study, we established that acceptability and tolerability of CAB-LA or RPV-LA injections was high. The MOCHA study data provide timely evidence for the high acceptability and tolerability of these injections, given the CAB + RPV-LA regimen has been FDA approved for treatment of adolescents 12 years of age and older and weighing at least 35kg including an optional oral lead-in (for tolerability) as well as an every-2-months dosing option¹⁶. A previous study including five individual interviews with parents of children living with HIV-1 in the U.S. showed that parents’ interest in LA ART varied according to their child’s age and sensitivity to injections¹⁷. However, a survey of 303 youth living with HIV between the ages of 13–24 years at four U.S. clinical sites revealed high enthusiasm with 88% reporting that they were probably or definitely willing to use LA ART¹⁸. Data from this study suggest that 12–<18-year-olds are likely to maintain their enthusiasm after experiencing receipt of this treatment modality. Adolescents in this phase of the study were required to continue their oral ART. When able to stop their oral ART, their enthusiasm may be higher. However, tolerability in adolescents after receiving both injections over a longer period still needs to be evaluated. The ongoing MOCHA Study Cohort 2 will provide some of these data.

A particularly notable aspect of the qualitative data from the current study is the initial discordance between parental and adolescent attitudes about LA ART, with the interviewed adolescents showing less hesitancy. This may be a reflection of parents’ overall higher risk aversion when making decisions for their adolescents¹⁹. However, the convergence of positive views of the LA ART after receipt suggests likelihood that both participant-reported and parent-reported outcomes after use of the combined CAB-LA and RPV-LA without pre-study oral ART may be similar to the high acceptability in adult treatment studies^4,11,20.

Although minor consent laws throughout the U.S. allow adolescents to consent for their own HIV treatment²¹, parental consent was required for study participation. Therefore, adolescents whose parents had recalcitrant hesitancy might have been excluded from this study. The generalizability of our findings may also be limited by the data being primarily from U.S. sites. Social desirability bias may also have led to participants reporting more favorable views of the study products. Questionnaires were completed with support from site staff who generally were known to the participants. While having staff ask the questions was efficient and avoided missing data issues, participants might have been less willing to give negative assessments directly to site staff. We attempted to minimize the risk of social desirability bias in the in-depth interviews by conducting interviews in a private space over the phone. Interviewers who were not known to participants connected from a distant site and ensured participants that information identifying individual participant views would not be shared with site staff. The major limitation of the interviews was that we did not conduct as many as initially planned due to the study opening to international sites without approval being granted for in-depth interviews of non-U.S. participants. Since we were unable to sample to thematic saturation for younger adolescents, we cannot say whether developmental issues of early adolescence may raise unique concerns with regards to LA ART.

It is notable that the reported desire to use LA ART was strong in participating adolescents despite most reporting that they do not find it difficult to take pills daily. Individual enrolling in clinical trials are frequently a lower-risk population than those in larger real-world populations²². Desire for the LA ART option may be stronger among adolescents with current struggles with adherence to pill-based regimens. The qualitative data from MOCHA Cohort 1 revealed adolescent-specific issues that may have implications on a successful LA ART treatment rollout for the adolescent population. Sustainable effective implementation of LA ART for adolescents will need to consider the implementation determinants stressed by participants in the MOCHA Cohort 1 IDI’s including the need for adolescent-friendly and comprehensive family-centered clinical environments for delivery, flexible options for adolescents going away to college, and supporting attendance for the more frequent clinic visits required with an in-clinic monthly or every-2-months injection dosing regimen.

Table 3:

Quantitative Acceptability Data from Surveys Administered to Adolescents. Pain during Injection Questionnaire (FACES Scale)

Pain during Injection Questionnaire (FACES Scale)	Cohort 1Ca			Cohort 1Rb			TOTAL
	Week 4 (N=29) n(%)	Week 8 (N=29) n(%)	Week 12c (N=8) n(%)	Week 4 (N=23) n(%)	Week 8 (N=23) n(%)	Week 12 (N=13) n(%)	Week 4 (N=52) n(%)	Week 8 (N=52) n(%)	Week 12 (N=21) n(%)
No hurt	12 (41)	9 (31)	6	4 (17)d	3 (13)	3	16 (31)	12 (23)	9 (43)
Hurts little bit	13 (45)	15 (52)	1	14 (61)	11 (48)	4	27 (52)	26 (50)	5 (24)
Hurts little more	2 (7)	4 (14)	1	1 (4)	6 (26)	4	3 (6)	10 (19)	5 (24)
Hurts even more	2 (7)	1 (3)	0	3 (13)	2 (9)	2	5 (10)	3 (6)	2 (10)
Hurts whole lot	0	0	0	1 (4)	1 (4)	0	1 (2)	1 (2)	0
Hurts worst	0	0	0	0	0	0	0	0	0

^aCohort 1C consisted of participants assigned to receive long-acting cabotegravir injections.

^bCohort 1R consisted of participants assigned to receive long-acting rilpivirine injections.

^cOnly participants enrolled in Protocol Version 2.0 received a Week 12 injection.

^dPercent values given in parentheses may not add up to 100 due to rounding.

Table 4:

Quantitative Acceptability Data from Surveys Administered to Adolescents. Quality of Life Questionnaire Summary Scores

Quality of Life Questionnaire Summary Scores	Cohort 1Ca		Cohort 1Rb		TOTAL
	Baseline (N=30) Median (IQR)	Week 16 (N=29) Median (IQR)	Baseline (N=25) Median (IQR)	Week 16 (N=23) Median (IQR)	Baseline (N=55) Median (IQR)	Week 16 (N=52) Median (IQR)
Physical functioning dimension	97 (94, 100)	97 (91, 100)	100 (97, 100)	100 (94, 100)	100 (94, 100)	98 (91, 100)
Emotional functioning dimension	90 (80, 100)	95 (80, 100)	90 (70, 100)	95 (90, 100)	90 (75, 100)	95 (88, 100)
Social functioning dimension	100 (90, 100)	100 (95, 100)	95 (90, 100)	100 (95, 100)	100 (90, 100)	100 (95, 100)
School functioning dimension	80 (70, 90)	80 (65, 90)	70 (60, 88)	85 (80, 95)	80 (65, 90)	85 (70, 90)
Psychosocial functioning dimension	90 (82, 97)	92 (77, 97)	83 (77, 95)	92 (87, 97)	90 (78, 95)	92 (86, 97)
Total functioning dimension	93 (87, 97)	94 (83, 97)	89 (84, 96)	95 (90, 98)	91 (84, 96)	94 (87, 97)

^aCohort 1C consisted of participants assigned to receive long-acting cabotegravir injections.

^bCohort 1R consisted of participants assigned to receive long-acting rilpivirine injections.

Research in context.

Evidence before this study

Long-acting injectable Cabotegravir (CAB-LA) and long-acting injectable Rilpivirine (RPV-LA) have been shown to be safe, efficacious, and well-tolerated in adults living with HIV; however, new formulations that are appropriate for adults may not be acceptable to or well-tolerated by children and adolescents. We searched PubMed for articles published prior to writing the study proposal, starting 01 January 2017, using the search terms “long-acting cabotegravir”, “long-acting rilpivirine”, “adolescents”, and “HIV” and found no studies. IMPAACT 2017 is the first study to administer CAB-LA and RPV-LA to adolescents with HIV.

Added value of this study

This study comprehensively evaluated the acceptability and tolerability of CAB-LA or RPV-LA among the first adolescents who received one of these products as part of the Phase I/II IMPAACT 2017/MOCHA study. The opinions of the parents and caregivers of these first adolescents who received LA injectable antiretroviral therapies evaluated key areas of concern for long-term implementation success in adolescents.

Implications of all the available evidence

These data suggest that long-acting injectable antiretroviral therapy is a well-accepted and well-tolerated treatment option for adolescents living with HIV who have chosen to be the first to try these formulations. Taken with the PK and safety data reported separately as a companion manuscript, these data indicate that uptake and continuation of these formulations are likely to be favorable in adolescents.

Data Sharing Statement:

The data cannot be made publicly available due to the ethical restrictions in the study’s informed consent documents and in the IMPAACT Network’s approved human subjects protection plan; public availability may compromise participant confidentiality. However, data are available to all interested researchers upon request to the IMPAACT Statistical and Data Management Center’s Data Access Committee (email: sdac.data@fstrf.org) for quantitative data and to Dr. Lowenthal (email: lowenthale@chop.edu) for in-depth-interview data, following formal agreement of the IMPAACT Network.