Safety and pharmacokinetics of oral and long-acting injectable cabotegravir or long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA): a phase 1/2, multicentre, open-label, non-comparative, dose-finding study

Abstract

Background: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents.

Methods: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m²) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC_0-tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment.

Findings: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC_0-tau was 148·5 (range 37·2-433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22-6·19) and 1·15 μg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults.

Interpretation: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg.

Funding: The National Institutes of Health and ViiV Healthcare.

Figure 1.. Cohort 1 Overview.

Assignment to CAB vs. RPV was based on pre-study cART, which continued during Steps 1 and 2. Abbreviations: CAB, cabotegravir; cART, combination antiretroviral treatment; LA, long acting; Q, every; RPV, rilpivirine.

Figure 2.. CONSORT Flow Diagram of Cohort 1.

Enrollment into Cohort 1C or Cohort 1R was based on the participant’s ongoing pre-study ART regimen. Abbreviations: cART, combination antiretroviral treatment; Q4Weeks, every 4 weeks dosing regimen; Q8Weeks, every 8 weeks dosing regimen.

Figure 3.. Median CAB (A) and RPV (B) concentrations after repeated intramuscular administration during Step 2.

The bars represent the 95% confidence intervals of the medians at each collection point. They were generated through bootstrapping with 1000 replications. The red horizontal line shows the median minimum Week 16 target trough for this study. In the Q4Weeks-dosing regimen, study medication was injected at Weeks 4, 8, and 12; in the Q8Weeks-dosing regimen, at Weeks 4 and 8. No interim PK samples were collected between Weeks 8 and 12 in the Q4Weeks-dosing regimen. PK profiles after the first and third Q4Weeks doses are shown.

Figure 3.. Median CAB (A) and RPV (B) concentrations after repeated intramuscular administration during Step 2.

The bars represent the 95% confidence intervals of the medians at each collection point. They were generated through bootstrapping with 1000 replications. The red horizontal line shows the median minimum Week 16 target trough for this study. In the Q4Weeks-dosing regimen, study medication was injected at Weeks 4, 8, and 12; in the Q8Weeks-dosing regimen, at Weeks 4 and 8. No interim PK samples were collected between Weeks 8 and 12 in the Q4Weeks-dosing regimen. PK profiles after the first and third Q4Weeks doses are shown.

Figure 4.. Observed and predicted CAB and RPV concentrations.

Observed (triangles) and model-predicted (with 90% prediction interval) CAB concentrations in Cohort 1C participants who received Q4Weeks dosing (i.e., CAB-LA injections at Weeks 4 [Loading/Initiation dose], 8, and 12 [Continuation therapy injections every 4 weeks) (A) or Q8Weeks dosing (i.e., CAB-LA injections at Weeks 4 and 8 [Loading/Initiation dose includes two injections 4 weeks apart]) (B). Observed (triangles) and model-predicted (with 90% prediction interval) of RPV concentrations of Cohort 1R participants who received Q4Weeks (C) or Q8Weeks (D) dosing of RPV-LA. A continuation therapy dose was deemed unnecessary for PK assessment on the Q8Weeks-dosing regimen. The model-predicted concentrations represent median (solid line) and 90% prediction interval (5^th and 95^th percentiles [dashed lines]) from simulations based on existing population PK models in adult participants.^,

Figure 4.. Observed and predicted CAB and RPV concentrations.

Observed (triangles) and model-predicted (with 90% prediction interval) CAB concentrations in Cohort 1C participants who received Q4Weeks dosing (i.e., CAB-LA injections at Weeks 4 [Loading/Initiation dose], 8, and 12 [Continuation therapy injections every 4 weeks) (A) or Q8Weeks dosing (i.e., CAB-LA injections at Weeks 4 and 8 [Loading/Initiation dose includes two injections 4 weeks apart]) (B). Observed (triangles) and model-predicted (with 90% prediction interval) of RPV concentrations of Cohort 1R participants who received Q4Weeks (C) or Q8Weeks (D) dosing of RPV-LA. A continuation therapy dose was deemed unnecessary for PK assessment on the Q8Weeks-dosing regimen. The model-predicted concentrations represent median (solid line) and 90% prediction interval (5^th and 95^th percentiles [dashed lines]) from simulations based on existing population PK models in adult participants.^,

Figure 4.. Observed and predicted CAB and RPV concentrations.

Observed (triangles) and model-predicted (with 90% prediction interval) CAB concentrations in Cohort 1C participants who received Q4Weeks dosing (i.e., CAB-LA injections at Weeks 4 [Loading/Initiation dose], 8, and 12 [Continuation therapy injections every 4 weeks) (A) or Q8Weeks dosing (i.e., CAB-LA injections at Weeks 4 and 8 [Loading/Initiation dose includes two injections 4 weeks apart]) (B). Observed (triangles) and model-predicted (with 90% prediction interval) of RPV concentrations of Cohort 1R participants who received Q4Weeks (C) or Q8Weeks (D) dosing of RPV-LA. A continuation therapy dose was deemed unnecessary for PK assessment on the Q8Weeks-dosing regimen. The model-predicted concentrations represent median (solid line) and 90% prediction interval (5^th and 95^th percentiles [dashed lines]) from simulations based on existing population PK models in adult participants.^,

Figure 4.. Observed and predicted CAB and RPV concentrations.

Observed (triangles) and model-predicted (with 90% prediction interval) CAB concentrations in Cohort 1C participants who received Q4Weeks dosing (i.e., CAB-LA injections at Weeks 4 [Loading/Initiation dose], 8, and 12 [Continuation therapy injections every 4 weeks) (A) or Q8Weeks dosing (i.e., CAB-LA injections at Weeks 4 and 8 [Loading/Initiation dose includes two injections 4 weeks apart]) (B). Observed (triangles) and model-predicted (with 90% prediction interval) of RPV concentrations of Cohort 1R participants who received Q4Weeks (C) or Q8Weeks (D) dosing of RPV-LA. A continuation therapy dose was deemed unnecessary for PK assessment on the Q8Weeks-dosing regimen. The model-predicted concentrations represent median (solid line) and 90% prediction interval (5^th and 95^th percentiles [dashed lines]) from simulations based on existing population PK models in adult participants.^,