Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Cabotegravir

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Cabotegravir (CAB) is metabolized primarily by uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1). CAB is contraindicated in patients receiving strong inducers of UGT1A1 because such inducers decrease CAB plasma concentrations which may result in a loss of virologic response.
• Rilpivirine (RPV) is a cytochrome P450 (CYP) 3A substrate, and RPV concentrations may be affected when administered with CYP3A-modulating medications.
• A patient’s medication profile should be carefully reviewed for potential drug interactions before CAB plus RPV is administered.
• CAB and RPV are both highly protein bound and unlikely to be removed by hemodialysis.
• Coadministering oral RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV.
  • Antacids should not be taken less than 2 hours before or less than 4 hours after oral RPV.
  • H2 receptor antagonists should not be administered less than 12 hours before or less than 4 hours after oral RPV.
  • Oral RPV is contradicted with proton pump inhibitors.
• Rifamycin drugs significantly reduce CAB and RPV plasma concentrations. For patients who are concomitantly receiving rifabutin and oral RPV, the dose of RPV should be doubled to 50 mg once daily and taken with a meal. Coadministration of the following drugs is contraindicated:
  • Rifampin and oral RPV
  • Rifampin or rifapentine and CAB
  • Rifabutin and intramuscular (IM) CAB and RPV

Major Toxicities

• More common: Injection site reactions, insomnia, headache, rash, elevated creatine phosphokinase serum concentrations
• More common: In studies of adults, 7.3% of patients who were treated with RPV showed a change in adrenal function characterized by an abnormal 250-microgram adrenocorticotropic hormone stimulation test (peak cortisol level <18.1 micrograms/dL). In a study of adolescents, 6 of 30 patients (20%) developed this abnormality.¹ The clinical significance of these results is unknown.
• Less common (more severe): Depression or mood changes, suicidal ideation
• Rare: Hepatotoxicity, post-injection reactions, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure
• Rare: RPV drug-induced liver injury has been reported.²

Resistance

The International Antiviral Society–USA maintains a list of updated HIV Drug Resistance Mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

CAB oral tablets (Vocabria) and co-packaged LA CAB/RPV (Cabenuva) are approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV in children or adolescents aged ≥12 years and weighing ≥35 kg (2022) and adults (2021). They are not approved for use in children aged <12 years. CAB tablets were approved by the FDA in 2021 for use in adults as part of the oral lead-in prior to beginning LA CAB/RPV or as an oral interim treatment when people miss planned injections.^3,4 CAB and RPV co-packaged extended-release injectable suspensions for IM use are approved for use in people (monthly or every 2 months) who are virologically suppressed on a stable antiretroviral (ARV) regimen with no history of virologic failure or known resistance affecting either of the component drugs.³

In December 2021, the FDA approved CAB IM (Apretude) for HIV pre-exposure prophylaxis (PrEP) in adults and adolescents weighing at least 35 kg; an oral lead-in period of approximately 1 month may be used to assess safety and tolerability but is optional. Refer to the package insert for additional information about dosing and administration,⁵ and see the Centers for Disease Control and Prevention Guidelines for Pre-Exposure Prophylaxis for the Prevention of HIV in the United States for further information about the use of CAB for PrEP.

Efficacy and Pharmacokinetics in Clinical Trials

Clinical Trials in Pediatric Patients 12 years to <18 years

The safety and efficacy of CAB, an HIV-1 integrase inhibitor, given in combination with RPV, a non-nucleoside reverse transcriptase inhibitor (NNRTI), has been characterized in a series of clinical trials conducted in adults, which form the basis for approval.

The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network Study 2017, More Options for Children and Adolescents (MOCHA), is currently in progress to evaluate the safety, tolerability, acceptability, and pharmacokinetics of this injectable regimen in adolescents (MOCHA Trial) and has reported results leading to FDA approval in this age group.

MOCHA evaluated the safety and pharmacokinetics of intramuscular (IM) long-acting CAB and long-acting RPV in virologically suppressed adolescents aged 12 to 17 years weighing ≥35 kg).  In cohort 1, after 4 to 6 weeks of oral CAB (n=30) or RPV (n=25), participants received IM long-acting CAB or long-acting RPV every 4 weeks or 8 weeks per the adult dosing regimens while continuing pre-study ART.  Injection site reactions were observed but did not lead to any treatment discontinuations. Two adolescents experienced Grade 3 drug-related adverse events, one due to insomnia (CAB arm) and one due to hypersensitivity reaction to oral RPV, which led to discontinuation.^6,7 In a concurrent assessment of adolescent and parental experiences with IM treatment in MOCHA, overall perceptions of the injectable treatment were favorable. Of the 21 adolescents who received all three study injections, >90% “definitely” or “probably” wanted to continue IM treatment.^8,9 For participants receiving IM CAB or IM RPV, exposures were similar to those observed in adults. In cohort 2, 144 virologically suppressed adolescents with HIV-1 received 4 weeks of oral CAB plus RPV followed by IM CAB 600 mg and IM RPV 900 mg every 2 months. The 1st and 2nd injections were 4 weeks apart, with subsequent injections every 8 weeks.  Adverse reactions were reported in 35% of adolescents receiving CAB plus RPV with the majority classified as Grade 1 or Grade 2 injection site reactions. Two participants had Grade 3 injection site reactions: injection site abscess (n = 2) and injection site pain (symptoms resolved in both participants). Non-injection-site associated adverse reactions reported by more than one participant (regardless of severity) were headache (n = 3), nausea (n = 2), rash (n = 2) and pruritic rash (n = 2).¹⁰ No virologic failure was observed through Week 24. Predose concentrations of CAB and RPV were similar to those in adults. One participant had a low CAB pre-dose concentration at Week 24 (0.03 µg/mL). Overall, 97% participants at week 8 and 99% of participants at week 24 preferred injectable medications over daily oral dosing which was driven primarily by convenience and burden reduction (i.e., adherence-related stress and increased privacy).¹¹

Intermittent viremias have been reported in young adults transitioned to LA CAB/RPV with oral lead-in.¹² The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV notes that significant questions remain regarding the use of LA CAB/RPV in children and adolescents, including whether an oral lead-in is beneficial in the adolescent population, whether there are additional adverse effects specific to the pediatric population, whether the use of a two-drug nucleoside-sparing regimen for children with significant ARV treatment history is appropriate, and what potential implementation challenges might exist (e.g., cost, procurement and access, retention in care).¹³

Clinical Trials in Adults

The Phase 3 Antiretroviral Therapy as Long-Acting Suppression (ATLAS) study randomized stable, virologically suppressed adults to receive either CAB and RPV (n = 308) or continue their oral antiretroviral therapy (ART) (n = 308). Participants assigned to CAB and RPV initiated therapy with an oral regimen for 4 weeks prior to beginning monthly IM injections. The initial assessment at 48 weeks demonstrated that switching to monthly LA CAB/RPV was noninferior to continuing a three-drug oral therapy. After 48 weeks, participants were allowed to transition to injections every 2 months in a follow-up study (ATLAS-2M, see below); 52 participants remaining on the original ATLAS study were included in the 96-week analysis. Adverse events were more common among participants receiving injectable ART; injection site reactions were common, but only 1% withdrew from the study because of these events.¹⁴ The ATLAS-2M trial randomized participants to monthly IM CAB 400 mg and RPV 600 mg (n = 523) or every-2-month injections of CAB 600 mg and RPV 900 mg (n = 522); it enrolled both new participants and those continuing from the ATLAS trial. After 96 weeks, the every-2-month injections were noninferior to monthly injections, with 11 (2%) confirmed virologic failures in the every-2-month injection group and 6 (1%) in the monthly injection group. No new safety signals were identified, and the rate of injection site reactions—the most common adverse event—was similar across treatment arms. Of those failing the every-2-month injection regimen, a majority had NNRTI resistance–associated mutations.¹⁵

The First Long-Acting Injectable Regimen (FLAIR) study enrolled 631 treatment-naive adults and initiated treatment with a standard oral ARV regimen consisting of dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) for 20 weeks. Those participants with documented HIV-1 RNA <50 copies/mL after 16 weeks were randomized to either continue oral DTG/ABC/3TC (n = 283) or switch to oral CAB and RPV for 4 weeks, followed by monthly injections of CAB and RPV (n = 283). After 96 weeks of randomized therapy, nine participants (3.2%) in each arm had HIV RNA >50 copies/mL. Adverse events were common in both treatment groups, but adverse events leading to withdrawal from the study were observed in only 14 (5%) participants in the LA CAB/RPV group and 4 (1%) in the oral standard care group. Injection site reactions were the most common adverse events, reported by 245 (88%) participants in the LA CAB/RPV, and lasted a median of 3 days.¹⁶ The FLAIR study was extended to include an assessment of switching those participants remaining in the oral ARV arm after 120 weeks to LA CAB/RPV either with or without the initial oral lead-in phase. There were no differences between the lead-in group and the direct-to-injection group in terms of safety, tolerability, or efficacy through an additional 24 weeks on the study.¹⁷

These studies demonstrated noninferiority of switching to monthly LA CAB/RPV compared to continuing oral ART. In all studies, adults expressed a high degree of treatment satisfaction and preference for the LA CAB/RPV regimen. Although documented virologic failure with the LA CAB/RPV regimen has been rare to date, investigators have attempted to assess the baseline factors associated with treatment failure. In a multivariate analysis of the adult LA CAB/RPV Phase 3 trials, presence of at least two baseline factors of RPV resistance–associated mutations, HIV-1 subtype A6/A1, and body mass index >30 kg/m² was associated with increased risk of virologic failure at 48 weeks.¹⁸

Pharmacokinetics

The pharmacokinetics (PK) of IM CAB are driven by slow absorption from the injection site. IM CAB reaches its maximum plasma concentration in adults in about 7 days and has a mean half-life of 5.6 to 11.5 weeks. Measurable levels of CAB can be detected in plasma for up to a year or longer. Due to this prolonged drug exposure, it is essential to initiate an alternative, fully suppressive ARV regimen no later than 1 month after the final injections of CAB and RPV to minimize the potential risk of developing viral resistance.³ The PK profiles observed in adolescents enrolled in MOCHA were comparable to those observed in adults receiving monthly long-acting injectable CAB and RPV in the ATLAS and FLAIR studies described above.⁶

References

1. Vocabria (cabotegravir) tablets,for oral use [package insert]. Food and Drug Administration. 2025. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212887s011lbl.pdf.  

2. Lee MJ, Berry P, D'Errico F, et al. A case of rilpivirine drug-induced liver injury. Sex Transm Infect. 2020;96(8):618-619. Available at: https://pubmed.ncbi.nlm.nih.gov/31974214.

3. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use [package insert]. Food and Drug Administration. 2023. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212888s011lbl.pdf.  

4. Vocabria (cabotegravir) tablets,for oral use [package insert]. Food and Drug Administration. 2023. Available at: https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Vocabria/pdf/VOCABRIA-PI-PIL.PDF.  

5. Apretude (cabotegravir extended-release injectable suspension), for intramuscular use [package insert]. Food and Drug Administration. 2025. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/215499s009lbl.pdf.  

6. Moore CB, Capparelli E, Calabrese K, et al. Safety and PK of long-acting cabotegravir and rilpivirine in adolescents. Presented at: Conference on Retroviruses and Opportunistic Infections 2022. Virtual. Available at: https://www.croiconference.org/abstract/safety-and-pk-of-long-acting-cabotegravir-and-rilpivirine-in-adolescents/.

7. Gaur AH, Capparelli EV, Calabrese K, et al. 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. Lancet HIV. 2024;11(4):e211-e221. Available at: https://pubmed.ncbi.nlm.nih.gov/38538160.

8. Lowenthal E, Chapman J, Calabrese K, et al. Adolescent and parent experiences with long-acting injectables in the MOCHA study. Presented at: Conference on Retroviruses and Opportunistic Infections; 2022. Virtual. Available at: https://www.croiconference.org/abstract/adolescent-and-parent-experiences-with-long-acting-injectables-in-the-mocha-study.

9. Lowenthal ED, Chapman J, Ohrenschall R, et al. Acceptability and tolerability of long-acting injectable cabotegravir or rilpivirine in the first cohort of virologically suppressed adolescents living with HIV (IMPAACT 2017/MOCHA): a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study. Lancet HIV. 2024;11(4):e222-e232. Available at: https://pubmed.ncbi.nlm.nih.gov/38538161.

10. Gaur A, Capparelli E, Baltrusaitis K, et al. Long-acting cabotegravir plus rilpivirine in adolescents with HIV: week 24 IMPAACT 2017(MOCHA) study Presented at: Conferences on Retroviruses and Opportunistic Infections 2024. Denver, CO. Available at: https://www.croiconference.org/abstract/long-acting-cabotegravir-plus-rilpivirine-in-adolescents-with-hiv-week-24-impaact-2017mocha-study.

11. Lowenthal ED, Chapman J, Vaca MZ, et al. IMPACCT 2017 Adolescent/Parent experiences with LA Cabotegravir plus Rilpivirine for HIV treatment. Presented at: Conference on Retroviruses and Opportunistic Infections; 2024. Denver, Colorado. . Available at: https://www.natap.org/2024/CROI/croi_49.htm.

12. Rakhmanina N, Richards K, Adeline Koay WL. Transient viremia in young adults with HIV after the switch to long-acting cabotegravir and rilpivirine: considerations for dosing schedule and monitoring. J Acquir Immune Defic Syndr. 2023;92(3):e14-e17. Available at: https://pubmed.ncbi.nlm.nih.gov/36480701.

13. Rakhmanina N. Are we ready for long-acting HIV treatment for adolescents? Lancet HIV. 2024;11(4):e200-e201. Available at: https://pubmed.ncbi.nlm.nih.gov/38538156.

14. Swindells S, Lutz T, Van Zyl L, et al. Week 96 extension results of a Phase 3 study evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment. AIDS. 2022;36(2):185-194. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34261093.

15. Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, Phase 3b, non-inferiority study. Lancet HIV. 2021;8(11):e679-e689. Available at: https://pubmed.ncbi.nlm.nih.gov/34648734.

16. Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, Phase 3 FLAIR study. Lancet HIV. 2021;8(4):e185-e196. Available at: https://pubmed.ncbi.nlm.nih.gov/33794181.

17. Orkin C, Bernal Morell E, Tan DHS, et al. Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label Phase 3 FLAIR study. Lancet HIV. 2021;8(11):e668-e678. Available at: https://pubmed.ncbi.nlm.nih.gov/34656207.

18. Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021;35(9):1333-1342. Available at: https://pubmed.ncbi.nlm.nih.gov/33730748.