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). Drugs that are strong inducers of UGT1A1 may decrease CAB concentrations and decrease effectiveness.
• 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.
  • Do not use oral RPV 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 CAB and RPV for injection (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 injectable IM CAB and RPV or as an oral interim treatment when patients miss planned injections.^1,3 CAB and RPV co-packaged extended-release injectable suspensions for IM use are approved for use in patients (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.¹

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,⁴ and see the Centers for Disease Control and Prevention Guidelines for Pre-exposure Prophylaxis for the Prevention of HIV in the United States (PDF) 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.

International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 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 initial results leading to FDA approval in this age group. MOCHA evaluated 23 virologically suppressed adolescents on stable therapy who received either a 4-week lead-in of oral CAB followed by IM CAB 600 mg at Week 4 and 400 mg at Weeks 8 and 12 (n = 8) or a lead-in of oral RPV followed by IM RPV 900 mg at Week 4 and 600 mg at Weeks 8 and 12 (n = 13). Injection site reactions were observed but none led to treatment discontinuations. Two adolescents experienced Grade 3 adverse events, one due to insomnia (CAB arm) and one due to hypersensitivity reaction to oral RPV which led to discontinuation.⁵ 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.⁶ It should be noted, however, that none of the MOCHA participants received both monthly IM CAB and monthly IM RPV as a dual complete regimen, and clinical experience with this product remains very limited. The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV notes that significant questions remain regarding the use of IM CAB and RPV in pediatric patients, 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.

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). Patients 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 IM CAB and 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 patients remaining on the original ATLAS study were included in the 96-week analysis. Adverse events were more common among patients receiving injectable ART; injection site reactions were common, but only 1% withdrew from the study because of these events.⁷ 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 patients 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—were similar across treatment arms. Of those failing the every-2-month injection regimen, a majority had NNRTI resistance–associated mutations.⁸

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 patients 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 IM CAB and 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 IM CAB and RPV group, and lasted a median of 3 days.⁹ The FLAIR study was extended to include an assessment of switching those participants remaining in the oral ARV arm after 120 weeks to IM CAB and 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.¹⁰

These studies demonstrated noninferiority of switching to monthly IM CAB and RPV compared to continuing oral ART. In all studies, adult patients expressed a high degree of treatment satisfaction and preference for the IM CAB and RPV regimen. Although documented virologic failure with the IM CAB and 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 IM CAB and 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.¹¹

Pharmacokinetics

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.¹ The PK profiles observed in adolescents enrolled in MOCHA were comparable to those observed in adults receiving monthly IM CAB and RPV in the ATLAS and FLAIR studies described above.⁵

References

1. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212888s002lbl.pdf.
2. Lee MJ, Berry P, D'Errico F, Miquel R, Kulasegaram R. A case of rilpivirine drug-induced liver injury. Sex Transm Infect. 2020;96(8):618-619. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31974214.
3. Vocabria (cabotegravir) tablets,for oral use [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212887s005s006lbl.pdf.
4. Apretude (cabotegravir extended-release injectable suspension), for intramuscular use [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215499s000lbl.pdf.
5. 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 Conference. Available at: https://www.croiconference.org/abstract/safety-and-pk-of-long-acting-cabotegravir-and-rilpivirine-in-adolescents.
6. 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 Conference. Available at: https://www.croiconference.org/abstract/adolescent-and-parent-experiences-with-long-acting-injectables-in-the-mocha-study
7. 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.
8. 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://www.ncbi.nlm.nih.gov/pubmed/34648734.
9. 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://www.ncbi.nlm.nih.gov/pubmed/33794181.
10. 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://www.ncbi.nlm.nih.gov/pubmed/34656207.
11. 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://www.ncbi.nlm.nih.gov/pubmed/33730748.