Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Drug Interactions

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

• Metabolism: Rilpivirine (RPV) is a cytochrome P450 (CYP) 3A substrate, and concentrations may be affected when administered with CYP3A-modulating medications.
• A patient’s medication profile should be carefully reviewed for potential drug interactions before RPV is administered.
• Coadministering RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV.
  • Antacids should only be taken at least 2 hours before or at least 4 hours after RPV.
  • H2 receptor antagonists should only be administered at least 12 hours before or at least 4 hours after RPV.
  • Do not use RPV with proton pump inhibitors.
• All the rifamycins significantly reduce RPV plasma concentrations; coadministration of rifampin and oral RPV is contraindicated. 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. Intramuscular (IM) RPV given with IM CAB is contraindicated with rifampin, rifabutin, and rifapentine.
• In a cohort of adolescent patients, RPV exposure was two to three times greater when RPV was administered in combination with darunavir/ritonavir (DRV/r) than when RPV was administered alone.²

Major Toxicities

• More common: Insomnia, headache, rash 
• Less common (more severe): Depression or mood changes, suicidal ideation 

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 (mcg) adrenocorticotropic hormone (ACTH) stimulation test (peak cortisol level <18.1 mcg/dL). In a study of adolescents, 6 out of 30 patients (20%) developed this abnormality.3 The clinical significance of these results is unknown. 

• Rare: RPV drug-induced liver injury has been reported.4 

Resistance

The International Antiviral Society–USA (IAS–USA) maintains a list of updated HIV drug resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Transmitted drug resistance to second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) may be present in infants and children who have recently received a diagnosis of HIV.

Pediatric Use

Approval

With the viral load and antiretroviral (ARV) resistance restrictions noted above, RPV (Edurant) used in combination with other ARV agents, the fixed-dose combination (FDC) tablet emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF; Complera), the FDC tablet emtricitabine/rilpivirine/tenofovir alafenamide (FTC/RPV/TAF; Odefsey), and the long-acting regimen of cabotegravir (CAB) and RPV for IM injection (IM CAB and RPV; Cabenuva) are all approved by the U.S. Food and Drug Administration (FDA) for use in people aged ≥12 years and weighing ≥35 kg. The FDC tablet dolutegravir/rilpivirine (DTG/RPV; Juluca) is not approved for use in pediatric or adolescent patients at the time of this review.

Efficacy in Clinical Trials

An RPV-containing regimen has been compared to an efavirenz (EFV)-containing regimen in two large clinical trials in adults—ECHO and THRIVE. In both studies, RPV was shown to be non-inferior to EFV. Patients with pretreatment HIV viral loads ≥100,000 copies/mL who received RPV had higher rates of virologic failure than those who received EFV. These findings resulted in FDA approval for initial therapy with RPV only in patients with HIV viral loads ≤100,000 copies/mL.^5-8

A study of antiretroviral therapy (ART)–naive adolescents aged 12 to 17 years demonstrated that RPV 25 mg, given once daily in combination with two nucleoside reverse transcriptase inhibitors (NRTIs), was well tolerated over 48 weeks. In adolescents with baseline viral loads ≤100,000 copies/mL, 86% had a virologic response at 24 weeks and 79% had a virologic response at 48 weeks. In adolescents with baseline viral loads >100,000 copies/mL, 38% had a virologic response at 24 weeks and 50% had a virologic response at 48 weeks.⁹

Patients must be able to take RPV on a regular schedule and with a full meal, which may limit its usefulness for some adolescents with irregular schedules. The FDC formulation Odefsey is a small pill and can be useful for certain patients who have difficulty swallowing pills and want to switch from a multipill regimen, and who do not have any drug resistance mutations that are associated with the components of Odefsey.

A Spanish multicenter observational study enrolled 17 adolescents (aged <18 years) who acquired HIV perinatally to receive FTC/RPV/TDF (Complera) as part of an off-label medication use program. At the time of enrollment, 12 patients were on a protease inhibitor-based regimen, 4 were on an NNRTI-based regimen, and 1 had not received ART. After a median follow-up of 90 weeks (for participants with undetectable viral loads at baseline) or 40 weeks (for participants with detectable viral loads at baseline), 86% and 89% of patients, respectively, achieved and maintained an undetectable viral load. None of the patients discontinued RPV-based therapy because of adverse events (AEs); no skin rashes or central nervous system (CNS)-related events were observed. In addition, serum lipids improved, and two adolescents with a history of insomnia and abnormal dreams while receiving EFV-based therapy did not report similar problems while receiving RPV-based therapy.¹⁰

Another study evaluated 102 virologically-suppressed Thai adolescents who were switched from an EFV- to an RPV-based therapy. Ninety-four of the adolescents remained virologically suppressed through 48 weeks; six experienced virologic failure. Overall, RPV was well tolerated. No improvement in EFV-related symptoms (e.g., sleep, mood, dizziness, headache, concentration) was observed, and no change in quality of life or depression scores could be documented; however, there were significant improvements in some assessments of cognitive and executive function as measured at week 24.¹¹

Pharmacokinetics

The pharmacokinetics (PKs), safety, and efficacy of RPV in children aged <12 years have not been established but are currently being studied in patients aged 6 years to <12 years and weighing ≥17 kg (ClinicalTrials.gov identifier NCT00799864). The Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the Panel) has agreed that the use of RPV may be appropriate in certain children aged <12 years and weighing ≥35 kg. However, the Panel advises consulting an expert in pediatric HIV infection prior to prescribing RPV for a child in this age and weight group.

An international (India, Thailand, Uganda, and South Africa) Phase 2 trial, Pediatric Study in Adolescents Investigating a New NNRTI TMC278 (PAINT), investigated a 25-mg dose of RPV given in combination with two NRTIs in ARV-naive adolescents aged 12 years to <18 years who weighed ≥32 kg and who had viral loads ≤100,000 copies/mL.⁹ In the dose-finding phase of the study, 11 youth aged >12 years to ≤15 years and 12 youth aged >15 years to ≤18 years underwent intensive PK assessment after they took an observed dose of RPV with a meal. PKs were comparable to those in adults; results are listed in the table below.¹²

In a PK study of youth aged 13 to 23 years who received RPV,² RPV exposure was comparable to the exposure observed during the PAINT study in patients who received 25-mg doses of RPV without DRV/r and substantially higher than the exposure observed in those who received 25-mg doses of RPV with DRV/r (RPV area under the curve in this study was 6,740 ng·h/mL). No dose adjustments are currently recommended for adults when RPV is coadministered with DRV/r, where a similar twofold to threefold increase in RPV exposure has been reported.³

RPV has been reported to have fewer CNS AEs than EFV, and it has been promoted as a replacement ARV drug for some patients who experience CNS effects while receiving EFV. However, concern exists that the prolonged half-life of EFV might result in residual drug levels that could have an impact on RPV levels. A Thai study evaluated 20 Thai adolescents 4 weeks after they switched from EFV to RPV. The PK parameters of RPV in this study population were comparable to those in previous pediatric (PAINT) and adult (ECHO/THRIVE) PK substudies. No virologic failure was detected at 12 or 24 weeks, and no patients discontinued RPV because of AEs.¹³

Simplification of Treatment

Juluca is an FDC tablet that contains DTG 50 mg and RPV 25 mg. The results from two trials in adults (SWORD-1 and SWORD-2) supported FDA approval of DTG/RPV as a complete regimen for treatment simplification or maintenance therapy in certain patients. The two identical SWORD trials enrolled 1,024 patients with suppressed viral replication who had been on stable ART for at least 6 months and had no history of treatment failure or evidence of resistance mutations that are associated with DTG or RPV. The participants were randomized to receive DTG/RPV (“early switch”) or to continue their suppressive ARV regimen. After 48 weeks of treatment, 95% of patients in both arms maintained HIV RNA <50 copies/mL.¹⁴ After 52 weeks, the participants who had been randomized to continue their suppressive ARV regimen were switched to DTG/RPV (“late switch”). At 148 weeks of treatment, 84% of the early switch patients and 90% of the late switch patients remained virologically suppressed, and only 11 patients receiving dual therapy (DTG/RPV) met virologic failure criteria. No integrase inhibitor resistance was identified.¹⁵ More AEs were reported, and more AEs led to treatment discontinuation in the DTG/RPV arm during the comparative randomized phase. In a subgroup of SWORD study patients whose original ARV regimen contained TDF, small but statistically significant increases in hip and spine bone mineral density were observed.¹⁶ Although DTG/RPV as Juluca is not approved for use in adolescents, the doses of both component drugs that make up Juluca are approved for use in adolescents. This product may be appropriate for certain adolescents; however, because the strategy of treatment simplification has not been evaluated in adolescents, who may have difficulties adhering to therapy, the Panel does not recommend using Juluca in adolescents and children until more data are available.

Long-Acting Injectable Rilpivirine

A long-acting IM injectable formulation of RPV has recently been approved for coadministration with IM CAB as a complete ARV regimen for children and adolescents aged ≥12 years and weighing ≥35 kg and adults with HIV RNA levels <50 copies/mL, on a stable ARV regimen, with no history of treatment failure, and no known or suspected resistance to CAB or RPV.¹⁷ This formulation has been evaluated in adults as monthly or every-2 month intramuscular injections following an initial oral, lead-in daily dose for 4 weeks to assess toxicity.^18-20 These studies in adult patients demonstrated non-inferior efficacy to standard oral therapy and good participant satisfaction and tolerability through 96 weeks. A follow-on study demonstrated that dosing IM CAB and RPV every 2 months in virally suppressed participants provided similar safety and efficacy to monthly injections through 48 weeks.²¹ Additionally, an extension of one study evaluated the benefit of oral lead-in therapy prior to initiating IM CAB and RPV, demonstrating that initial oral therapy can be optional based on the needs and desires of persons initiating treatment.²²IMPAACT study 2017, More Options for Children and Adolescents (MOCHA), is currently evaluating the safety, tolerability, acceptability, and PK profile of this injectable regimen in adolescents weighing ≥35 kg (ClinicalTrials.gov identifier NCT03497676) and has reported acceptable PKs and safety for the single IM products administered monthly and good acceptability by both adolescents and their parents.^23,24 However, MOCHA has not completed evaluating the dual injectable regimen long term, and clinical experience with IM CAB and RPV remains limited. See the Cabotegravir section for more information about this regimen.

Toxicity

In the PAINT study, the observed AEs were similar to those reported in adults (e.g., somnolence, nausea, vomiting, abdominal pain, dizziness, headache). The incidence of depressive disorders was 19.4% (7 of 36 participants) compared to 9% in the Phase 3 trials in adults. The incidence of Grade 3 and 4 depressive disorders was 5.6% (2 of 36 participants).³

Six out of 30 adolescents (20%) with a normal ACTH stimulation test at baseline developed an abnormal test during the trial. No serious AEs, deaths, or treatment discontinuations were attributed to adrenal insufficiency. The clinical significance of abnormal ACTH stimulation tests is not known, but this finding warrants further evaluation.³

Crushing Tablets for Enteral Administration

Some cases report DTG/RPV tablets’ being crushed and successfully administered via an enteral tube.²⁵ If DTG/RPV is administered via enteral tube, care should be taken to disperse the tablets completely and flush the tube to avoid clogging.

References

1. Mehta R, Piscitelli J, Wolstenholme A, et al. The effect of moderate- and high-fat meals on the bioavailability of dolutegravir/rilpivirine fixed-dose combination tablet. Clin Pharmacol. 2020;12:49-52. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32607002.
2. Foca M, Yogev R, Wiznia A, et al. Rilpivirine pharmacokinetics without and with darunavir/ritonavir once daily in adolescents and young adults. Pediatr Infect Dis J. 2016;35(9):e271-274. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27187753.
3. Rilpivirine (Edurant) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/202022s016lbl.pdf.
4. 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.
5. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378(9787):229-237. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21763935.
6. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE trials. J Acquir Immune Defic Syndr. 2012;60(1):33-42. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22343174.
7. Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS. 2013;27(6):939-950. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23211772.
8. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238-246. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21763936.
9. Lombaard J, Bunupuradah T, Flynn PM, et al. Rilpivirine as a treatment for HIV-infected antiretroviral-naive adolescents: week 48 safety, efficacy, virology and pharmacokinetics. Pediatr Infect Dis J. 2016;35(11):1215-1221. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27294305.
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11. Phongsamart W, Jantarabenjakul W, Chantaratin S, et al. Switching efavirenz to rilpivirine in virologically suppressed adolescents with HIV: a multi-centre 48-week efficacy and safety study in Thailand. J Int AIDS Soc. 2022;25(1):e25862. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35001501.
12. Crauwels H, Hoogstoel A, Vanveggel S, et al. Rilpivirine pharmacokinetics in HIV-1-infected adolescents: a substudy of PAINT (Phase II trial). Presented at: Conference on Retroviruses and Opportunistic Infections; 2014. Boston, MA. Available at: https://www.croiconference.org/sessions/rilpivirine-pharmacokinetics-hiv-1-infected-adolescents-substudy-paint-phase-ii-trial.
13. Jantarabenjakul W, Anugulruengkitt S, Kasipong N, et al. Pharmacokinetics of rilpivirine and 24-week outcomes after switching from efavirenz in virologically suppressed HIV-1-infected adolescents. Antivir Ther. 2018;23(3):259-265. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28994660.
14. Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-849. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29310899.
15. van Wyk J, Orkin C, Rubio R, et al. Brief Report: Durable suppression and low rate of virologic failure 3 years after switch to dolutegravir + rilpivirine 2-drug regimen: 148-week results from the SWORD-1 and -2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;85(3):325-330. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32675772.
16. McComsey GA, Lupo S, Parks D, et al. Switch from tenofovir disoproxil fumarate combination to dolutegravir with rilpivirine improves parameters of bone health. AIDS. 2018;32(4):477-485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29239893.
17. 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.
18. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390(10101):1499-1510. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28750935.
19. 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.
20. 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.
21. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021;396(10267):1994-2005. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33308425.
22. 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.
23. 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.
24. 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.
25. Turley SL, Fulco PP. Enteral administration of twice-daily dolutegravir and rilpivirine as a part of a triple-therapy regimen in a critically ill patient with HIV. J Int Assoc Provid AIDS Care. 2017;16(2):117-119. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28198203.