Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Doravirine

Drug Interactions

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

• Doravirine (DOR) is a cytochrome P450 (CYP) 3A substrate that is associated with several important drug interactions with drugs that are strong CYP3A enzyme inducers. Coadministration with these drugs may cause significant decreases in DOR plasma concentrations and potential decreases in efficacy, which can lead to the development of resistance. Before DOR is administered, a child’s medication profile should be reviewed carefully for potential drug interactions with DOR.^1,2
• In a Phase 1 trial (described below under Efficacy in Clinical Trials), DOR plasma exposure transiently decreased by 62% when DOR was started immediately after stopping efavirenz (EFV). A post hoc analysis of the Phase 3 DRIVE-SHIFT study (described below under Efficacy in Clinical Trials), however, showed that at Week 4, DOR plasma levels in participants who had switched from an EFV-based regimen to a DOR-based regimen were similar to DOR plasma levels in participants who switched from a protease inhibitor (PI)–based regimen to a DOR-based regimen (all of the regimens in the study used a backbone of lamivudine [3TC] plus tenofovir disoproxil fumarate [TDF]).³ A similar effect of prior EFV-based antiretroviral therapy (ART) on the pharmacokinetics (PK) of DOR was demonstrated in IMPAACT 2014 (described below under Efficacy in Clinical Trials) among adolescents weighing ≥45 kg who switched from EFV-based ART to DOR-based ART with 3TC/TDF.⁴
• DOR should not be coadministered with the following drugs: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; or St. John’s wort.^5,6
• Drug interactions between DOR and rifabutin induce the metabolism of DOR and require an additional dose of DOR 100 mg to be administered 12 hours after a fixed-dose combination of DOR/3TC/TDF or an increase of the DOR dose to 100 mg twice daily.^2,5,6

Major Toxicities

• More common: Nausea, headache, fatigue, diarrhea, abdominal pain, abnormal dreams
• Less common (more severe): Neuropsychiatric adverse events (AEs), including insomnia, somnolence, dizziness, depression, suicidality, altered consciousness, and altered sensorium. Autoimmune disorder and immune reconstitution inflammatory syndrome may occur. Serious reactions can also include severe skin and hypersensitivity reactions.

Resistance

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

DOR is expected to have activity against HIV with isolated NNRTI resistance that is associated with mutations at positions 103, 181, or 190. Some single mutations and combinations of viral mutations, however, have been shown to significantly decrease susceptibility to DOR. Specifically, clinical HIV isolates containing the Y188L mutation alone or in combinations with K103N or V106I, combinations of V106A with G190A and F227L, or combinations of E138K with Y181C and M230L have shown ≥100-fold reduction in susceptibility to DOR.^5,6 In children with multiple NNRTI mutations, consult an HIV expert and a resistance database to evaluate the potential efficacy of DOR.

Pediatric Use

Approval

DOR is approved by the U.S. Food and Drug Administration for use in children or adolescents weighing ≥35 kg.^5,6IMPAACT 2014, a Phase 1/2 study (described below under Efficacy in Clinical Trials), evaluated the PKs, safety, and tolerability of DOR and DOR/3TC/TDF in children and adolescents with HIV.^4,7

Efficacy in Clinical Trials

The efficacy of DOR was evaluated using data from four randomized adult clinical trials. The first study was a Phase 2b dose-selection, double-blind trial that enrolled treatment-naive adults with HIV.⁸ The efficacy trials included two randomized, multicenter, double-blind, active-controlled Phase 3 trials (DRIVE-FORWARD and DRIVE-AHEAD) in treatment-naive adults^9-13 and one open-label, active-controlled, randomized, noninferiority trial that enrolled virologically suppressed ART (DRIVE-SHIFT).¹⁴

The dose-selection trial enrolled treatment-naive adults stratified by HIV RNA level at screening (≤100,000 copies/mL or >100,000 copies/mL) and randomized participants to receive one of four different doses (25 mg, 50 mg, 100 mg, or 200 mg) of once-daily DOR or EFV 600 mg with open-label emtricitabine (FTC) 200 mg/TDF 300 mg. After dose selection at Week 24, all participants were switched to DOR 100 mg and, with additional enrollment, 216 participants were randomized to receive once-daily DOR 100 mg (n = 108) or EFV 600 mg (n = 108) for 96 weeks with FTC/TDF. At Week 24, 72.9% of participants on DOR 100 mg and 73.1% of participants on EFV 600 mg had HIV RNA <40 copies/mL.⁷

In the DRIVE-FORWARD trial, adult subjects with HIV were randomized to receive either DOR 100 mg (n = 383) or darunavir 800 mg/ritonavir 100 mg (DRV/r) (n = 383) once daily, each in combination with emtricitabine (FTC)/TDF or abacavir/3TC.^9,11 In the DRIVE-AHEAD trial, adult subjects received either coformulated DOR/3TC/TDF (n = 364) or EFV/FTC/TDF (n = 364) once daily.^10,12 An integrated efficacy analysis from both trials (DRIVE-FORWARD and DRIVE-AHEAD) at Week 48 demonstrated that 84.1% of participants who were treated with the DOR-based regimen achieved HIV RNA <50 copies/mL, compared with 79.9% of participants who were treated with the DRV/r-based regimen and 80.8% of participants who were treated with EFV/FTC/TDF. Results were similar across different baseline viral loads, genders, races, and HIV-1 subtypes.¹⁰ In a long-term extension arm for both trials (DRIVE-FORWARD and DRIVE-AHEAD) at Week 192, of 1,494 participants treated in the double-blind phase, 550 continued DOR-based regimens and 502 switched to DOR-based regimens.¹³ In the FDA snapshot analysis, HIV RNA <50 copies/mL was maintained in 457 (83%) of 550 participants who continued DOR-based ART and 404 (80%) of 502 participants who switched to DOR-based regimens. Protocol-defined virological failure and development of resistance were low, occurring mainly before Week 96.¹³

In the DRIVE-SHIFT study, adult subjects with HIV who were virologically suppressed for ≥6 months on two nucleoside reverse transcriptase inhibitors (NRTIs) plus a boosted PI, boosted elvitegravir or an NNRTI were randomized to switch to a once-daily, single-tablet regimen of DOR 100 mg/3TC 300 mg/TDF 300 mg or to continue their current therapy (baseline regimen). At Week 24, 93.7% on DOR/3TC/TDF versus 94.6% on baseline regimen had HIV-1 RNA <50 copies/mL (difference −0.9 [−4.7 to 3.0]). At Week 48, 90.8% on DOR/3TC/TDF had HIV-1 RNA <50 copies/mL, demonstrating noninferiority versus baseline regimen at Week 24 (difference −3.8 [−7.9 to 0.3]).¹⁴ Long-term efficacy in the extension arm at Week 144 showed HIV RNA <50 copies/mL in 80.1% of those who switched to DOR/3TC/TDF immediately and 83.7% of those who switched to DOR/3TC/TDF during the open-label extension in FDA snapshot analysis.¹⁵

IMPAACT 2014 study data in treatment-naive or treatment-experienced virologically suppressed adolescents aged 12 years to ≤18 years demonstrated efficacy comparable to adult data.^4,7 A total of 45 participants (median age 15 years; 58% females; two ART-naive) were treated with DOR/3TC/TDF. At Week 24, 42 out of 45 (93.3%) participants achieved or maintained HIV-1 RNA <40 copies/mL in FDA snapshot (intent-to-treat) analysis, while 42 out of 43 (97.7%) achieved or maintained HIV-1 RNA <40 copies/mL in observed failure (on-treatment) analysis.⁴ At Week 48, 41 of 42 (97.6%) participants had achieved or maintained HIV-1 RNA <40 copies/mL, and at Week 96, 37 of 40 (92.5%) had achieved or maintained HIV-1 RNA <40 copies/mL.⁷

Toxicity in Clinical Trials

In trials that compared DOR-based regimens and EFV-based regimens, central nervous system (CNS) AEs (dizziness, sleep disorder and disturbances, and altered sensorium) occurred less frequently among the participants who received DOR than among those who received EFV.⁸ In the dose-finding trial, CNS AEs were reported in 26.9% of patients on DOR-based regimens, compared with 47.2% of patients on EFV-based regimens at Week 24.⁷ In the integrated safety analysis from the DRIVE-FORWARD and DRIVE-AHEAD trials, 25.5% of participants on DOR-based regimens experienced CNS AEs at Week 48, compared with 55.9% of participants on EFV-based regimes.^10,16 In a long-term follow-up including extension stages for both trials (DRIVE-FORWARD and DRIVE-AHEAD), at Week 192, <1% of 550 participants who continued DOR-based ART reported serious drug-related AEs, and 1% who continued DOR-based regimens and <1% of those who switched to DOR-based ART discontinued ART due to drug-related AEs. Participants continuing or switching to DOR showed generally favorable lipid profiles, little weight gain, and small decreases in estimated glomerular filtration rates, with no discontinuations due to increased creatinine or renal AEs.¹³ In the DRIVE-SHIFT study, among adults who were receiving a ritonavir-boosted PI at study entry, the reduction in fasting lipids was achieved at Week 24 and maintained through Week 144 in the extension arm of the DRIVE-SHIFT study.¹⁵

In the IMPAACT 2014 study of 43 treatment-experienced (50% who switched from EFV-based ART) and 2 ARV-naive adolescents aged 12 years to <18 years on DOR/3TC/TDF at Week 24, there were no Grade 3 or 4 AEs, serious AEs, or premature study drug discontinuations due to AEs.⁴ At Week 96, there were no treatment-related discontinuations due to AEs and no deaths or drug-related AEs ≥Grade 3.⁷ While the study did not measure fasting lipids in all adolescents, favorable lipid profile changes from baseline to Week 96 were observed.

References

1. Boyle A, Moss CE, Marzolini C, Khoo S. Clinical pharmacodynamics, pharmacokinetics, and drug interaction profile of doravirine. Clin Pharmacokinet. 2019;58(12):1553-1565. Available at: https://pubmed.ncbi.nlm.nih.gov/31388941.
2. Khalilieh SG, Yee KL, Sanchez RI, et al. Doravirine and the potential for CYP3A-mediated drug-drug interactions. Antimicrob Agents Chemother. 2019;63(5). Available at: https://pubmed.ncbi.nlm.nih.gov/30783000.
3. Greaves W, Wan H, Yee KL, et al. Doravirine exposure and HIV-1 suppression after switching from an efavirenz-based regimen to doravirine/lamivudine/tenofovir disoproxil fumarate. Antimicrob Agents Chemother. 2019;63(12):e01298-01219. Available at: https://pubmed.ncbi.nlm.nih.gov/31548188.
4. Melvin AJ, Yee KL, Gray KP, et al. Pharmacokinetics, tolerability, and safety of doravirine and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination tablets in adolescents living with HIV: week 24 results from IMPAACT 2014. J Acquir Immune Defic Syndr. 2023;92(2):153-161. Available at: https://pubmed.ncbi.nlm.nih.gov/36215957.
5. Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210807s008lbl.pdf.
6. Doravirine [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210806s007lbl.pdf.
7. Rungmaitree S, Aurpibul L, Best BM, et al. Efficacy, safety, and tolerability of doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination tablets in adolescents living with HIV: results through week 96 from IMPAACT 2014. J Pediatric Infect Dis Soc. 2023;12(12):602-609. Available at: https://pubmed.ncbi.nlm.nih.gov/37815035.
8. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial. Antivir Ther. 2019;24(6):425-435. Available at: https://pubmed.ncbi.nlm.nih.gov/31355775.
9. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-e220. Available at: https://pubmed.ncbi.nlm.nih.gov/29592840.
10. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis. 2019;68(4):535-544. Available at: https://pubmed.ncbi.nlm.nih.gov/30184165.
11. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, Phase 3 trial. Lancet HIV. 2020;7(1):e16-e26. Available at: https://pubmed.ncbi.nlm.nih.gov/31740348.
12. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate (TDF) versus efavirenz/emtricitabine/TDF in treatment-naive adults with human immunodeficiency virus type 1 infection: week 96 results of the randomized, double-blind, Phase 3 DRIVE-AHEAD noninferiority trial. Clin Infect Dis. 2021;73(1):33-42. Available at: https://pubmed.ncbi.nlm.nih.gov/33336698.
13. Orkin C, Molina JM, Cahn P, et al. Safety and efficacy of doravirine as first-line therapy in adults with HIV-1: week 192 results from the open-label extensions of the DRIVE-FORWARD and DRIVE-AHEAD phase 3 trials. Lancet HIV. 2024;11(2):e75-e85. Available at: https://pubmed.ncbi.nlm.nih.gov/38141637.
14. Johnson M, Kumar P, Molina JM, et al. Switching to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains HIV-1 virologic suppression through 48 weeks: results of the DRIVE-SHIFT trial. J Acquir Immune Defic Syndr. 2019;81(4):463-472. Available at: https://pubmed.ncbi.nlm.nih.gov/30985556.
15. Kumar P, Johnson M, Molina JM, et al. Brief report: switching to DOR/3TC/TDF maintains HIV-1 virologic suppression through week 144 in the DRIVE-SHIFT trial. J Acquir Immune Defic Syndr. 2021;87(2):801-805. Available at: https://pubmed.ncbi.nlm.nih.gov/33633036.
16. Thompson M, Orkin C, Molina JM, et al. Once-daily doravirine for initial treatment of adults living with HIV-1: an integrated safety analysis. Clin Infect Dis. 2019;70(7):1336-1343 Available at: https://pubmed.ncbi.nlm.nih.gov/31121013.