by Carolyn Chu, MD, MSc, AAHIVS, AAHIVM Chief Medical Officer
February 14, 2023
Melvin AJ, Yee KL, Gray KP, et al. Pharmacokinetics, tolerability, and safety of doravirine and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dosed combination tablets in adolescents living with HIV: Week 24 results from IMPAACT 2014. J Acquir Immune Defic Syndr. 2023 Feb 1; 92(2): 153-161. PMID: 36215957.
IMPAACT 2014 is a phase I/II open-label, nonrandomized multicenter study investigating the safety, tolerability, and pharmacokinetics of the adult doravirine tablet and adult doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) FDC tablet in youth with HIV-1 infection. This study presents single-dose pharmacokinetics analyses (Cohort 1, with 9 participants having complete data) and 24-week treatment outcomes for DOR/3TC/TDF in adolescents aged 12 to <18 years (Cohort 2, with 45 participants all weighing ≥ 45 kg). Two Cohort 2 participants were ARV-naïve and 43 were virologically suppressed, with over half switching from efavirenz-based regimens (median ART duration prior to enrollment: 2.8 years). Overall, doravirine was well-tolerated by all participants. Three Cohort 2 participants had grade 3 decreased eGFR, 2 with concomitant grade 3 increased creatinine. Actual creatinine and eGFR values remained normal for age despite these changes, and no participant met the safety end point (i.e., eGFR < 60 mL/min/1.73m2). There were no medication discontinuations related to adverse events. 42/45 (93.3%) of Cohort 2 participants achieved or maintained HIV-1 RNA < 50 copies/mL. There were no significant changes in liver or kidney function measurements, and BMI remained stable. For Cohort 2 participants transitioning from efavirenz-containing regimens, the effects of CYP3A induction waned by week 4 and did not affect virologic efficacy.
Results of this study were initially presented at CROI 2021, and 24-week virologic efficacy results show favorable effects comparable to data reported from adult trials. DOR plus a two-NRTI backbone is currently recommended as an alternative NNRTI-based regimen for initial treatment of HIV infection in children and adolescents weighing at least 35 kg, and DOR is also listed as a potential switch option for children and adolescents weighing at least 35 kg who are virologically suppressed on an efavirenz- or nevirapine-based combination. DOR may present an attractive option for scenarios where providers or caregivers/patients wish to avoid INSTI-associated weight gain or increases in lipid levels, however this should be balanced with potential concerns regarding TDF, since the only currently available FDC containing DOR utilizes TDF. Nevertheless, PK analyses suggest that DOR concentrations for the 100-mg tablet in adolescents are comparable with adult levels and is generally safe and well-tolerated.
The author has no conflicts of interest to disclose.
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