Once vs twice-daily abacavir and lamivudine in African children

Abstract

Background: Antiretroviral therapy (ART) adherence is critical for successful HIV treatment outcomes. Once-daily dosing could improve adherence. Plasma concentrations of once-daily vs twice-daily abacavir + lamivudine are bioequivalent in children, but no randomized trial has compared virological outcomes.

Methods: Children taking abacavir + lamivudine-containing first-line regimens twice daily for more than 36 weeks in the ARROW trial (NCT02028676, ISRCTN24791884) were randomized to continue twice-daily vs move to once-daily abacavir + lamivudine (open-label). Co-primary outcomes were viral load suppression at week 48 (12% noninferiority margin, measured retrospectively) and lamivudine or abacavir-related grade 3/4 adverse events.

Results: Six hundred and sixty-nine children (median 5 years, range 1-16) were randomized to twice daily (n = 333) vs once daily (n = 336) after median 1.8 years on twice-daily abacavir + lamivudine-containing first-line ART. Children were followed for median 114 weeks. At week 48, 242/331 (73%) twice daily vs 236/330 (72%) once daily had viral load less than 80 copies/ml [difference -1.6% (95% confidence interval -8.4,+5.2%) P = 0.65]; 79% twice daily vs 78% once daily had viral load less than 400 copies/ml (P = 0.76) (week 96 results similar). One grade 3/4 adverse event was judged uncertainly related to abacavir + lamivudine (hepatitis; once daily). At week 48, 9% twice daily vs 10% once daily reported missing one or more ART pills in the last 4 weeks (P = 0.74) and 8 vs 8% at week 96 (P = 0.90). Carers strongly preferred once-daily dosing. There was no difference between randomized groups in postbaseline drug-resistance mutations or drug-susceptibility; WHO 3/4 events; ART-modifying, grade 3/4 or serious adverse events; CD4% or weight-for-age/height-for-age (all P > 0.15).

Conclusion: Once-daily abacavir + lamivudine was noninferior to twice daily in viral load suppression, with similar resistance, adherence, clinical, immunological and safety outcomes. Abacavir + lamivudine provides the first once-daily nucleoside backbone across childhood that can be used to simplify ART.

Figure 1. Virologic suppression on twice-daily vs once-daily lamivudine+abacavir

Note: excluding missing VLs at week-0 (2 twice-daily, 1 once-daily), week-48 (2 twice-daily, 6 once-daily), and week-96 (7 twice-daily, 5 once-daily) due to assay failure or died/lost before week 96.

Figure 2. <400 c/ml on twice-daily vs once-daily lamivudine+ abacavir by (a) age (b) baseline VL and (c) third antiretroviral

Note: Each panel shows VL suppression <400 c/ml in children randomised to twice-daily (black circles) vs once-daily (gray squares), according to different subgroups of age (a), VL at randomisation (b) and third drug (c). In each subgroup, VL suppression at randomisation (week 0), and 48 and 96 weeks later are connected by lines. Similar responses to once- and twice-daily lamivudine+abacavir are reflected in parallel lines. Heterogeneity (interaction) in response to once- and twice-daily lamivudine+abacavir is reflected by different relative positions of black and gray lines in the different subgroups. Overall effect of the subgroup factor is reflected by different average suppression levels in the different subgroups

Figure 3. Predicted drug susceptibility

Note: Approximately one-half of children with genotypes were receiving triple NRTI (no NNRTI). 3TC=lamivudine, FTC=emtricitabine, ABC=abacavir, DDI=didanosine, ZDV=zidovudine, D4T=stavudine, TDF=tenofovir, EFV=efavirenz, NVP=nevirapine, ETR=etravirine, RPV=rilpivirine.