Efavirenz 400 mg daily remains non‐inferior to 600 mg: 96 week data from the double‐blind, placebo‐controlled ENCORE1 study

ENCORE1 compared the efficacy and safety of reduced versus standard dose efavirenz (EFV) with tenofovir/emtricitabine (TDF/FTC) as first‐line HIV therapy. The primary analysis at 48 weeks showed 400 mg EFV was safe and virologically non‐inferior to 600 mg. This analysis explores over 96 weeks the durability of efficacy and safety. Materials and Methods A multinational, double‐blind, placebo‐controlled, non‐inferiority trial in treatment‐naïve HIV‐positive adults randomized to TDF/FTC plus reduced (400 mg, EFV400) or standard dose (600 mg, EFV600) EFV. The difference between proportions of participants with plasma HIV RNA (VL) <200 log 10 copies/mL by intention‐to‐treat (ITT missing=failure) was compared using a non‐inferiority margin of −10%. Non‐inferiority was also examined in per protocol (PP) and non‐completer = failure (NC=F) populations. Adverse events (AEs) and serious adverse events (SAEs) were summarized by treatment arm. Results The ITT population comprised 630 patients (EFV400 = 321; EFV600 = 309); 32% were female; 37%, 33% and 30% were African, Asian and Caucasian, respectively. A total of 585 (EFV400 = 299; EFV600 = 286) completed 96 weeks on randomized therapy. At 96 weeks, proportions with VL <200 copies/mL were EFV400 (90.0%) and EFV600 (90.6%) (difference −0.6; 95% CI −5.2 to 4.0; p =0.72) demonstrating continued non‐inferiority. Non‐inferior efficacy was also observed for VL thresholds of <50 and <400 copies/mL irrespective of baseline VL (<100,000 versus ≥100,000 copies/mL). There was no between‐arm difference in time to loss of virological response (>200 copies/mL) ( p =0.47) or mean change from baseline VL ( p =0.74). Mean change from baseline in CD4 T‐cell counts at week 96 remained significantly higher for EFV400 than EFV600 (difference 25 cells/µL; 95% CI 2–48; p =0.03). There was no difference in the frequency or severity of AEs (EFV400 = 89.4%, EFV600 = 89.3%; difference 0.09; 95% CI −4.73 to 4.90; p =0.97). The proportions ever reporting an AE definitely or probably EFV‐related were EFV400 (37.7%) and EFV600 (47.9%) (difference −10.2%; 95% CI −17.9 to −2.51; p =0.01). SAEs did not differ in frequency (EFV400 = 7.5%, EFV600 = 10.4%; difference −2.9%; 95% CI −7.3 to 1.6; p =0.20). Conclusions Non‐inferiority of EFV 400 mg to EFV 600 mg when combined with TDF/FTC as initial HIV therapy was confirmed at week 96. Both doses demonstrated similar safety profiles. These results support the use of a lower EFV dose as part of routine HIV management.