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

Abstract

Background: Doravirine (DOR) is a nonnucleoside reverse-transcriptase inhibitor. In the phase 3 DRIVE-AHEAD trial in treatment-naive adults with human immunodeficiency virus type 1 (HIV-1) infection, DOR demonstrated noninferior efficacy compared with efavirenz (EFV) and superior profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96.

Methods: DRIVE-AHEAD is a phase 3, multicenter, double-blind, noninferiority trial in antiretroviral treatment-naive adults with HIV-1 RNA ≥1000 copies/mL. Participants were randomized to a daily fixed-dose tablet of DOR (100 mg), lamivudine (3TC; 300 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) (DOR/3TC/TDF) or EFV (600 mg), emtricitabine (FTC; 200 mg) and TDF (300 mg) (EFV/FTC/TDF). The efficacy end point of interest at week 96 was the proportion of participants with HIV-1 RNA levels <50 copies/mL (Food and Drug Administration Snapshot Approach) with a predefined noninferiority margin of 10% to support week 48 results. Safety end points of interest included prespecified neuropsychiatric adverse events and the mean change in fasting lipids at week 96.

Results: Of 734 participants randomized, 728 received study drugs and were included in analyses. At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF vs 73.6% of EFV/FTC/TDF participants, with a treatment difference of 3.8% (95% confidence interval, -2.4% to 10%). Virologic failure rates were low and similar across treatment arms, with no additional resistance to DOR observed between weeks 48 and 96. Prespecified neuropsychiatric adverse events and rash were less frequent in DOR/3TC/TDF than in EFV/FTC/TDF participants through week 96. At week 96, fasting low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol (HDL-C) levels increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group; the mean changes from baseline in total cholesterol/HDL-C ratio were similar.

Clinical trials registration: NCT02403674.

Keywords: HIV-1; NNRTI; doravirine; efavirenz; treatment-naive.

Figure 1.

Trial design. Abbreviations: 3TC, lamivudine; DOR, doravirine; EFV, efavirenz; FTC, emtricitabine; PBO, placebo; QD, once daily; TDF, tenofovir disoproxil fumarate.

Figure 2.

Disposition of participants through week 96. Abbreviations: 3TC, lamivudine; DOR, doravirine; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate.

Figure 3.

Proportion of participants with human immunodeficiency virus type 1 RNA level <50 copies/mL over time (Food and Drug Administration snapshot approach). Abbreviations: 3TC, lamivudine; CI, confidence interval; DOR, doravirine; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate.

Figure 4.

Efficacy by subgroup (observed failure approach) at week 96. Abbreviations: 3TC, lamivudine; CI, confidence interval; DOR, doravirine; EFV, efavirenz; FTC, emtricitabine; HBV, hepatitis B virus, HCV, hepatitis C virus; HIV-1, human immunodeficiency virus type 1; TDF, tenofovir disoproxil fumarate.

Figure 5.

Proportion of participants with neuropsychiatric adverse events in prespecified categories through week 96. Abbreviations: 3TC, lamivudine; CI, confidence interval; DOR, doravirine; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate. (Between-group difference calculated as follows: DOR – EFV.)

Figure 6.

Mean change in fasting lipid levels at week 96. Abbreviations: 3TC, lamivudine; CI, confidence interval; DOR, doravirine; EFV, efavirenz; FTC, emtricitabine; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; non-HDL-C, non-HDL cholesterol; TDF, tenofovir disoproxil fumarate. (Between-group difference calculated as follows: DOR – EFV.)