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.

In the phase 3 DRIVE-FORWARD trial, DOR demonstrated noninferior efficacy and a superior lipid profile compared with darunavir-ritonavir at 48 weeks of combination treatment with 2 nucleoside reverse-transcriptase inhibitors (NRTIs) [9]. In the phase 3 DRIVE-AHEAD trial, DOR/3TC/ TDF demonstrated efficacy noninferior to efavirenz (EFV; 600 mg) emtricitabine (FTC; 200 mg), and TDF (300 mg) (EFV/FTC/TDF) at week 48 and was well tolerated, with significantly fewer neuropsychiatric adverse events (AEs) and minimal changes in low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol (HDL-C) compared with EFV/FTC/TDF [10]. Because durability of virologic response and long-term safety and tolerability are critical factors when evaluating a novel HIV-1 treatment, the double-blind period of the DRIVE-AHEAD trial was planned for a total of 96 weeks; herein we report the results of the DRIVE-AHEAD trial through week 96.

Trial Design
DRIVE-AHEAD (MK-1439A protocol 021; NCT02403674) is a randomized, active-controlled, double-blind, noninferiority phase 3 trial in antiretroviral treatment-naive adults with HIV-1 RNA levels ≥1000 copies/mL conducted at 126 global study sites in 23 countries. Full methods have been previously reported in detail with the 48-week results [10]. The trial was conducted in accordance with principles of Good Clinical Practice requirements and was approved by the appropriate institutional review boards and regulatory agencies. Participants were randomly assigned (1:1 by interactive voice response system/interactive Web response system) to a single-tablet regimen of DOR/3TC/TDF (plus placebo for EFV/FTC/TDF) or EFV/ FTC/TDF (plus placebo for DOR/3TC/TDF), after stratification according to screening HIV-1 RNA (≤100 000 or >100 000 copies/mL) and chronic hepatitis B and/or C coinfection (yes or no). DOR/3TC/TDF or its matching placebo was taken orally once daily without regard to food at approximately the same time each day for 96 weeks, and EFV/FTC/TDF or matching placebo was taken orally once daily on an empty stomach ( Figure 1).

Assessments
Plasma HIV-1 RNA levels were measured at all study visits by the central laboratory using the Abbott RealTime HIV-1 assay (lower limit of quantification, 40 copies/mL). Protocol-defined virologic failure (PDVF) was defined as nonresponse (HIV-1 RNA ≥200 copies/mL at week 24 or 36 or ≥50 copies/mL at week 48) or viral rebound (HIV-1 RNA ≥50 copies/mL after initial response of HIV-1 RNA <50 copies/mL at any time during the trial). Initial PDVF measurement required an additional confirmatory measurement of HIV-1 RNA taken ≥1 week apart. Participants who met these criteria were discontinued from the trial.
Viral resistance testing to the study drugs was performed for participants with PDVF and those who discontinued the trial for any reason if HIV-1 RNA was >400 copies/mL. Postbaseline genotypic viral resistance to DOR was defined as any of the following mutations in the RT gene: A98G, L100I, K101E, V106A, V106I,V106M, V108I, E138K, Y188L, G190A, G190S, H221Y, P225H, F227C, F227L, F227V, M230I, M230L, L234I, P236L, and Y318F. Postbaseline genotypic resistance to EFV, FTC, 3TC, and TDF was assessed by Monogram Biosciences, LabCorp Specialty Testing Group. Phenotypic viral resistance to EFV and NRTIs was defined by Monogram Biosciences based on the difference (fold change) between the IC 50 values for a participant's virus and wild-type virus. Because no threshold for defining phenotypic resistance to DOR was clinically defined, a 2.5-fold change in IC 50 versus wild-type virus was used as a broad assay reproducibility threshold for potential phenotypic resistance to DOR. To evaluate the immunologic effects of DOR, CD4 + T-cell counts were assessed at screening, day 1, and weeks 8, 24, 48, 72, and 96, using flow cytometry at a central laboratory.
Safety was monitored by AE reporting, treatment-emergent laboratory abnormalities, and physical examinations. AEs were assessed by the investigator for intensity (mild, moderate, severe) and relationship to study therapy. Laboratory values were graded in severity based on Division of Acquired Immunodeficiency Syndrome criteria [11]. Detailed statistical methods were previously reported in the week 48 publication [10].

Participants
A total of 992 participants were screened, of whom 734 were randomized with 368 participants in the DOR/3TC/TDF group and 366 in the EFV/FTC/TDF group. Of the randomized participants, 364 received study medication in each group and were included in both efficacy and safety analyses. Demographics and baseline characteristics were generally similar between the treatment groups (Table 1). A total of 68 participants (18.5%) from the DOR/3TC/TDF group and 88 (24.0%) from the EFV/ FTC/TDF discontinued treatment early without completing week 96 of the trial; the most common reasons for discontinuation were lack of efficacy, AEs, and withdrawal of consent ( Figure 2). Between weeks 48 and 96, 17 participants discontinued from the DOR/3TC/TDF group, and 27 discontinued from the EFV/FTC/TDF group. In the DOR/3TC/TDF group, discontinuations after week 48 included 13 due to lack of efficacy, 1 due to an AE, 2 due to withdrawal of consent, and 1 due to pregnancy. In the EFV/FTC/TDF group discontinuations after week 48 included 13 due to lack of efficacy, 3 due to an AEs, 6 due to withdrawal of consent, 1 due to pregnancy, 1 lost to follow-up, 2 for nonadherence, and 1 due to death.
At week 96, the proportions of participants who met the definition of PDVF (rebound and nonresponse) were low and similar in the DOR/3TC/TDF (9.3%) and EFV/FTC/TDF (7.7%) treatment groups, as compared with rates of 5.7% and 3.8%, respectively at week 48. Rates of treatment-emergent drug resistance was low for both DOR/3TC/TDF and EFV/FTC/TDF    groups (Table 3). No additional participants in the DOR/3TC/ TDF group developed treatment-emergent resistance to DOR after week 48. We do report 1 additional instance of DOR resistance that was not in the previous week 48 publication. Viral drug resistance information for 1 participant in the DOR/3TC/TDF group who had discontinued without PDVF due to a physician decision at week 4 became available after finalization of the week 48 publication. This participant had a genotypic mutation (V106I) known to be associated with NNRTI resistance; phenotype analysis showed that the virus remained susceptible to DOR. In the EFV/FTC/TDF group, 1 additional participant who discontinued due to PDVF developed resistance to EFV after week 48. Two additional participants who discontinued without PDVF were identified with resistance to EFV after week 48; 1 had virus with both genotypic and phenotypic resistance, and the other had virus with an accessory T369V mutation but unsuccessful phenotype testing. In the DOR/3TC/TDF group, of the 8 participants with virus with documented DOR-associated NNRTI resistance mutations, 7 also had virus with documented NRTI resistance. In the EFV/FTC/TDF group, of the 14 participants with virus who had documented EFV-associated NNRTI resistance mutations 6 also had virus with documented NRTI resistance.

Safety
Overall rates of any AEs, drug-related AEs, and discontinuation due to AEs through week 96 were lower in the DOR/3TC/ TDF group than in the EFV/FTC/TDF group, consistent with the results from week 48 (Table 4). Through week 96, a total of 38 participants experienced AEs that resulted in discontinuation from the study (11 [3.0%] in the DOR/3TC/TDF group and 27 [6.6%] in the EFV/FTC/TDF group). This total included 1 additional participant from the DOR/3TC/TDF group (depression) and 3 additional participants who discontinued since the week 48-time point in the EFV/FTC/TDF group (1 each with dizziness/headache/somnolence, sleep disorder, and abnormal dreams). The most common AE that led to discontinuation in the EFV/FTC/TDF group was rash, with 10 participants total; only 1 additional case of rash was reported in the EFV/FTC/TDF group after week 48. No participants in the DOR/3TC/TDF group discontinued due to rash. No AE leading to discontinuation in the DOR/3TC/TDF group occurred in >1 participant.
The frequency of Division of Acquired Immunodeficiency Syndrome grade 3-4 laboratory abnormalities was low and similar between the treatment groups (Table 5). Laboratory abnormalities that indicate renal dysfunction occurred infrequently in both arms of the study. Fifteen participants (10 in the DOR/3TC/TDF group and 5 in the EFV/FTC/TDF, with a treatment difference of 1.4% [95% CI, −.8% to 3.8%]) had grade 3 creatinine levels, defined as either a >1.8-to <3.5-foldincrease above the upper normal limit or as a 1.5-to <2.0 foldincrease from the patient's baseline value. All grade 3 creatinine values were <2.0 mg/dL and transient; most of these met grade 3 criteria due to a change from baseline value and remained Genotypic and/or phenotypic NRTI 6 (1.  within the normal range. Two participants (1 in each treatment group) had grade 4 creatinine elevations. One participant in the DOR/3TC/TDF group had a creatinine elevation (to 1.69 mg/ dL from 0.83 mg/dL at baseline) on day 595 with no prior elevations. The participant continued in the trial, and creatinine levels returned to below grade 1 by the next study visit. One participant in the EFV/FTC/TDF group had grade 4 creatinine elevation (to 12.63 mg/dL from 0.64 mg/dL at baseline) on day 172 in the setting of moderate diabetic decompensation and with acute renal failure noted the same day; this participant was withdrawn from the trial. At week 48, the primary safety end points were the proportions of participants with prespecified neuropsychiatric events, which were significantly lower in the DOR/3TC/TDF group than in the EFV/FTC/TDF group. Consistent with results from weeks 0-48, overall neuropsychiatric AEs (weeks 0-96) were None of the deaths were considered related to study therapy. c Prespecified AEs included dizziness, sleep disorders and disturbances, altered sensorium, depression and suicide/self-injury, and psychosis and psychotic disorders. d AEs with ≥10% incidence in either treatment group.  less common for DOR/3TC/TDF (26.4%) than for EFV/FTC/ TDF (58.5%) (treatment difference, −32.1%; 95% CI, −38.8% to −25.2%). By category, the 95% CI for the treatment difference excluded 0 for 2 of the 5 predefined categories: dizziness and sleep disorders/disturbances ( Figure 5). The majority of reported neuropsychiatric AEs occurred before week 48 for both groups, with minimal difference in new-onset neuropsychiatric AEs between groups after week 48. Consistent with the week 48 findings, DOR/3TC/TDF had a favorable lipid profile with respect to mean changes from baseline in fasting low-density lipoprotein cholesterol and non-HDL-C levels at week 96 with minimal changes (−0.6 and −2.1 mg/dL, respectively) in the DOR/3TC/TDF group versus, compared with mean increases of 10.8 and 15.0 mg/dL, respectively, in the EFV/FTC/TDF group ( Figure 6). A similar trend was observed for changes in baseline for fasting cholesterol, triglycerides, and HDL-C levels ( Figure 6). The mean change from baseline in the total cholesterol/HDL-C ratio was however similar between arms: −0.12 for DOR/3TC/TDF and −0.10 for EFV/FTC/TDF (treatment difference, −0.04; 95% CI, −.23 to .15). In both the DOR/3TC/TDF and EFV/FTC/TDF groups, similar small mean increases in weight were noted from baseline to week 96 (2.1 kg and 1.6 kg, respectively).

DISCUSSION
The 96-week results of this phase 3 double-bind trial in treatmentnaive adults living with HIV-1 support the noninferior efficacy of DOR/3TC/TDF relative to EFV/FTC/TDF, established at 48 weeks. At week 96, 77.5% of participants in the DOR/3TC/ TDF group and 73.6% in the EFV/FTC/TDF group achieved HIV-1 RNA levels <50 copies/mL using the Food and Drug Administration snapshot approach, which is somewhat lower than the week 48 results for both groups (84.3% for DOR/3TC/ TDF and 80.8% for EFV/FTC/TDF). One likely reason for the observed decrease in efficacy at week 96 is missing data. When missing data are excluded using the observed failure approach, higher virologic response rates were demonstrated for both treatment groups and were more closely aligned with what was observed at week 48 (83.7% for DOR/3TC/TDF and 85.9% for EFV/FTC/TDF). The virologic response rate in the EFV/FTC/ TDF group at 96 weeks was consistent with rates reported for this regimen in previous clinical trials [12][13][14].
Antiviral response rates were consistent regardless of baseline demographic or prognostic factors. In both treatment groups, the virologic response rate was lower among participants with baseline HIV-1 RNA >100 000 copies/mL (71.0% for DOR/3TC/TDF and 79.7% for EFV/FTC/TDF) compared with those with baseline HIV-1 RNA ≤100 000 copies/mL (86.9% and 87.5%, respectively); this trend was also observed at week 48. Virologic response rates were also lower in patients with baseline CD4 + T-cell counts ≤200/μL (65% in the DOR/3TC/TDF vs 82% in EFV/FTC/TDF arm); however, only 12% of the total randomized population had low baseline CD4 + T-cell counts. In general, lower response rates in participants with high baseline viral load and low CD4 + T-cell counts have been observed in other clinical trials and across several antiretroviral classes [15,16]. Immunologic responses, as measured by increases in CD4 + T-cell counts, were similar between the 2 treatment groups. Resistance to both DOR and EFV occurred primarily within the first 48 weeks of the trial. Between weeks 48 and 96, no new resistance to DOR and only 2 additional participants with resistance to EFV were observed. The DOR-associated NNRTI mutations identified in this trial were consistent with the mutations identified in previous in vitro resistance analyses [3,4].
In this trial, the definition of PDVF and the criterion for required discontinuation were more stringent than in other recent  trials. Other recent trials allowed participants to remain in the study despite meeting PDVF criteria or used a higher PDVF threshold of 200 or 400 copies/mL HIV-1 RNA [17][18][19]. In each treatment group, many participants with viral rebound had HIV-1 RNA ≤200 copies/mL at the viral failure confirmation visit, and, for the majority of those participants, HIV-1 RNA was between 50 and 100 copies/mL at that visit. However, even with this stringent definition for PDVF, rates of PDVF were low for both groups (9.3% for DOR/3TC/TDF and 7.7% for EFV/FTC/TDF).
A strength of our trial is the double-blind comparison between the 2 treatment groups through week 96. A potential limitation is that participants took 2 pills per day, 1 active drug and 1 placebo. with 1 pill taken while fasting, which may have been taken at different times, resulting in a twice-daily regimen. Although adherence to study therapy was high, it is possible that adherence would be improved with a single-pill, once-daily regimen. Furthermore, it is possible that this twice-daily dosing requirement of the study could have driven discontinuations in both arms.
The favorable safety profile of DOR/3TC/TDF was established in prior clinical studies [9,10]. At week 96 of the DRIVE-AHEAD study, DOR/3TC/TDF continues to demonstrate a favorable safety and tolerability profile. Fewer participants in the DOR/3TC/TDF group experienced any AEs, drug-related AEs, or discontinuations due to AEs compared with the EFV/ FTC/TDF group. Renal events were infrequent for both the DOR/3TC/TDF and EFV/FTC/TDF arms in this young cohort (median age, 31 years), with only 1 discontinuation due to a renal AE in the EFV/FTC/TDF group. The frequency of rash remained lower in the DOR/3TC/TDF group (5% vs 12% in the EFV/FTC/TDF group) and was consistent with rates previously reported for DOR [9]. Furthermore, no participants in the DOR/3TC/TDF group discontinued treatment due to rash.
Week 96 data also continue to support the favorable lipid profile of DOR/3TC/TDF relative to EFV/FTC/TDF that was established at week 48. Because dyslipidemia occurs in a large proportion of people living with HIV and is a greater concern as patients age, it is important that antiretroviral medications do not exacerbate these conditions, especially for those already at high risk of cardiovascular disease.
At week 48, DOR/3TC/TDF exhibited favorable neuropsychiatric tolerability and was superior to EFV/FTC/TDF in the prespecified analysis of dizziness, sleep disorders/disturbances, and altered sensorium, showing fewer events in each of these categories. The week 96 results continue to show that DOR/3TC/TDF has a more favorable neuropsychiatric tolerability than EFV/FTC/TDF. EFV is known to be associated with neuropsychiatric AEs, and as a result it is possible that neuropsychiatric AEs were overreported in both arms in this blinded trial due to an ascertainment bias with EFV as comparator. In our trial the EFV/FTC/TDF arm still had a significantly higher percentage of neuropsychiatric AEs than the DOR/3TC/TDF arm (59% vs 26%, respectively).
In summary, the week 96 results of the DRIVE-AHEAD study show that the noninferior efficacy of DOR/3TC/TDF relative to EFV/FTC/TDF was maintained through week 96. Fewer patients developed treatment-emergent viral drug resistance to DOR than to EFV, with no additional resistance identified between weeks 48 and week 96 in the DOR group. In addition, DOR/3TC/TDF demonstrated a more favorable safety profile than EFV/FTC/TDF with fewer discontinuations due to AEs, fewer neuropsychiatric AEs, and a favorable lipid profile.