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Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial Clinical Infectious Diseases, Volume 68, Issue 4, 1 February 2019 supplementary material
 
 
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Abstract
 
Background

 
Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile.
 
Methods
 
DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%).
 
Results
 
Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0).
 
DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients.
 
Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively).
 
Conclusions
 
In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF.
 
Figure 4. Mean change in fasting lipid levels from baseline to week 48. Abbreviations: DOR/3TC/TDF, doravirine at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate at 300 mg; EFV/FTC/TDF, efavirenz at 600 mg, emtricitabine at 200 mg, and tenofovir disoproxil fumarate at 300 mg; HDL-C, high-density lipoprotein cholestoral; LDL-C, low-density lipoprotein cholestoral. *P < .0001. aStatistical testing was not pre-specified for cholesterol, triglycerides, or HDL-C.
 

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Human Immunodeficiency Virus (HIV)-1 infection has been successfully treated with a wide array of antiretroviral therapies, which can vastly improve life expectancy and reduce the risk of HIV-1 transmission, but cannot eradicate the infection. Because lifelong treatment is required, safeguarding against toxicity and comorbidity is important. Adverse events that may lead to treatment discontinuation include neuropsychiatric toxicities, skin rashes, gastrointestinal toxicities, abnormal serum lipid levels, abnormal renal or bone parameters, and drug-drug interactions [1]. Therefore, new antiretroviral therapies with fewer unwanted side effects are needed.
 
Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI) of HIV-1, is active in vitro against both wild-type virus and the most common NNRTI-resistant variants at concentrations achieved with 100 mg once-daily (QD) dosing [2, 3] and has a favorable in vitro resistance profile that is unique among NNRTIs [4]. Because it is not a metabolic inducer or inhibitor [5], DOR is not a perpetrator of pharmacokinetic drug-drug interactions. No clinically meaningful interactions were observed when DOR was co-administered with atorvastatin, an oral contraceptive, a magnesium-based antacid, or a proton-pump inhibitor in healthy volunteers [6-8]. As a substrate of cytochrome P450 (CYP)3A4, exposure to DOR is reduced in the presence of moderate or strong inducers of CYP3A4 [9]. DOR can be taken once daily without regard to food [10], and its bioavailability is not affected by age, gender, or moderate hepatic impairment [11, 12].
 
In a phase 2b study in treatment-naive adults, DOR at 100 mg QD with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) demonstrated comparable efficacy to efavirenz with FTC/TDF and had a favorable safety profile, with lower rates of drug-related adverse events and central nervous system (CNS) events than efavirenz [13-15]. In the phase 3 DRIVE-FORWARD trial, DOR at 100 mg QD demonstrated non-inferior efficacy and a superior lipid profile compared with darunavir-ritonavir after 48 weeks of combination treatment with 2 nucleoside reverse-transcriptase inhibitors (NRTIs) [16].
 
DOR is in development as both a single-entity tablet and a combination tablet containing DOR at 100 mg, lamivudine at 300 mg, and TDF at 300 mg (DOR/3TC/TDF; MK-1439A). This report presents the results of a Phase 3 trial comparing the combination tablet, DOR/3TC/TDF, to ATRIPLA (efavirenz at 600 mg, FTC at 200 mg, and TDF at 300 mg; EFV/FTC/TDF) in adults with previously-untreated HIV-1 infections.
 
RESULTS
 
Of the 734 participants assigned to DOR/3TC/TDF (n = 368) or EFV/FTC/TDF (n = 366), 364 in each group received study therapy and were included in the analyses. Demographics and baseline characteristics were generally similar between the treatment groups (Table 1). By week 48, 14% of the DOR/3TC/TDF group and 17% of the EFV/FTC/TDF group had discontinued study treatment, primarily due to lack of efficacy, adverse events, withdrawal of consent, and loss to follow-up (Figure 1).
 
Efficacy
 
DOR/3TC/TDF was non-inferior to EFV/FTC/TDF on the primary efficacy endpoint, with 84.3% (307/364) and 80.8% (294/364) of participants, respectively, achieving HIV-1 RNA of <50 copies/mL at week 48 (difference, 3.5%; 95% CI, -2.0, 9.0). Virologic response rates were similar between the treatment groups at each time point (Figure 2) and across all baseline prognostic and demographic factors except age (see Supplementary Appendix), with response rates favoring EFV/FTC/TDF in participants ≤31 years old and DOR/3TC/TDF in those older than 31. Among participants with high baseline HIV-1 RNA (>100000 copies/mL), 56/69 (81.2%) in the DOR/3TC/TDF group and 59/73 (80.8%) in the EFV/FTC/TDF group achieved HIV-1 RNA of <50 copies/mL at week 48.
 
Similar results were observed for the virologic endpoints of HIV-1 RNA of <40 copies/mL (83.8% for DOR/3TC/TDF vs 79.7% for EFV/FTC/TDF; difference, 4.1%; 95% CI, -1.5, 9.7) and HIV-1 RNA of <200 copies/mL (Table 2). The mean change in CD4+ T-cell count from baseline to week 48 was similar in the DOR/3TC/TDF and EFV/FTC/TDF groups (198 vs 188 cells/mm3; difference, 10.1; 95% CI, -16.1, 36.3).
 
Viral Drug Resistance
 
Only 22 participants (6.0%) in the DOR/3TC/TDF group and 14 (3.8%) in the EFV/FTC/TDF group met the criteria for confirmed PDVF, which was viral rebound in most cases (16/22 and 10/14, respectively). Participants with PDVF generally had low-level viremia at the time of failure. Among those with viral rebound, 10/16 in the DOR/3TC/TDF group and 4/10 in the EFV/FTC/TDF group had HIV-1 RNA between 50 and 200 copies/mL at the viral failure confirmation visit.
 
Results from viral drug-resistance testing are available for 13 DOR/3TC/TDF recipients and 10 EFV/FTC/TDF recipients who met PDVF criteria, and for 9 and 13, respectively, who discontinued early without PDVF (Table 3). In the DOR/3TC/TDF group, isolates from 7 participants (6 with non-response; 1 rebound) had mutations associated with DOR resistance: 6 isolates had both genotypic and phenotypic resistance to DOR (conferred through V106 in 4 cases, in combination with other mutations such as F227C) and to EFV; and 1 isolate had a DOR-associated resistance mutation (Y318Y/F), but no phenotypic resistance to DOR or EFV. Five of the 7 isolates also had genotypic resistance to 3TC. In the EFV/FTC/TDF group, isolates from 12 participants (4 with non-response, 5 rebound, and 3 early discontinuation) had mutations associated with EFV resistance: 11 isolates had both genotypic and phenotypic resistance to EFV (conferred through K103N in 10 and G190E in 1); and one isolate had genotypic resistance to EFV (G190E), but phenotypic testing failed. Two isolates with EFV resistance did not retain phenotypic sensitivity to DOR: 1 had G190E and 1 had K103N/M230L. Five of the 12 isolates also had genotypic resistance to FTC.
 
Safety
 
Overall rates of any AE, drug-related AE, and discontinuation due to an AE were lower in the DOR/3TC/TDF group compared with the EFV/FTC/TDF group (Table 4). The most common reasons for discontinuation were rashes (10 EFV/FTC/TDF, 0 DOR/3TC/TDF) and CNS-related events (9 EFV/FTC/TDF, 4 DOR/3TC/TDF). The most common drug-related AEs for DOR/3TC/TDF and EFV/FTC/TDF were dizziness (7% vs 32%, respectively), abnormal dreams (5% vs 9%), nausea (5% vs 7%), and rash (2% vs 9%). Among the most common AEs of any causality, the largest treatment differences were observed for dizziness, abnormal dreams, and rash (Table 4).
 
On the primary safety endpoint, the proportion of participants with pre-specified neuropsychiatric events by week 48 was significantly lower in the DOR/3TC/TDF group compared with the EFV/FTC/TDF group for the categories of dizziness (8.8% vs 37.1%, respectively; P ≤ .001), sleep disorders/disturbances (12.1% vs 25.2%; P ≤ .001), and altered sensorium (4.4% vs 8.2%; P = .033). For the secondary categories, the proportion of participants with depression/suicide/self-injury or psychosis/psychotic disorders was numerically lower for DOR/3TC/TDF than EFV/FTC/TDF (Figure 3). These neuropsychiatric events were mild in the majority of cases in each group (DOR/3TC/TDF, 72%; EFV/FTC/TDF, 75%).
 
Figure 4 displays the mean change in fasting lipid levels from baseline to week 48. For LDL-C and non-HDL-C, the treatment difference was statistically significant (1-sided P < .0001), with minimal changes (-1.6 and -3.8 mg/dL, respectively) in the DOR/3TC/TDF group versus mean increases (8.7 and 13.3 mg/dL, respectively) in the EFV/FTC/TDF group. The mean change from baseline in the total cholesterol/HDL-C ratio was -0.23 for DOR/3TC/TDF and -0.18 for EFV/FTC/TDF (difference, -0.07; 95% CI, -0.21, 0.07). Lipid-lowering therapy was modified during the study by 2.2% (8/364) of DOR/3TC/TDF recipients and 2.5% (9/364) of EFV/FTC/TDF recipients (difference, 0.3%; 95% CI, -2.7, 2.1). The incidence of DAIDS grade 3-4 laboratory abnormalities, including serum creatinine, was low and similar between the treatment groups (see Supplementary Appendix). Specific bone and renal parameters were not evaluated in this trial; however, fractures and drug-related renal AEs occurred in <1% of each treatment group.
 
DISCUSSION
 
This Phase 3 trial evaluated the efficacy and safety of DOR/3TC/TDF compared to the widely-used regimen of EFV/FTC/TDF in treatment-naive HIV-1-infected adults. The efficacy of DOR/3TC/TDF was non-inferior to that of EFV/FTC/TDF at week 48 (84.3% vs 80.8%, respectively) and was similar across baseline characteristics of gender, race, baseline viral load, and viral subtype. In both treatment groups, the virologic response rate was lower among participants with baseline HIV-1 RNA of >100000 copies/mL (81.2% for DOR/3TC/TDF; 80.8% for EFV/FTC/TDF) compared to those with baseline HIV-1 RNA of ≤100000 copies/mL (90.6% and 91.1%, respectively). Lower response rates in participants with high baseline viral loads has been observed in other clinical trials and across various antiretroviral classes [20, 21]. Response rates based on HIV-1 RNA thresholds of <40 and <200 copies/mL were consistent with the primary endpoint, and there was no notable difference between treatment groups in the change from baseline in CD4+ T-cell counts at week 48.
 
The virologic response rate in the EFV/FTC/TDF group (80.8%) was similar to rates reported for this regimen in previous clinical trials: 81% [21] and 81.6% [22]. In both trials, discontinuation due to AEs was more frequent in the EFV/FTC/TDF group than in the comparator group (10% vs 2% and 8.7% vs 2.5%, respectively), which also occurred in our study (6.3% vs 2.7%). These discontinuations reduced the observed response rate by the Food and Drug Administration snapshot approach, which treats all missing data as failures. When missing data are excluded (using the observed failure approach), higher virologic response rates were observed for both treatment groups (DOR/3TC/TDF, 88.7%; EFV/FTC/TDF, 88.8%).
 
Response rates were also influenced by the conservative definition of PDVF used in this study, which required discontinuation of participants with HIV-1 RNA of ≥50 copies/mL at week 48, as well as those who became suppressed but later had confirmed HIV-1 RNA of ≥50 copies/mL, regardless of time point. Some participants had re-suppressed between the virologic failure confirmation visit and the discontinuation visit, but were required to discontinue per protocol. Other participants who were discontinued due to PDVF criteria but had very low-level viremia may have re-suppressed if they had continued on treatment.
 
Through 48 weeks of treatment, genotypic resistance to DOR developed in 7 participants in the DOR/3TC/TDF group (1.9% overall; 32% of those with resistance testing), and genotypic resistance to EFV developed in 12 participants in the EFV/FTC/TDF group (3.3% overall; 52% of those with resistance testing). The rate and pattern of resistance observed in the EFV/FTC/TDF group was consistent with previous reports [21-25]. Resistance to DOR was primarily conferred by a substitution in RT V106, in combination with 1 or more mutations, which is consistent with in vitro data showing that DOR has a unique mechanism of resistance requiring multiple mutations or base-pair changes [4]. In a recent report, the prevalence of doravirine-associated mutations was lower than other NNRTI mutations among treatment-naive patients in Europe [26]. With in vitro activity against commonly-transmitted NNRTI mutations, and multiple mutations needed for resistance in most cases, doravirine is likely to be effective in the majority of treatment-naive patients with transmitted NNRTI resistance. However, the DRIVE-AHEAD trial was not designed to address this question, since patients with NNRTI resistance were excluded. DOR/3TC/TDF was generally well-tolerated, with fewer drug-related AEs and discontinuations due to AEs than EFV/FTC/TDF. DOR/3TC/TDF exhibited favorable neuropsychiatric tolerability and was superior to EFV/FTC/TDF in the analysis of dizziness, sleep disorders/disturbances, and altered sensorium, showing lower event rates in each of these categories. The incidence of rashes was also lower in the DOR/3TC/TDF group (5% vs 12% in the EFV/FTC/TDF group) and was similar to that reported previously for doravirine (7%) [16]. Furthermore, no participants in the DOR/3TC/TDF group discontinued treatment due to rashes. DOR/3TC/TDF demonstrated a favorable overall profile for plasma lipid levels, including significant differences between treatment groups for LDL-C and non-HDL-C (minimal changes in the DOR/3TC/TDF group versus mean increases in the EFV/FTC/TDF group). A similar favorable lipid profile was observed for doravirine in the DRIVE-FORWARD trial [16].
 
Our study had several limitations. Participants took 2 pills per day (1 active drug and 1 placebo), which could be taken together or at different times; since some participants may have taken the study medications at different times, resulting in a twice-daily regimen, the effects of improved adherence with a 1-pill, once-daily regimen [27] could not be fully captured in this trial. Although the response rates appeared similar across most subgroups, several of these groups were relatively small, such as women (15.4%), Blacks/African Americans (18.5%), and those with high baseline viral loads (>100000 copies/mL, 21.3%), low CD4+ T-cell counts (≤200/mm3, 12.4%), or hepatitis B/C co-infections (2.7%). The small difference in treatment responses by age (favoring EFV/FTC/TDF in younger participants and DOR/3TC/TDF in older participants) was not observed in the DRIVE-FORWARD trial [13] and may be due to chance, since no adjustment was made for multiple comparisons and the trial was not powered to detect statistically-significant differences within subgroups [28].
 
In summary, DOR/3TC/TDF demonstrated robust antiretroviral efficacy that was statistically non-inferior to that of EFV/FTC/TDF, immunologic efficacy similar to that of EFV/FTC/TDF, and a low rate of treatment-emergent viral drug resistance. DOR/3TC/TDF was superior to EFV/FTC/TDF for neuropsychiatric AEs and changes in LDL-C and non-HDL-C, and was associated with lower rates of rashes, drug-related AEs, and discontinuation due to AEs. The favorable safety profile of DOR/3TC/TDF may reduce the likelihood of non-compliance and treatment discontinuation. Overall, DOR/3TC/TDF is a promising new treatment option for adults with HIV-1 infections.

 
 
 
 
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