Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Doravirine dose Selection and 96-Week Safety and Efficacy versus Efavirenz in Antiretroviral Therapy-Naive Adults with HIV-1 Infection in a Phase IIb Trial

Doravirine dose Selection and 96-Week Safety and Efficacy versus Efavirenz in Antiretroviral... Antiviral Therapy 2019; 24:425–435 (doi: 10.3851/IMP3323) Original article Doravirine dose selection and 96-week safety and efc fi acy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial 1,2 3 4 5 6 Jose M Gatell , Javier O Morales-Ramirez , Debbie P Hagins , Melanie Thompson , Keikawus Arastéh , 7 8 9 10 11 Christian Hoffmann , François Raffi , Olayemi Osiyemi , Robin Dretler , Charlotte Harvey , 11 12 13 14 15 11 Xia Xu , Andreas Plettenberg , Don E Smith , Joaquín Portilla , Sorin Rugina , Sushma Kumar , 11 11 11 11 11 Colleen Frobose , Hong Wan , Anthony Rodgers , Carey Hwang , Hedy Teppler * Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain Present address: ViiV Healthcare, Barcelona, Spain Clinical Research Puerto Rico, San Juan, Puerto Rico Chatham County Health Department, Savannah, GA, USA AIDS Research Consortium of Atlanta, Atlanta, GA, USA EPIMED/Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany ICH Study Center, Hamburg, Germany Infectious Diseases Department and INSERM CIC 1413, University Hospital of Nantes, Nantes, France Triple O Research Institute PA, West Palm Beach, FL, USA Infectious Disease Specialists of Atlanta, Decatur, GA, USA Merck & Co., Inc., Kenilworth, NJ, USA ifi-Institute for Infections, Hamburg, Germany Albion Centre, Sydney, Australia Hospital General Universitario de Alicante/ISABIAL, Alicante, Spain Ovidius University, Clinical Infectious Diseases Hospital, Constanta, Romania *Corresponding author e-mail: hedy_teppler@merck.com Background: The safety and efficacy of doravirine were system (CNS) adverse events (AEs) by weeks 8 and 24 compared with that of efavirenz as initial treatment of (Parts I+II combined). adults living with HIV-1 infection (NCT01632345). Results: 210 and 132 participants were randomized in Methods: A Phase IIb double-blind trial with partici- Parts I and II, respectively, and 216 (108 on doravirine pants stratified by screening HIV-1 RNA (≤ or >100,000 100 mg, 108 on efavirenz) were evaluable for Parts I+II copies/ml) and randomized 1:1:1:1:1 to receive once- combined. At week 24, the proportion of participants daily doravirine (25, 50, 100 or 200 mg) or efavirenz with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 600 mg (Part I) for up to 96 weeks, with open-label teno- 100 mg and 73.1% for efavirenz (difference -0.5 [95% fovir disoproxil fumarate 300 mg/emtricitabine 200 mg CI -12.3, 11.2]). In addition, CNS AEs were reported by (TDF/FTC). After dose selection at week 24, doravirine 26.9% and 47.2% of doravirine and efavirenz recipi- 100 mg was provided to participants receiving the other ents, respectively (difference -20.4 [95% CI -32.6, -7.5]; doses of doravirine and additional participants were ran- P=0.002). domized 1:1 to receive once-daily doravirine 100 mg or Conclusions: Doravirine 100 mg with TDF/FTC demon- efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Pri- strated similar antiretroviral activity and superior CNS mary outcomes were the proportion of participants with safety compared with efavirenz 600 mg with TDF/FTC. HIV-1 RNA <40 copies/ml at week 24, and central nervous ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 425 AVT-19-OA-4512_Gatell.indd 425 AVT-19-OA-4512_Gatell.indd 425 22/11/2019 11:48:52 22/11/2019 11:48:52 JM Gatell et al. Introduction of doravirine versus efavirenz for 96 weeks (Part  II; Additional file 1). Participants were enrolled at 63 cen- Currently, each of the four non-nucleoside reverse tres across Australia, Belgium, Canada, France, Germany, transcriptase inhibitors (NNRTIs) for the treatment of the Netherlands, Puerto Rico, Romania, Russia, Spain HIV-1 infection has limitations. Efavirenz is associated and the US. The trial was conducted in accordance with with frequent central nervous system (CNS) adverse principles of Good Clinical Practice and was approved by events (AEs) [1], including increased risk of suicidal- the appropriate institutional review boards and regula- ity [2]. Rilpivirine must be taken with food, has sig- tory agencies. All participants provided written informed nificant interactions with acid-reducing agents, and has consent. limited efficacy in individuals with high baseline HIV-1 RNA (>100,000 copies/ml) and low CD4 T-cell counts Participants (<200 cells/mm ) [3–5]. Etravirine is not approved for Eligible participants were adults (≥18 years of age) with first-line treatment and requires twice-daily dosing [6]. plasma HIV-1 RNA ≥1,000 copies/ml, CD4 T-cell count Finally, nevirapine is associated with skin and liver ≥100 cells/mm and no prior ART experience. Partici- hypersensitivity reactions, and has prescribing restric- pants were required to be clinically stable for ≥2 weeks tions based on gender and CD4 T-cell counts [7]. These before the trial, with no signs or symptoms of acute infec- limitations have led to changes in recommendations for tion (non-HIV-1) and no significant laboratory abnor - NNRTI-containing regimens from preferred to alter- malities within 45 days of treatment. Those with known native first-line antiretroviral therapy (ART) in most HIV-1 genotypic resistance to FTC, TDF or efavirenz, international guidelines [3,4,8,9]. Alternative NNRTI or active hepatitis B or C infection were excluded. Addi- treatment options with both high efficacy and tolerabil- tional exclusion criteria are shown in Additional file 2. ity are needed. Doravirine (MK-1439) is an NNRTI that has high Randomization and assessment in vitro potency versus a broad panel of isolates, includ- Participants were stratified by screening HIV-1 RNA ing some common NNRTI-resistant variants  [10]. In ≤100,000 or >100,000 copies/ml prior to randomiza- Phase I studies, doravirine demonstrated good tolerabil- tion. In Part I, participants were randomized 1:1:1:1:1 ity across a wide dose range and a pharmacokinetic pro- to receive doravirine (Merck & Co., Inc., Kenilworth, file suitable for once-daily dosing, irrespective of food NJ, USA) 25 mg, 50 mg, 100 mg or 200 mg once intake and coadministration of antacids or acid-reducing daily; or efavirenz 600 mg once daily, both in combi- agents [11–13]. Doravirine is a substrate for cytochrome nation with co-formulated TDF 300 mg/FTC 200 mg P450 (CYP450) 3A-mediated metabolism  [14]; coad- (Gilead Sciences Inc., Foster City, CA, USA), for up to ministration with strong CYP450 3A inducers may 96 weeks. Following the interim analysis for dose selec- significantly decrease doravirine plasma levels  [15,16]. tion at week 24 in Part I, additional participants were Drug–drug interactions via other major drug-metab- randomized 1:1 in Part II to receive the selected dose olizing enzymes and transporters are unlikely  [14], of doravirine (100 mg) or efavirenz 600 mg once daily, enabling coadministration with a wide range of treat- each in combination with TDF/FTC, for 96 weeks. Par- ments for HIV-1 infection and associated concurrent ticipants receiving the non-selected doses of doravirine illnesses [11,14]. In ART-naive adults with HIV-1 infec- in Part I were switched to the selected dose at the next tion, doravirine monotherapy given for 7 days dem- planned study visit. For both parts of the trial, efavirenz onstrated robust antiviral activity, without evidence of and open-label TDF/FTC were administered according viral resistance [17]. Here we present the final results of to the prescribing information [1,22]. a Phase IIb, dose selection trial that compared the safety A combination of active drugs and placebo was given and efficacy of doravirine with that of efavirenz (both to maintain blinding of doravirine and efavirenz: par- administered with tenofovir disoproxil fumarate [TDF]/ ticipants took six tablets per day before dose selection emtricitabine [FTC]) in ART-naive adults with HIV-1 (four doravirine or matching placebo, one efavirenz or infection. The 24-week and 48-week interim results of matching placebo, one TDF/FTC) and three tablets per this trial have been previously reported [18–21]. day after dose selection. Doravirine (or placebo) was to be taken in the morning. Open-label TDF/FTC was to be taken in the morning with food. Efavirenz (or pla- Methods cebo) was to be taken at bedtime without food on an Study design empty stomach. This Phase IIb, randomized, double-blind trial (MK-1439 Participants visited the study site at days 1 and 14; Protocol 007; NCT01632345) consisted of two parts: a weeks 4, 8, 12, 16 and 24; and every 12 weeks there- 24-week dose selection phase (Part I), followed by com- after up to week 96. At each visit, participants were parison of the safety and efficacy of the selected dose assessed through physical examination, laboratory 426 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 426 AVT-19-OA-4512_Gatell.indd 426 22/11/2019 11:48:52 22/11/2019 11:48:52 Doravirine versus efavirenz Phase IIb trial tests including haematological analysis, serum chemis- (acute psychosis, hallucination [including auditory try tests, fasting lipid parameters, CD4 T-cell counts and/or visual], psychotic disorder), or nervous system and measurement of HIV-1 RNA (Abbott RealTime disorder. All such events regardless of attribution were HIV-1 assay; Abbott Laboratories, IL, USA; lower limit pooled and evaluated as CNS events. of quantification: 40 copies/ml). Clinical AEs were assessed at every visit by patient report. No question- Statistical analysis naires were used to solicit specific symptoms, including The primary objective of the study was to support the for CNS events. Medication compliance was monitored doravirine dose selection for the Phase III clinical pro- with diary cards completed by the participants and gramme. The primary population for the efficacy analy- returned at each study visit. ses included all randomized participants who had at Protocol-defined virological failure (PDVF) included least one post-randomization observation after receiv- two categories: non-response (participants who did not ing at least one dose of blinded study treatment. The achieve HIV-1 RNA <40 copies/ml by week 24) and non-completer = failure (NC=F) approach to missing rebound (initial response of HIV-1 RNA <40 copies/ml, data was used for the primary and secondary virologi- followed by two consecutive measurements of HIV-1 cal response end points (participant proportions with RNA ≥40 copies/ml at least 1 week apart at or after HIV-1 RNA <40 copies/ml and <200 copies/ml, respec- week 24). Participants with PDVF and sufficient viral tively). All missing values were considered failures with RNA (>400 copies/ml) in the confirmatory plasma sam- the exception of intermittent missing values flanked by ple were assessed for genotypic and phenotypic viral two successes, which were excluded. Sensitivity analy- resistance (Monogram Biosciences, South San Fran- ses were conducted for the primary end point using the cisco, CA, USA). Participants with PDVF were recom- following missing data approaches: treatment-related mended, but not required, to discontinue the study. discontinuation = failure (discontinuations due to lack of efficacy or AEs were considered failures thereafter), Outcomes observed failure (OF; discontinuations due to lack of Efficacy and safety outcomes were assessed for each efficacy were considered failures thereafter), and the doravirine dose versus efavirenz in Part I, and for the FDA snapshot method [24]. selected dose of doravirine (100 mg) versus efavirenz For all virological end points in Part I and Parts using data from these groups in Part I and Part II com- I+II, the difference in proportion of participants with bined (hereafter referred to as Parts I+II). Since there virological responses between treatment groups and was no clear evidence of heterogeneity across the dora- the associated 95% CIs were calculated using Miet- virine dose groups, data displays include an additional tinen and Nurminen’s method [25] with stratification doravirine group that includes all participants rand- by screening HIV-1 RNA ≤100,000 or >100,000 cop- omized to any dose of doravirine in Part I. ies/ml. To assess the consistency of the treatment effect The primary efficacy outcome was the proportion of in Parts I+II, the between-group differences for the participants with HIV-1 RNA <40 copies/ml at week 24 primary end point were estimated within subgroups in Part I and in Parts I+II. Secondary efficacy outcomes defined by baseline HIV-1 RNA level (≤ or >100,000 were the proportion of participants with HIV-1 RNA copies/ml) using the OF approach. <200 copies/ml and the change from baseline in CD4 For the secondary end point of change from baseline T-cell count. in CD4 T-cell counts, descriptive statistics including Safety was assessed by physical examinations, labora- 95% CIs were provided and missing data were handled tory tests, 12-lead electrocardiogram, and recording of using the OF approach. Baseline values were carried AEs coded using the Medical Dictionary for Regulatory forward for participants who discontinued due to lack Activities (MedDRA; version 17.1). Changes in labora- of efficacy. tory values were classified according to the Division of The safety analyses used the ‘all patients as treated’ AIDS criteria [23]. The primary safety end point was population, including all randomized participants who the proportion of participants experiencing CNS events received at least one dose of study treatment. The pri- (from the following pre-specified list of MedDRA mary hypothesis of Parts I+II was that doravirine at the terms) by weeks 8 and 24 of Parts I+II: dizziness, sleep final selected dose is superior to efavirenz, each in com- disorders (abnormal dreams, insomnia, nightmare), bination with TDF/FTC, as measured by proportion of altered sensorium (concentration impaired, confusional participants with CNS events by week 8 (with hypoth- state, delirium, depressed level of consciousness, dis- esis testing also at week 24 if superior at week 8). CNS turbance in attention, somnolence), depression/suicide events occurring by week 8 and week 24 in Parts I+II (depressed mood, depressive symptom, depression, were subjected to inferential testing for statistical sig- major depression, suicidal behaviour, suicidal ideation, nificance with P-values and 95% CIs provided for suicide attempt, completed suicide), psychotic disorders between-group comparisons. Antiviral Therapy 24.6 427 AVT-19-OA-4512_Gatell.indd 427 AVT-19-OA-4512_Gatell.indd 427 22/11/2019 11:48:52 22/11/2019 11:48:52 JM Gatell et al. Sample size was calculated according to the power of efavirenz participants discontinued study therapy for comparing the pre-specified CNS AEs between before week 96 (Additional file 3). In Part II, 16.7% doravirine at the selected dose and efavirenz; this deter- of participants in each treatment group discontinued mined the size of cohort II. With 100 participants per study therapy before week 96 (Additional file 3). treatment group in Parts I+II, and assuming the CNS The proportion of participants with HIV-1 RNA event rates were 20% for doravirine and 52% for efa- <40  copies/ml at week 24 of Part I was over 70% virenz by week 8, the trial had >99% power, with 95% for all doravirine doses (25 mg, 80.0% [95% CI, confidence, to detect whether the selected dose of dora- 64.4, 90.9]; 50 mg, 74.4% [58.8, 86.5]; 100 mg, 71.4% virine had a significantly lower rate of CNS events than [55.4,  84.3]; 200 mg, 80.5% [65.1, 91.2]) compared efavirenz. Assuming CNS event rates of 30% for dora- with 64.3% (48.0, 78.4) for efavirenz, with similar virine and 50% for efavirenz, 100 participants per arm results observed regardless of missing data approach provided 83% power, with 95% confidence, to demon- (Additional file 4). The proportion of participants with strate superiority of doravirine over efavirenz. HIV-1 RNA <200  copies/ml at week 24 ranged from 83.7–92.9% in the doravirine groups compared with 81.0% for efavirenz. The mean change from baseline Results in CD4 T-cell count at week 24 of Part I ranged from The trial was conducted between 15 October 2012 and 113–154 cells/mm in the doravirine groups compared 21 March 2016. Participant disposition for both parts with 121 cells/mm for efavirenz. are shown in Additional file 3. Of the 462 individuals Doravirine was generally well tolerated at all doses screened, 342 were enrolled and randomized across 63 studied in Part I (Table 2). There was no apparent pat- sites. Demographics and baseline clinical characteristics tern of dose-related toxicity. The proportion of par- were generally well balanced across treatment groups ticipants with drug-related AEs was lower in each of (Table 1). In Part I, 26.9% of doravirine participants the doravirine groups (16.7–46.5%) versus the efa- (range 19.5% [200 mg] to 34.9% [50 mg]) and 30.2% virenz group (57.1%). In total, 3.0% of participants Table 1. Baseline demographics and participant characteristics (Parts I+II) Doravirine All dose Efavirenz 25 mg (n=40) 50 mg (n=43) 100 mg (n=108) 200 mg (n=41) groups (n=232) 600 mg (n=108) Male, n (%) 38 (95.0) 37 (86.0) 99 (91.7) 40 (97.6) 214 (92.2) 101 (93.5) Median age, years (range) 37 (21–69) 36 (25–66) 35 (19–67) 32 (21–50) 35 (19–69) 34 (20–57) Race/ethnicity White, n (%) 23 (57.5) 31 (72.1) 86 (79.6) 31 (75.6) 171 (73.7) 87 (80.6) Black, n (%) 13 (32.5) 8 (18.6) 16 (14.8) 6 (14.6) 43 (18.5) 17 (15.7) Hispanic or Latino, n (%) 5 (12.5) 8 (18.6) 15 (13.9) 10 (24.4) 38 (16.4) 17 (15.7) Asian, n (%) 3 (7.5) 3 (7.0) 5 (4.6) 2 (4.9) 13 (5.6) 2 (1.9) Other , n (%) 1 (2.5) 1 (2.3) 1 (0.9) 2 (4.9) 5 (2.2) 2 (1.9) Geographic region Asia–Pacific, n (%) 4 (10.0) 5 (11.6) 15 (13.9) 8 (19.5) 32 (13.8) 15 (13.9) Europe, n (%) 11 (27.5) 17 (39.5) 59 (54.6) 16 (39.0) 103 (44.4) 49 (45.4) North America, n (%) 25 (62.5) 21 (48.8) 34 (31.5) 17 (41.5) 97 (41.8) 44 (40.7) History of AIDS, n (%) 6 (15.0) 5 (11.6) 4 (3.7) 6 (14.6) 21 (9.1) 7 (6.5) Baseline HIV-1 RNA Mean log copies/ml (sd ) 4.4 (0.75) 4.7 (0.68) 4.6 (0.78) 4.6 (0.65) 4.6 (0.74) 4.6 (0.72) ≤100,000 copies/ml, n (%) 28 (70.0) 30 (69.8) 73 (67.6) 29 (70.7) 160 (69.0) 76 (70.4) >100,000 copies/ml, n (%) 12 (30.0) 13 (30.2) 35 (32.4) 12 (29.3) 72 (31.0) 32 (29.6) Baseline CD4 T-cell count Mean cells/mm (sd ) 411 (210) 464 (239) 432 (187) 419 (215) 432 (206) 448 (189) ≤200 cells/mm , n (%) 7 (17.5) 3 (7.0) 7 (6.5) 5 (12.2) 22 (9.5) 10 (9.3) >200 and ≤350 cells/mm , n (%) 11 (27.5) 13 (30.2) 35 (32.4) 12 (29.3) 71 (30.6) 25 (23.1) >350 cells/mm , n (%) 22 (55.0) 27 (62.8) 66 (61.1) 24 (58.5) 139 (59.9) 73 (67.6) Subtype B, n (%) 35 (87.5) 34 (79.1) 75 (69.4) 36 (87.8) 180 (77.6) 86 (79.6) Note: both doravirine and efavirenz were administered with tenofovir disoproxil fumarate/emtricitabine. Other race includes: American Indian or Alaska Native, multiracial and unknown (missing data). 428 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 428 AVT-19-OA-4512_Gatell.indd 428 22/11/2019 11:48:52 22/11/2019 11:48:52 Doravirine versus efavirenz Phase IIb trial Table 2. Summary of clinical AEs up to week 24 (Part I) Doravirine Efavirenz 25 mg 50 mg 100 mg 200 mg All dose groups 600 mg Participants in population 40 43 42 41 166 42 With any clinical AE, n (%) 36 (90.0) 40 (93.0) 30 (71.4) 35 (85.4) 141 (84.9) 35 (83.3) With drug-related clinical AE, n (%) 16 (40.0) 20 (46.5) 7 (16.7) 18 (43.9) 61 (36.7) 24 (57.1) With serious clinical AE, n (%) 3 (7.5) 1 (2.3) 0 (0.0) 2 (4.9) 6 (3.6) 3 (7.1) Discontinued due to clinical AE, n (%) 1 (2.5) 3 (7.0) 1 (2.4) 0 (0.0) 5 (3.0) 2 (4.8) Most common clinical AEs Constipation, n (%) 0 (0.0) 4 (9.3) 1 (2.4) 0 (0.0) 5 (3.0) 0 (0.0) Diarrhoea, n (%) 7 (17.5) 2 (4.7) 2 (4.8) 4 (9.8) 15 (9.0) 5 (11.9) Nausea, n (%) 2 (5.0) 6 (14.0) 5 (11.9) 9 (22.0) 22 (13.3) 1 (2.4) Fatigue, n (%) 5 (12.5) 4 (9.3) 1 (2.4) 5 (12.2) 15 (9.0) 2 (4.8) Bronchitis, n (%) 2 (5.0) 1 (2.3) 0 (0.0) 4 (9.8) 7 (4.2) 2 (4.8) Nasopharyngitis, n (%) 1 (2.5) 4 (9.3) 4 (9.5) 6 (14.6) 15 (9.0) 2 (4.8) Upper respiratory tract infection, n (%) 1 (2.5) 2 (4.7) 4 (9.5) 3 (7.3) 10 (6.0) 0 (0.0) Dizziness, n (%) 1 (2.5) 3 (7.0) 0 (0.0) 3 (7.3) 7 (4.2) 10 (23.8) Headache, n (%) 5 (12.5) 5 (11.6) 3 (7.1) 7 (17.1) 20 (12.0) 4 (9.5) Abnormal dreams, n (%) 4 (10.0) 9 (20.9) 2 (4.8) 4 (9.8) 19 (11.4) 4 (9.5) Insomnia, n (%) 1 (2.5) 5 (11.6) 3 (7.1) 2 (4.9) 11 (6.6) 3 (7.1) Nightmare, n (%) 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 1 (0.6) 4 (9.5) Sleep disorder, n (%) 1 (2.5) 1 (2.3) 0 (0.0) 0 (0.0) 2 (1.2) 4 (9.5) Note: both doravirine and efavirenz were administered with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). Determined by investigator to be related to blinded therapy or to open-label TDF/FTC. Reported by ≥4 participants in any treatment group. AE, adverse event. receiving any dose of doravirine discontinued due to In the subgroup analyses of Parts I+II, the proportion AEs compared with 4.8% of those receiving efavirenz. of participants with baseline HIV-1 RNA ≤100,000 Through week 24 of Part I, the most common labo- copies/ml who achieved HIV-1 RNA <40 copies/ml ratory abnormalities were primarily Grade 1 changes at week 96 was similar between doravirine 100 mg (Additional file 5). and efavirenz (88.9% [95% CI 78.4, 95.4] versus Based on Part I week 24 efficacy and safety results, 87.3% [76.5, 94.4], treatment difference 1.6 [-10.4, doravirine 100 mg was selected for enrolment in Part II. 13.7]). Among participants with baseline HIV-1 RNA Participants who received doravirine at 25, 50 and >100,000 copies/ml, the proportion who achieved 200  mg doses were all switched to doravirine 100 mg HIV-1 RNA <40 copies/ml at week 96 was 78.1% after dose selection; however, the data shown below for (60.0, 90.7) for doravirine 100 mg versus 93.1% (77.2, doravirine 100 mg from Parts I and II combined includes 99.2) for efavirenz (difference -15.0 [-33.4, 3.5]). only those Part I participants randomized to 100 mg, plus Over the course of the trial, 43 doravirine recipi- all Part II participants randomized to doravirine, all of ents (26 non-responders [11.2%] and 17 rebounders whom received the 100 mg dose. In Parts I+II, the propor- [7.3%]) and 14 efavirenz recipients (10 non-responders tion of participants with HIV-1 RNA <40 copies/ml at [9.3%] and 4 rebounders [3.7%]) met the criteria for week 24 was 72.9% for doravirine 100 mg versus 73.1% PDVF. In the doravirine 100 mg group, 19 (17.6%) par- for efavirenz (difference [95% CI], -0.5 [-12.3, 11.2]). ticipants met criteria for PDVF, including 16 (14.8%) Similar response rates were observed at subsequent time non-responders. A substantial proportion of the non- points through week  96 (Figure 1A) and were similar responders achieved virological suppression later in the between treatment groups regardless of missing data trial: 12/26 of the doravirine recipients and 5/10 of the approach (Additional file 6). The proportion of partici- efavirenz recipients at week 48; 16/26 and 8/10, respec- pants with HIV-1 RNA <200 copies/ml was 89.7% and tively, at week 96. 79.6% at weeks 24 and 96, respectively, for doravirine In total, 18 participants with PDVF had samples 100 mg compared with 87.0% and 75.9% at weeks 24 with sufficient HIV-1 RNA (> 400 copies/ml) for and 96, respectively, for efavirenz. The mean change in resistance testing. Two participants in the doravirine CD4 T-cell counts increased throughout the study in 25 mg group showed genotypic resistance associ- both treatment groups, reaching 259 cells/mm for dora- ated with NNRTIs (K101K/E, P236P/L mutations in virine 100 mg and 264 cells/mm for efavirenz at week 96 one participant, and V106V/I, F227C mutations in (Figure 1B). one participant), and one participant in the 100 mg Antiviral Therapy 24.6 429 AVT-19-OA-4512_Gatell.indd 429 AVT-19-OA-4512_Gatell.indd 429 22/11/2019 11:48:52 22/11/2019 11:48:52 JM Gatell et al. Figure 1. Primary and secondary end points over time, up to week 96, Parts I+II Difference in percent response versus efavirenz (95% CI) Week 96 n/total n (%) Doravirine 100 mg 81/108 (75.0) -0.8 (-12.4, 10.7) Doravirine combined 160/232 (69.0) -6.6 (-16.2, 3.9) Efavirenz 600 mg 82/108 (75.9) 0 2 4 8 16 24 36 48 60 72 84 96 Week Doravirine 100 mg Doravirine combined Efavirenz 600 mg Mean change Difference in CD4 T-cell from baseline count change versus (95% CI) efavirenz (95% CI) Week 96 Doravirine 100 mg 259 (220, 298) -4 (-64, 55) Doravirine combined 237 (210, 265) -27 (-77, 24) Efavirenz 600 mg 264 (218, 309) 0 2 4 8 16 24 36 48 60 72 84 96 Week Doravirine 100 mg (n=95) Doravirine combined (n=196) Efavirenz 600 mg (n=93) (A) Percent of participants with HIV-1 RNA <40 copies/ml. (B) Mean change from baseline in CD4 T-cell count. Graphical data are presented with 95% CI. group showed mutations associated with resistance to and K103N, N348I in one participant) and pheno- NNRTIs (E138E/G, V179D) and nucleoside reverse typic resistance to efavirenz. transcriptase inhibitors (A62V). Only the virus with The occurrence of pre-specified CNS events by week 8 V106V/I, F227C mutations displayed phenotypic and 24 in Parts I+II was a key safety end point of the resistance to doravirine, with a 66-fold decrease in trial. At week 8, the proportion of participants with susceptibility; this participant also developed resist- CNS events was significantly lower in the doravirine ance to FTC (M184V). Two of the three efavirenz 100 mg group (24.1%) compared with the efavirenz participants with PDVF had virus with efavirenz resist- group (44.4%; P=0.002; difference -20.4%; 95% CI ance mutations (K101K/Q, G190S in one participant, -32.4, -7.8). The difference was also observed through 430 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 430 AVT-19-OA-4512_Gatell.indd 430 22/11/2019 11:48:52 22/11/2019 11:48:52 Mean change from baseline in Percent of participants with + 3 CD4 T-cell count, cells/mm HIV-1 RNA <40 copies/ml Doravirine versus efavirenz Phase IIb trial week 24, with 26.9% and 47.2% of participants who and 96.3% of the efavirenz group and led to discon- received doravirine 100 mg and efavirenz, respectively, tinuation in 4.6% and 10.2%, respectively (Table 3). reporting at least one of the pre-specified CNS events No deaths occurred during the study. The proportion (P=0.002; difference -20.4%; 95% CI -32.6, -7.5). of participants with drug-related AEs in Parts I+II was At both time points, dizziness and abnormal dreams lower for doravirine 100 mg (35.2%) versus efavirenz accounted for most of the difference between dora- (58.3%; difference [95% CI] -23.1 [-35.6, -9.9]). Over- virine 100 mg and efavirenz (Figure 2). all, the most commonly reported drug-related AEs Through week 96 of Parts I+II, one or more AEs were dizziness (7.4% versus 26.9%), abnormal dreams occurred in 89.8% of the doravirine 100 mg group (5.6% versus 14.8%) and nausea (7.4% versus 6.5%) Figure 2. CNS events in Parts I+II at week 8 and week 24 Percent of participants with ≥1 CNS event 0.9 Suicidal ideation Doravirine 100 mg Efavirenz 600 mg Difference (95% CI) 3.7 Disturbance in attention 24.1% 44.4% -20.4 (-32.4, -7.8) 0.9 Somnolence 0.9 Efavirenz 600 mg 2.8 Hallucination 0.9 Doravirine 100 mg 1.9 Depression 0.9 8.3 Nightmare 5.6 16.7 Abnormal dreams 6.5 2.8 Insomnia 7.4 28.7 Dizziness 9.3 0 5 10 15 20 25 30 % of participants with ≥1 event 0.9 Depressed mood Percent of participants with ≥1 CNS event 2.8 Suicidal ideation Doravirine 100 mg Efavirenz 600 mg Difference (95% CI) Depressive symptom 0.9 26.9% 47.2% -20.4 (-32.6, -7.5) 0.9 Somnolence 0.9 2.8 Hallucination Efavirenz 600 mg 0.9 Doravirine 100 mg 3.7 Disturbance in attention 0.9 4.6 Depression 1.9 8.3 Nightmare 6.5 17.6 Abnormal dreams 6.5 2.8 Insomnia 7.4 28.7 Dizziness 9.3 0 5 10 15 20 25 30 % of participants with ≥1 event (A) Week 8. (B) Week 24. CNS, central nervous system. Antiviral Therapy 24.6 431 AVT-19-OA-4512_Gatell.indd 431 AVT-19-OA-4512_Gatell.indd 431 22/11/2019 11:48:53 22/11/2019 11:48:53 JM Gatell et al. Table 3. Summary of clinical AEs up to week 96 (Parts I+II) Doravirine all dose groups (n=232) Doravirine 100 mg (n=108) Efavirenz 600 mg (n=108) a a a All causality Drug-related All causality Drug-related All causality Drug-related Participants with any clinical AE, n (%) 212 (91.4) 96 (41.4) 97 (89.8) 38 (35.2) 104 (96.3) 63 (58.3) Participants with serious clinical AE, n (%) 19 (8.2) 0 (0.0) 11 (10.2) 0 (0.0) 13 (12.0) 3 (2.8) Participants discontinued due to 11 (4.7) 5 (2.2) 5 (4.6) 2 (1.9) 11 (10.2) 10 (9.3) clinical AE, n (%) Most common clinical AEs Diarrhoea, n (%) 35 (15.1) 8 (3.4) 16 (14.8) 1 (0.9) 18 (16.7) 7 (6.5) Nausea, n (%) 32 (13.8) 17 (7.3) 13 (12.0) 8 (7.4) 11 (10.2) 7 (6.5) Bronchitis, n (%) 18 (7.8) 0 (0.0) 5 (4.6) 0 (0.0) 12 (11.1) 0 (0.0) Nasopharyngitis, n (%) 39 (16.8) 1 (0.4) 19 (17.6) 1 (0.9) 13 (12.0) 0 (0.0) Upper respiratory infection, n (%) 19 (8.2) 0 (0.0) 10 (9.3) 0 (0.0) 13 (12.0) 0 (0.0) Dizziness, n (%) 29 (12.5) 13 (5.6) 16 (14.8) 8 (7.4) 32 (29.6) 29 (26.9) Headache, n (%) 32 (13.8) 7 (3.0) 14 (13.0) 3 (2.8) 15 (13.9) 6 (5.6) Abnormal dreams, n (%) 25 (10.8) 21 (9.1) 7 (6.5) 6 (5.6) 19 (17.6) 16 (14.8) Depression, n (%) 8 (3.4) 2 (0.9) 4 (3.7) 0 (0.0) 11 (10.2) 2 (1.9) Note: both doravirine and efavirenz were administered with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). Determined by investigator to be related to blinded therapy or to open label TDF/FTC. Reported by ≥10% participants in any of these groups. AE, adverse event. for doravirine 100 mg and efavirenz, respectively. The in the presence of CYP3A inducers or following a proportion of participants with treatment-emergent missed dose, and providing coverage of a variety of laboratory abnormalities of Grade 2 or higher was sim- NNRTI mutations, including K103N, Y181C and ilar between doravirine 100 mg and efavirenz through G190A mutations and the dual K103N/Y181C muta- week 96 of Parts I+II, with two exceptions: Grade 2 ele- tions [10,26]. Based on all available data, doravirine vations in total cholesterol and low-density lipoprotein 100 mg once daily was selected for Part II of the trial (LDL)-cholesterol were less common with doravirine and the Phase III clinical programme. 100 mg (0.0% and 2.0%, respectively) than with efa- In all participants who received the selected dose, virenz (9.7% and 9.8%, respectively; Additional file 7). doravirine 100 mg once daily demonstrated antiretro- For the overall doravirine group (all dose groups com- viral activity similar to that of efavirenz. In both treat- bined), Grade 2 elevations in total cholesterol and LDL- ment groups, the proportion of participants with HIV-1 cholesterol were also less common (0.9% and 1.4%, RNA <40 copies/ml increased through week 24 and was respectively) than in the efavirenz group. Grade  3 maintained up to week 96. The efficacy observed in par - total cholesterol and Grade 3 LDL-cholesterol events ticipants with baseline HIV-1 RNA >100,000 copies/ml occurred in 2 participants in the efavirenz group only was numerically lower for doravirine 100 mg than for (no Grade 4 events). Grade 2 creatinine elevations were efavirenz at week 96; however, this difference should more common in the overall doravirine group (8.3%) be interpreted in the context of the relatively small than in the efavirenz group (0.9%). No Grade 3 or 4 subgroup size (32 receiving doravirine 100 mg and 29 creatinine elevations and no discontinuations due to receiving efavirenz). In ongoing Phase III trials, dora- renal AEs occurred in any treatment group. virine 100 mg has demonstrated similar efficacy to the comparator regimens among participants with baseline HIV-1 RNA >100,000 copies/ml [27,28]. In this trial, Discussion doravirine 100 mg also demonstrated an immunologi- Doravirine 100 mg in combination with TDF/FTC cal effect similar to that of efavirenz, as measured by demonstrated similar antiretroviral efficacy to efa- the change from baseline in CD4 T-cell counts. virenz and was associated with a significantly lower Doravirine 100 mg was generally safe and well toler- incidence of CNS AEs in ART-naive adults with HIV-1 ated in this trial. In the key safety analyses, the propor- infection. In Part I of the trial, all studied doses of tion of participants who experienced CNS AEs was sig- doravirine were generally well tolerated and dem- nificantly lower for doravirine 100 mg compared with onstrated antiretroviral activity and immunological efavirenz at weeks 8 and 24. Drug-related AEs were effect similar to efavirenz through 24 weeks of treat- also less common with doravirine compared with efa- ment. Therefore, the selection of the dose for further virenz, driven primarily by lower rates of drug-related study included additional considerations, such as CNS AEs, such as dizziness and abnormal dreams, maintaining therapeutic concentrations of doravirine in the doravirine group. The favourable CNS profile 432 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 432 AVT-19-OA-4512_Gatell.indd 432 22/11/2019 11:48:53 22/11/2019 11:48:53 Doravirine versus efavirenz Phase IIb trial of doravirine versus efavirenz has been confirmed by doravirine showing non-inferior efficacy to ritonavir- the week 48 results of the Phase III DRIVE-AHEAD boosted darunavir in the DRIVE-FORWARD trial trial, in which the fixed-dose combination of dora- and to efavirenz in the DRIVE-AHEAD trial [27,28], virine/lamivudine (3TC)/TDF was compared with the supporting the recent approval of doravirine in the fixed-dose combination of efavirenz/FTC/TDF [28]. US [34,35], Europe [36,37] and elsewhere. Doravirine Treatment-emergent Grade 2 creatinine elevations were has the potential to provide another convenient treat- more common in the overall doravirine group (all dose ment option that offers efficacy, good tolerability and groups combined) than in the efavirenz group; however, safety for people living with HIV. this finding was not seen in either of the Phase III trials, where the incidence of Grade 2 creatinine elevations Acknowledgements was low in the doravirine groups (2.6% and 2.2%, respectively) and similar to the comparator groups We thank all the study participants, and the staff of (4.2% and 1.4%, respectively) [29]. all the centres taking part in the study. Medical writ- Across all treatment groups, the rate of participant ing assistance, under the direction of the authors, was discontinuation was relatively high. For example, in provided by Edward Rochford and Annette Smith of Part I, 19% of the participants discontinued due to CMC AFFINITY, a division of McCann Health Medi- protocol violations, loss to follow-up, non-compliance cal Communications Ltd, Macclesfield, UK, and Kim or withdrawal by subject. The high discontinuation Strohmaier of Merck & Co., Inc., Kenilworth, NJ, USA, rate partially accounts for the relatively low response in accordance with Good Publication Practice (GPP3) rates observed compared with other Phase II trials with guidelines. This assistance was funded by Merck Sharp efavirenz [30–32], particularly in Part I, in which 64% & Dohme Corp., a subsidiary of Merck & Co., Inc., of participants in the efavirenz group achieved HIV-1 Kenilworth, NJ, USA. RNA <40 copies/ml at week 24. The relatively compli- JMG, JOM-R, DPH, MT, KA, C Hoffmann, FR, OO, cated dosing strategy and high pill burden may par- RD, AP, DES, JP and SR enrolled the study partici- tially explain the high discontinuation rate; the trial pants and collected the study data. C Harvey, SK, CF, required twice-daily dosing, including both active and C Hwang and HT contributed to the coordination and placebo tablets to maintain blinding (a total of six tab- oversight of the study. XX, HW and AR performed lets per day before and three tablets per day after dose the statistical analysis. All authors participated in data selection). A further limitation was the relatively small interpretation, contributed to the drafting and critical size of the treatment groups precluding a formal non- review of the article, and approved the final version of inferiority comparison of efficacy. However, the subse- the manuscript. quent Phase III DRIVE-AHEAD trial was adequately powered for statistical comparisons, lacked the high Disclosure statement pill burden of this trial, and demonstrated the non- inferior efficacy of doravirine/3TC/TDF versus efa- Funding for this research was provided by Merck Sharp virenz/FTC/TDF at week 48, with 84.3% and 80.8%, & Dohme Corp., a subsidiary of Merck & Co., Inc., respectively, achieving HIV-1 RNA <50 copies/ml [28]. Kenilworth, NJ, USA. C Harvey, XX, SK, CF, HW, AR, The trial population was primarily young male C Hwang and HT are current or former employees of participants with high baseline CD4 T-cell counts, Merck Sharp & Dohme Corp., a subsidiary of Merck potentially limiting the applicability of these results & Co., Inc., Kenilworth, NJ, USA, and may own stock to a more diverse patient population. Ongoing Phase and/or stock options in Merck & Co., Inc., Kenilworth, III trials of doravirine are composed of larger, more NJ, USA. diverse study populations and greater opportunity to Up to 30 April 2018, JMG received honoraria for speak- evaluate the relationships between demographics or ing and advisory boards, and research grants to his insti- baseline characteristics and the efficacy and safety of tution from ViiV Healthcare, Gilead Sciences, MSD and doravirine. Janssen. From 1 May 2018, he is an employee (Senior Overall, this trial showed promising results for Global Medical Director) of ViiV Healthcare. JOM-R has doravirine as initial treatment of adults with HIV-1 received honoraria for advisory panels and lectures from infection. The superior neuropsychiatric profile of MSD, Bristol-Myers Squibb, ViiV Healthcare and AbbVie; doravirine compared with efavirenz and the once- and research grants from MSD, Bristol-Myers Squibb, daily dosing regimen are likely to improve treatment GeneOne, Sanofi Pasteur, GlaxoSmithKline, Sangamo adherence [33]. An important outcome was the selec- Therapeutics and Gilead Sciences. DPH has received hon- tion of doravirine 100 mg as the dose for further clini- oraria for speaker’s bureau and advisory boards for Merck cal development in the Phase III trials. The 48-week & Co., Inc., Kenilworth, NJ, USA, Gilead Sciences, and results of the Phase III trials are favourable, with Bristol-Myers Squibb. MT has received research support Antiviral Therapy 24.6 433 AVT-19-OA-4512_Gatell.indd 433 AVT-19-OA-4512_Gatell.indd 433 22/11/2019 11:48:53 22/11/2019 11:48:53 JM Gatell et al. to AIDS Research Consortium of Atlanta from Bristol- Additional file 6: A table showing proportion of Myers Squibb, CytoDyn Inc., GlaxoSmithKline, Gilead participants with HIV-1 RNA <40 copies/ml at weeks Sciences, MSD, Roche Laboratories, TaiMed Biologics 24 and 96 (Parts I+II) can be found at https://www. Inc. and ViiV Healthcare. KA has received honoraria from intmedpress.com/uploads/documents/4512_Gatell_ lectures and advisory boards for MSD, Bristol-Myers Addfile6.pdf Squibb, GSK/ViiV Healthcare and Boehringer Ingelheim. C Hoffmann has received honoraria for lecturing, advi- Additional file 7: A table showing the most common sory boards, and/or travelling grants from AbbVie, Bris- treatment-emergent laboratory changes, occurring in tol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, ≥4 participants in any treatment group with DAIDS Hexal, Janssen, MSD and ViiV Healthcare; and research Grade ≥2 (based on DAIDS toxicity criteria) through grants from AbbVie, Janssen and Gilead Sciences. FR has week 96 (Parts I+II) can be found at https://www. received research funding or honoraria from, or consulted intmedpress.com/uploads/documents/4512_Gatell_ for, AbbVie, Bristol-Myers Squibb, Gilead Sciences, Jans- Addfile7.pdf sen, MSD and ViiV Healthcare. OO has received research grants from Gilead Sciences and Forest Laboratories, and Additional file 8: A redacted protocol can be found at honoraria for advisory boards from Gilead Sciences, Bris- https://www.intmedpress.com/uploads/documents/4512_ tol-Myers Squibb, ViiV Healthcare and Janssen. RD owns Gatell_Addfile8.pdf stock in Merck & Co., Inc., Kenilworth, NJ, USA. AP has received research and/or congress sponsoring, and/or trav- References elling grants from AbbVie, Bristol-Myers Squibb, Gilead 1. Food and Drug Administration (FDA). Full prescribing Sciences, Hexal, Janssen, MSD and ViiV Healthcare. DES information: SUSTIVA (efavirenz). 2017. (Accessed 29 has received travel sponsorship and research grant sup- April 2019.) Available from https://www.accessdata.fda. gov/drugsatfda_docs/label/2017/021360s044,020972s056 port from MSD, ViiV Healthcare and Gilead Sciences. JP lbl.pdf has received research and/or congress sponsoring, and/or 2. Mollan KR, Smurzynski M, Eron JJ, et al. Association travelling grants from AbbVie, Gilead Sciences, Janssen, between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or MSD and ViiV Healthcare. SR has no conflicts of interest completed suicide: an analysis of trial data. Ann Intern Med to declare. 2014; 161:1–10. 3. British HIV Association. BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015 Additional files (2016 interim update). 2016. (Accessed 29 April 2019.) Available from http://www.bhiva.org/HIV-1-treatment- Additional file 1: A figure showing the study design guidelines.aspx can be found at https://www.intmedpress.com/uploads/ 4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral documents/4512_Gatell_Addfile1.pdf Agents in Adults and Adolescents Living with HIV. 2018. (Accessed 14 May 2019.) Available from https://aidsinfo. nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf Additional file 2: Additional exclusion criteria can 5. Crauwels HM, van Heeswijk RP, Buelens A, Stevens M, be found at https://www.intmedpress.com/uploads/ Boven K, Hoetelmans RM. Impact of food and different documents/4512_Gatell_Addfile2.pdf meal types on the pharmacokinetics of rilpivirine. J Clin Pharmacol 2013; 53:834–840. Additional file 3: A figure showing participant flow 6. Food and Drug Administration (FDA). Full prescribing information: INTELENCE™ (etravirine). 2018. (Accessed through the study at week 96: Part I and Part II can 29 April 2019.) Available from https://www.accessdata.fda. be found at https://www.intmedpress.com/uploads/ gov/drugsatfda_docs/label/2018/022187s023lbl.pdf documents/4512_Gatell_Addfile3.pdf 7. Food and Drug Administration (FDA). Full prescribing information: VIRAMUNE (nevirapine). 2018. (Accessed 29 April 2019.) Available from https://www.accessdata.fda.gov/ Additional file 4: A table showing proportion of drugsatfda_docs/label/2018/020636s050,020933s040lbl.pdf participants with HIV-1 RNA <40 copies/ml at week 8. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 24 (Part I) can be found at https://www.intmedpress. 2018 Recommendations of the International Antiviral com/uploads/documents/4512_Gatell_Addfile4.pdf Society-USA Panel. JAMA 2018; 320:379–396. 9. World Health Organization. Updated recommendations on Additional file 5: A table showing most common first-line and second-line antiretroviral regimens and post- exposure prophylaxis and recommendations on early infant laboratory changes, occurring in ≥4 participants in any diagnosis of HIV: interim guidance. 2018 (WHO/CDS/ treatment group with indicated grade (based on DAIDS HIV/18.18). (Accessed 15 October 2018.) Available from http://www.who.int/hiv/pub/guidelines/ARV2018update/en/ toxicity criteria ) that was also an increase from baseline, 10. Lai MT, Feng M, Falgueyret JP, et al. In vitro through week 24 (Part I) can be found at https://www. characterization of MK-1439, a novel HIV-1 nonnucleoside intmedpress.com/uploads/documents/4512_Gatell_ reverse transcriptase inhibitor. Antimicrob Agents Addfile5.pdf Chemother 2014; 58:1652–1663. 434 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 434 AVT-19-OA-4512_Gatell.indd 434 22/11/2019 11:48:53 22/11/2019 11:48:53 Doravirine versus efavirenz Phase IIb trial 11. Anderson MS, Gilmartin J, Cilissen C, et al. Safety, 25. Miettinen O, Nurminen M. Comparative analysis of two tolerability and pharmacokinetics of doravirine, a novel rates. Stat Med 1985; 4:213–226. HIV non-nucleoside reverse transcriptase inhibitor, after 26. Feng M, Sachs NA, Xu M, et al. Doravirine suppresses single and multiple doses in healthy subjects. Antivir Ther common nonnucleoside reverse transcriptase inhibitor- 2015; 20:397–405. associated mutants at clinically relevant concentrations. 12. Behm MO, Yee KL, Liu R, Levine V, Panebianco D, Antimicrob Agents Chemother 2016; 60:2241–2247. Fackler P. The effect of food on doravirine bioavailability: 27. Molina JM, Squires K, Sax PE, et al. Doravirine versus results from two pharmacokinetic studies in healthy ritonavir-boosted darunavir in antiretroviral-naive adults subjects. Clin Drug Investig 2017; 37:571–579. with HIV-1 (DRIVE-FORWARD): 48-week results of a 13. Khalilieh SG, Yee KL, Sanchez RI, et al. A study to evaluate randomised, double-blind, Phase 3, non-inferiority trial. doravirine pharmacokinetics when coadministered with acid- Lancet HIV 2018; 5:e211–e220. reducing agents. J Clin Pharmacol 2019; 59:1093–1098. 28. Orkin C, Squires KE, Molina JM, et al. Doravirine/ 14. Bleasby K, Fillgrove KL, Houle R, et al. In vitro evaluation lamivudine/tenofovir disoproxil fumarate is non-inferior of the drug interaction potential of doravirine. Antimicrob to efavirenz/emtricitabine/tenofovir disoproxil fumarate Agents Chemother 2019; 63:e02492–18. in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD 15. Khalilieh SG, Yee KL, Sanchez RI, et al. Multiple doses of Trial. Clin Infect Dis 2019; 68:535–544. rifabutin reduce exposure of doravirine in healthy subjects. J Clin Pharmacol 2018; 58:1044–1052. 29. European Medicines Agency. Pifeltro public assessment report. 2019. (Accessed 22 May 2019.) Available from 16. Yee KL, Khalilieh SG, Sanchez RI, et al. The effect of single https://www.ema.europa.eu/en/documents/assessment- and multiple doses of rifampin on the pharmacokinetics report/pifeltro-epar-public-assessment-report_en.pdf of doravirine in healthy subjects. Clin Drug Investig 2017; 37:659–667. 30. Cohen C, Elion R, Ruane P, et al. Randomized, Phase 2 evaluation of two single-tablet regimens elvitegravir/ 17. Schürmann D, Sobotha C, Gilmartin J, et al. A randomized, cobicistat/emtricitabine/tenofovir disoproxil fumarate versus double-blind, placebo-controlled, short-term monotherapy efavirenz/emtricitabine/tenofovir disoproxil fumarate for the study of doravirine in treatment-naive HIV-infected initial treatment of HIV infection. AIDS 2011; 25:F7–F12. individuals. AIDS 2016; 30:57–63. 31. Pozniak AL, Morales-Ramirez J, Katabira E, et al. Efficacy 18. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Forty- and safety of TMC278 in antiretroviral-naive HIV-1 eight-week efficacy and safety and early CNS tolerability patients: week 96 results of a Phase IIb randomized trial. of doravirine (MK-1439), a novel NNRTI, with TDF/FTC AIDS 2010; 24:55–65. in ART-naive HIV-positive patients. J Int AIDS Soc 2014; 17:19532. 32. Vernazza P, Wang C, Pozniak A, et al. Efficacy and safety of lersivirine (UK-453,061) versus efavirenz in antiretroviral 19. Gatell JM, Raffi F, Plettenberg A, et al. Efficacy and safety of treatment-naive HIV-1-infected patients: week 48 primary doravirine 100 mg QD vs efavirenz 600 mg QD with TDF/ analysis results from an ongoing, multicenter, randomized, FTC in ART-naive HIV-infected patients: week 24 results. double-blind, Phase IIb trial. J Acquir Immune Defic Syndr J Int AIDS Soc 2015; 18 Suppl 4:36. 2013; 62:171–179. 20. Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety 33. Cohen CJ, Meyers JL, Davis KL. Association between and antiviral effect of MK-1439, a novel NNRTI (+FTC/ daily antiretroviral pill burden and treatment adherence, TDF) in ART-naive HIV-infected patients. Top Antiviral hospitalisation risk, and other healthcare utilisation and Med 2014; 22:46–47. costs in a US medicaid population with HIV. BMJ Open 21. Gatell JM, Raffi F, Plettenberg A, et al. Doravirine 100mg 2013; 3:e003028. QD vs efavirenz +TDF/FTC in ART-naive HIV+ patients: 34. Pifeltro (doravirine) prescribing information. Merck Sharp week 48 results. Top Antivir Med 2016; 24:183. & Dohme Corp., Whitehouse Station, NJ, USA. 2019. 22. Food and Drug Administration (FDA). Full prescribing (Accessed 7 October 2019.) Available from https://www. information: TRUVADA (emtricitabine/tenofovir disoproxil merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_ fumarate). 2018. (Accessed 29 April 2019.) Available pi.pdf from https://www.accessdata.fda.gov/drugsatfda_docs/ 35. Delstrigo (doravirine, lamivudine, and tenofovir disoproxil label/2018/021752s055lbl.pdf fumarate) prescribing information. Merck Sharp & Dohme 23. U.S. Department of Health and Human Services, Corp., Whitehouse Station, NJ, USA. 2019. (Accessed 7 National Institutues of Health, National Institute of October 2019.) Available from https://www.merck.com/ Allergy and Infectious Diseases, Division of AIDS. product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf Division of AIDS (DAIDS) Table for Grading the Severity 36. European Medicines Agency. Delstrigo. 2019. (Accessed 29 of Adult and Pediatric Adverse Events, Version 2.0. 2014. April 2019.) Available from https://www.ema.europa.eu/en/ (Accessed 15 October 2018.) Available from https://rsc. medicines/human/EPAR/delstrigo tech-res.com/clinical-research-sites/safety-reporting/daids- grading-tables 37. European Medicines Agency. Pifeltro. 2019. (Accessed 29 April 2019.) Available from https://www.ema.europa.eu/en/ 24. U.S. Department of Health and Human Services, Food medicines/human/EPAR/pifeltro and Drug Administration, Center for Drug Evaluation and Research. Human immunodeficiency virus-1 infection: developing antiretroviral drugs for treatment. Guidance for industry. 2015. (Accessed 15 October 2018.) Available from www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ ucm355128.pdf Accepted 24 May 2019; published online 29 July 2019 Antiviral Therapy 24.6 435 AVT-19-OA-4512_Gatell.indd 435 AVT-19-OA-4512_Gatell.indd 435 22/11/2019 11:48:53 22/11/2019 11:48:53 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Doravirine dose Selection and 96-Week Safety and Efficacy versus Efavirenz in Antiretroviral Therapy-Naive Adults with HIV-1 Infection in a Phase IIb Trial

Download PDF
11 pages

Loading next page...
 
/lp/sage/doravirine-dose-selection-and-96-week-safety-and-efficacy-versus-gQIASoFL0C

References (37)

Publisher
SAGE
Copyright
© 2019 SAGE Publications
ISSN
1359-6535
eISSN
2040-2058
DOI
10.3851/imp3323
Publisher site
See Article on Publisher Site

Abstract

Antiviral Therapy 2019; 24:425–435 (doi: 10.3851/IMP3323) Original article Doravirine dose selection and 96-week safety and efc fi acy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial 1,2 3 4 5 6 Jose M Gatell , Javier O Morales-Ramirez , Debbie P Hagins , Melanie Thompson , Keikawus Arastéh , 7 8 9 10 11 Christian Hoffmann , François Raffi , Olayemi Osiyemi , Robin Dretler , Charlotte Harvey , 11 12 13 14 15 11 Xia Xu , Andreas Plettenberg , Don E Smith , Joaquín Portilla , Sorin Rugina , Sushma Kumar , 11 11 11 11 11 Colleen Frobose , Hong Wan , Anthony Rodgers , Carey Hwang , Hedy Teppler * Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain Present address: ViiV Healthcare, Barcelona, Spain Clinical Research Puerto Rico, San Juan, Puerto Rico Chatham County Health Department, Savannah, GA, USA AIDS Research Consortium of Atlanta, Atlanta, GA, USA EPIMED/Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany ICH Study Center, Hamburg, Germany Infectious Diseases Department and INSERM CIC 1413, University Hospital of Nantes, Nantes, France Triple O Research Institute PA, West Palm Beach, FL, USA Infectious Disease Specialists of Atlanta, Decatur, GA, USA Merck & Co., Inc., Kenilworth, NJ, USA ifi-Institute for Infections, Hamburg, Germany Albion Centre, Sydney, Australia Hospital General Universitario de Alicante/ISABIAL, Alicante, Spain Ovidius University, Clinical Infectious Diseases Hospital, Constanta, Romania *Corresponding author e-mail: hedy_teppler@merck.com Background: The safety and efficacy of doravirine were system (CNS) adverse events (AEs) by weeks 8 and 24 compared with that of efavirenz as initial treatment of (Parts I+II combined). adults living with HIV-1 infection (NCT01632345). Results: 210 and 132 participants were randomized in Methods: A Phase IIb double-blind trial with partici- Parts I and II, respectively, and 216 (108 on doravirine pants stratified by screening HIV-1 RNA (≤ or >100,000 100 mg, 108 on efavirenz) were evaluable for Parts I+II copies/ml) and randomized 1:1:1:1:1 to receive once- combined. At week 24, the proportion of participants daily doravirine (25, 50, 100 or 200 mg) or efavirenz with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 600 mg (Part I) for up to 96 weeks, with open-label teno- 100 mg and 73.1% for efavirenz (difference -0.5 [95% fovir disoproxil fumarate 300 mg/emtricitabine 200 mg CI -12.3, 11.2]). In addition, CNS AEs were reported by (TDF/FTC). After dose selection at week 24, doravirine 26.9% and 47.2% of doravirine and efavirenz recipi- 100 mg was provided to participants receiving the other ents, respectively (difference -20.4 [95% CI -32.6, -7.5]; doses of doravirine and additional participants were ran- P=0.002). domized 1:1 to receive once-daily doravirine 100 mg or Conclusions: Doravirine 100 mg with TDF/FTC demon- efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Pri- strated similar antiretroviral activity and superior CNS mary outcomes were the proportion of participants with safety compared with efavirenz 600 mg with TDF/FTC. HIV-1 RNA <40 copies/ml at week 24, and central nervous ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 425 AVT-19-OA-4512_Gatell.indd 425 AVT-19-OA-4512_Gatell.indd 425 22/11/2019 11:48:52 22/11/2019 11:48:52 JM Gatell et al. Introduction of doravirine versus efavirenz for 96 weeks (Part  II; Additional file 1). Participants were enrolled at 63 cen- Currently, each of the four non-nucleoside reverse tres across Australia, Belgium, Canada, France, Germany, transcriptase inhibitors (NNRTIs) for the treatment of the Netherlands, Puerto Rico, Romania, Russia, Spain HIV-1 infection has limitations. Efavirenz is associated and the US. The trial was conducted in accordance with with frequent central nervous system (CNS) adverse principles of Good Clinical Practice and was approved by events (AEs) [1], including increased risk of suicidal- the appropriate institutional review boards and regula- ity [2]. Rilpivirine must be taken with food, has sig- tory agencies. All participants provided written informed nificant interactions with acid-reducing agents, and has consent. limited efficacy in individuals with high baseline HIV-1 RNA (>100,000 copies/ml) and low CD4 T-cell counts Participants (<200 cells/mm ) [3–5]. Etravirine is not approved for Eligible participants were adults (≥18 years of age) with first-line treatment and requires twice-daily dosing [6]. plasma HIV-1 RNA ≥1,000 copies/ml, CD4 T-cell count Finally, nevirapine is associated with skin and liver ≥100 cells/mm and no prior ART experience. Partici- hypersensitivity reactions, and has prescribing restric- pants were required to be clinically stable for ≥2 weeks tions based on gender and CD4 T-cell counts [7]. These before the trial, with no signs or symptoms of acute infec- limitations have led to changes in recommendations for tion (non-HIV-1) and no significant laboratory abnor - NNRTI-containing regimens from preferred to alter- malities within 45 days of treatment. Those with known native first-line antiretroviral therapy (ART) in most HIV-1 genotypic resistance to FTC, TDF or efavirenz, international guidelines [3,4,8,9]. Alternative NNRTI or active hepatitis B or C infection were excluded. Addi- treatment options with both high efficacy and tolerabil- tional exclusion criteria are shown in Additional file 2. ity are needed. Doravirine (MK-1439) is an NNRTI that has high Randomization and assessment in vitro potency versus a broad panel of isolates, includ- Participants were stratified by screening HIV-1 RNA ing some common NNRTI-resistant variants  [10]. In ≤100,000 or >100,000 copies/ml prior to randomiza- Phase I studies, doravirine demonstrated good tolerabil- tion. In Part I, participants were randomized 1:1:1:1:1 ity across a wide dose range and a pharmacokinetic pro- to receive doravirine (Merck & Co., Inc., Kenilworth, file suitable for once-daily dosing, irrespective of food NJ, USA) 25 mg, 50 mg, 100 mg or 200 mg once intake and coadministration of antacids or acid-reducing daily; or efavirenz 600 mg once daily, both in combi- agents [11–13]. Doravirine is a substrate for cytochrome nation with co-formulated TDF 300 mg/FTC 200 mg P450 (CYP450) 3A-mediated metabolism  [14]; coad- (Gilead Sciences Inc., Foster City, CA, USA), for up to ministration with strong CYP450 3A inducers may 96 weeks. Following the interim analysis for dose selec- significantly decrease doravirine plasma levels  [15,16]. tion at week 24 in Part I, additional participants were Drug–drug interactions via other major drug-metab- randomized 1:1 in Part II to receive the selected dose olizing enzymes and transporters are unlikely  [14], of doravirine (100 mg) or efavirenz 600 mg once daily, enabling coadministration with a wide range of treat- each in combination with TDF/FTC, for 96 weeks. Par- ments for HIV-1 infection and associated concurrent ticipants receiving the non-selected doses of doravirine illnesses [11,14]. In ART-naive adults with HIV-1 infec- in Part I were switched to the selected dose at the next tion, doravirine monotherapy given for 7 days dem- planned study visit. For both parts of the trial, efavirenz onstrated robust antiviral activity, without evidence of and open-label TDF/FTC were administered according viral resistance [17]. Here we present the final results of to the prescribing information [1,22]. a Phase IIb, dose selection trial that compared the safety A combination of active drugs and placebo was given and efficacy of doravirine with that of efavirenz (both to maintain blinding of doravirine and efavirenz: par- administered with tenofovir disoproxil fumarate [TDF]/ ticipants took six tablets per day before dose selection emtricitabine [FTC]) in ART-naive adults with HIV-1 (four doravirine or matching placebo, one efavirenz or infection. The 24-week and 48-week interim results of matching placebo, one TDF/FTC) and three tablets per this trial have been previously reported [18–21]. day after dose selection. Doravirine (or placebo) was to be taken in the morning. Open-label TDF/FTC was to be taken in the morning with food. Efavirenz (or pla- Methods cebo) was to be taken at bedtime without food on an Study design empty stomach. This Phase IIb, randomized, double-blind trial (MK-1439 Participants visited the study site at days 1 and 14; Protocol 007; NCT01632345) consisted of two parts: a weeks 4, 8, 12, 16 and 24; and every 12 weeks there- 24-week dose selection phase (Part I), followed by com- after up to week 96. At each visit, participants were parison of the safety and efficacy of the selected dose assessed through physical examination, laboratory 426 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 426 AVT-19-OA-4512_Gatell.indd 426 22/11/2019 11:48:52 22/11/2019 11:48:52 Doravirine versus efavirenz Phase IIb trial tests including haematological analysis, serum chemis- (acute psychosis, hallucination [including auditory try tests, fasting lipid parameters, CD4 T-cell counts and/or visual], psychotic disorder), or nervous system and measurement of HIV-1 RNA (Abbott RealTime disorder. All such events regardless of attribution were HIV-1 assay; Abbott Laboratories, IL, USA; lower limit pooled and evaluated as CNS events. of quantification: 40 copies/ml). Clinical AEs were assessed at every visit by patient report. No question- Statistical analysis naires were used to solicit specific symptoms, including The primary objective of the study was to support the for CNS events. Medication compliance was monitored doravirine dose selection for the Phase III clinical pro- with diary cards completed by the participants and gramme. The primary population for the efficacy analy- returned at each study visit. ses included all randomized participants who had at Protocol-defined virological failure (PDVF) included least one post-randomization observation after receiv- two categories: non-response (participants who did not ing at least one dose of blinded study treatment. The achieve HIV-1 RNA <40 copies/ml by week 24) and non-completer = failure (NC=F) approach to missing rebound (initial response of HIV-1 RNA <40 copies/ml, data was used for the primary and secondary virologi- followed by two consecutive measurements of HIV-1 cal response end points (participant proportions with RNA ≥40 copies/ml at least 1 week apart at or after HIV-1 RNA <40 copies/ml and <200 copies/ml, respec- week 24). Participants with PDVF and sufficient viral tively). All missing values were considered failures with RNA (>400 copies/ml) in the confirmatory plasma sam- the exception of intermittent missing values flanked by ple were assessed for genotypic and phenotypic viral two successes, which were excluded. Sensitivity analy- resistance (Monogram Biosciences, South San Fran- ses were conducted for the primary end point using the cisco, CA, USA). Participants with PDVF were recom- following missing data approaches: treatment-related mended, but not required, to discontinue the study. discontinuation = failure (discontinuations due to lack of efficacy or AEs were considered failures thereafter), Outcomes observed failure (OF; discontinuations due to lack of Efficacy and safety outcomes were assessed for each efficacy were considered failures thereafter), and the doravirine dose versus efavirenz in Part I, and for the FDA snapshot method [24]. selected dose of doravirine (100 mg) versus efavirenz For all virological end points in Part I and Parts using data from these groups in Part I and Part II com- I+II, the difference in proportion of participants with bined (hereafter referred to as Parts I+II). Since there virological responses between treatment groups and was no clear evidence of heterogeneity across the dora- the associated 95% CIs were calculated using Miet- virine dose groups, data displays include an additional tinen and Nurminen’s method [25] with stratification doravirine group that includes all participants rand- by screening HIV-1 RNA ≤100,000 or >100,000 cop- omized to any dose of doravirine in Part I. ies/ml. To assess the consistency of the treatment effect The primary efficacy outcome was the proportion of in Parts I+II, the between-group differences for the participants with HIV-1 RNA <40 copies/ml at week 24 primary end point were estimated within subgroups in Part I and in Parts I+II. Secondary efficacy outcomes defined by baseline HIV-1 RNA level (≤ or >100,000 were the proportion of participants with HIV-1 RNA copies/ml) using the OF approach. <200 copies/ml and the change from baseline in CD4 For the secondary end point of change from baseline T-cell count. in CD4 T-cell counts, descriptive statistics including Safety was assessed by physical examinations, labora- 95% CIs were provided and missing data were handled tory tests, 12-lead electrocardiogram, and recording of using the OF approach. Baseline values were carried AEs coded using the Medical Dictionary for Regulatory forward for participants who discontinued due to lack Activities (MedDRA; version 17.1). Changes in labora- of efficacy. tory values were classified according to the Division of The safety analyses used the ‘all patients as treated’ AIDS criteria [23]. The primary safety end point was population, including all randomized participants who the proportion of participants experiencing CNS events received at least one dose of study treatment. The pri- (from the following pre-specified list of MedDRA mary hypothesis of Parts I+II was that doravirine at the terms) by weeks 8 and 24 of Parts I+II: dizziness, sleep final selected dose is superior to efavirenz, each in com- disorders (abnormal dreams, insomnia, nightmare), bination with TDF/FTC, as measured by proportion of altered sensorium (concentration impaired, confusional participants with CNS events by week 8 (with hypoth- state, delirium, depressed level of consciousness, dis- esis testing also at week 24 if superior at week 8). CNS turbance in attention, somnolence), depression/suicide events occurring by week 8 and week 24 in Parts I+II (depressed mood, depressive symptom, depression, were subjected to inferential testing for statistical sig- major depression, suicidal behaviour, suicidal ideation, nificance with P-values and 95% CIs provided for suicide attempt, completed suicide), psychotic disorders between-group comparisons. Antiviral Therapy 24.6 427 AVT-19-OA-4512_Gatell.indd 427 AVT-19-OA-4512_Gatell.indd 427 22/11/2019 11:48:52 22/11/2019 11:48:52 JM Gatell et al. Sample size was calculated according to the power of efavirenz participants discontinued study therapy for comparing the pre-specified CNS AEs between before week 96 (Additional file 3). In Part II, 16.7% doravirine at the selected dose and efavirenz; this deter- of participants in each treatment group discontinued mined the size of cohort II. With 100 participants per study therapy before week 96 (Additional file 3). treatment group in Parts I+II, and assuming the CNS The proportion of participants with HIV-1 RNA event rates were 20% for doravirine and 52% for efa- <40  copies/ml at week 24 of Part I was over 70% virenz by week 8, the trial had >99% power, with 95% for all doravirine doses (25 mg, 80.0% [95% CI, confidence, to detect whether the selected dose of dora- 64.4, 90.9]; 50 mg, 74.4% [58.8, 86.5]; 100 mg, 71.4% virine had a significantly lower rate of CNS events than [55.4,  84.3]; 200 mg, 80.5% [65.1, 91.2]) compared efavirenz. Assuming CNS event rates of 30% for dora- with 64.3% (48.0, 78.4) for efavirenz, with similar virine and 50% for efavirenz, 100 participants per arm results observed regardless of missing data approach provided 83% power, with 95% confidence, to demon- (Additional file 4). The proportion of participants with strate superiority of doravirine over efavirenz. HIV-1 RNA <200  copies/ml at week 24 ranged from 83.7–92.9% in the doravirine groups compared with 81.0% for efavirenz. The mean change from baseline Results in CD4 T-cell count at week 24 of Part I ranged from The trial was conducted between 15 October 2012 and 113–154 cells/mm in the doravirine groups compared 21 March 2016. Participant disposition for both parts with 121 cells/mm for efavirenz. are shown in Additional file 3. Of the 462 individuals Doravirine was generally well tolerated at all doses screened, 342 were enrolled and randomized across 63 studied in Part I (Table 2). There was no apparent pat- sites. Demographics and baseline clinical characteristics tern of dose-related toxicity. The proportion of par- were generally well balanced across treatment groups ticipants with drug-related AEs was lower in each of (Table 1). In Part I, 26.9% of doravirine participants the doravirine groups (16.7–46.5%) versus the efa- (range 19.5% [200 mg] to 34.9% [50 mg]) and 30.2% virenz group (57.1%). In total, 3.0% of participants Table 1. Baseline demographics and participant characteristics (Parts I+II) Doravirine All dose Efavirenz 25 mg (n=40) 50 mg (n=43) 100 mg (n=108) 200 mg (n=41) groups (n=232) 600 mg (n=108) Male, n (%) 38 (95.0) 37 (86.0) 99 (91.7) 40 (97.6) 214 (92.2) 101 (93.5) Median age, years (range) 37 (21–69) 36 (25–66) 35 (19–67) 32 (21–50) 35 (19–69) 34 (20–57) Race/ethnicity White, n (%) 23 (57.5) 31 (72.1) 86 (79.6) 31 (75.6) 171 (73.7) 87 (80.6) Black, n (%) 13 (32.5) 8 (18.6) 16 (14.8) 6 (14.6) 43 (18.5) 17 (15.7) Hispanic or Latino, n (%) 5 (12.5) 8 (18.6) 15 (13.9) 10 (24.4) 38 (16.4) 17 (15.7) Asian, n (%) 3 (7.5) 3 (7.0) 5 (4.6) 2 (4.9) 13 (5.6) 2 (1.9) Other , n (%) 1 (2.5) 1 (2.3) 1 (0.9) 2 (4.9) 5 (2.2) 2 (1.9) Geographic region Asia–Pacific, n (%) 4 (10.0) 5 (11.6) 15 (13.9) 8 (19.5) 32 (13.8) 15 (13.9) Europe, n (%) 11 (27.5) 17 (39.5) 59 (54.6) 16 (39.0) 103 (44.4) 49 (45.4) North America, n (%) 25 (62.5) 21 (48.8) 34 (31.5) 17 (41.5) 97 (41.8) 44 (40.7) History of AIDS, n (%) 6 (15.0) 5 (11.6) 4 (3.7) 6 (14.6) 21 (9.1) 7 (6.5) Baseline HIV-1 RNA Mean log copies/ml (sd ) 4.4 (0.75) 4.7 (0.68) 4.6 (0.78) 4.6 (0.65) 4.6 (0.74) 4.6 (0.72) ≤100,000 copies/ml, n (%) 28 (70.0) 30 (69.8) 73 (67.6) 29 (70.7) 160 (69.0) 76 (70.4) >100,000 copies/ml, n (%) 12 (30.0) 13 (30.2) 35 (32.4) 12 (29.3) 72 (31.0) 32 (29.6) Baseline CD4 T-cell count Mean cells/mm (sd ) 411 (210) 464 (239) 432 (187) 419 (215) 432 (206) 448 (189) ≤200 cells/mm , n (%) 7 (17.5) 3 (7.0) 7 (6.5) 5 (12.2) 22 (9.5) 10 (9.3) >200 and ≤350 cells/mm , n (%) 11 (27.5) 13 (30.2) 35 (32.4) 12 (29.3) 71 (30.6) 25 (23.1) >350 cells/mm , n (%) 22 (55.0) 27 (62.8) 66 (61.1) 24 (58.5) 139 (59.9) 73 (67.6) Subtype B, n (%) 35 (87.5) 34 (79.1) 75 (69.4) 36 (87.8) 180 (77.6) 86 (79.6) Note: both doravirine and efavirenz were administered with tenofovir disoproxil fumarate/emtricitabine. Other race includes: American Indian or Alaska Native, multiracial and unknown (missing data). 428 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 428 AVT-19-OA-4512_Gatell.indd 428 22/11/2019 11:48:52 22/11/2019 11:48:52 Doravirine versus efavirenz Phase IIb trial Table 2. Summary of clinical AEs up to week 24 (Part I) Doravirine Efavirenz 25 mg 50 mg 100 mg 200 mg All dose groups 600 mg Participants in population 40 43 42 41 166 42 With any clinical AE, n (%) 36 (90.0) 40 (93.0) 30 (71.4) 35 (85.4) 141 (84.9) 35 (83.3) With drug-related clinical AE, n (%) 16 (40.0) 20 (46.5) 7 (16.7) 18 (43.9) 61 (36.7) 24 (57.1) With serious clinical AE, n (%) 3 (7.5) 1 (2.3) 0 (0.0) 2 (4.9) 6 (3.6) 3 (7.1) Discontinued due to clinical AE, n (%) 1 (2.5) 3 (7.0) 1 (2.4) 0 (0.0) 5 (3.0) 2 (4.8) Most common clinical AEs Constipation, n (%) 0 (0.0) 4 (9.3) 1 (2.4) 0 (0.0) 5 (3.0) 0 (0.0) Diarrhoea, n (%) 7 (17.5) 2 (4.7) 2 (4.8) 4 (9.8) 15 (9.0) 5 (11.9) Nausea, n (%) 2 (5.0) 6 (14.0) 5 (11.9) 9 (22.0) 22 (13.3) 1 (2.4) Fatigue, n (%) 5 (12.5) 4 (9.3) 1 (2.4) 5 (12.2) 15 (9.0) 2 (4.8) Bronchitis, n (%) 2 (5.0) 1 (2.3) 0 (0.0) 4 (9.8) 7 (4.2) 2 (4.8) Nasopharyngitis, n (%) 1 (2.5) 4 (9.3) 4 (9.5) 6 (14.6) 15 (9.0) 2 (4.8) Upper respiratory tract infection, n (%) 1 (2.5) 2 (4.7) 4 (9.5) 3 (7.3) 10 (6.0) 0 (0.0) Dizziness, n (%) 1 (2.5) 3 (7.0) 0 (0.0) 3 (7.3) 7 (4.2) 10 (23.8) Headache, n (%) 5 (12.5) 5 (11.6) 3 (7.1) 7 (17.1) 20 (12.0) 4 (9.5) Abnormal dreams, n (%) 4 (10.0) 9 (20.9) 2 (4.8) 4 (9.8) 19 (11.4) 4 (9.5) Insomnia, n (%) 1 (2.5) 5 (11.6) 3 (7.1) 2 (4.9) 11 (6.6) 3 (7.1) Nightmare, n (%) 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 1 (0.6) 4 (9.5) Sleep disorder, n (%) 1 (2.5) 1 (2.3) 0 (0.0) 0 (0.0) 2 (1.2) 4 (9.5) Note: both doravirine and efavirenz were administered with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). Determined by investigator to be related to blinded therapy or to open-label TDF/FTC. Reported by ≥4 participants in any treatment group. AE, adverse event. receiving any dose of doravirine discontinued due to In the subgroup analyses of Parts I+II, the proportion AEs compared with 4.8% of those receiving efavirenz. of participants with baseline HIV-1 RNA ≤100,000 Through week 24 of Part I, the most common labo- copies/ml who achieved HIV-1 RNA <40 copies/ml ratory abnormalities were primarily Grade 1 changes at week 96 was similar between doravirine 100 mg (Additional file 5). and efavirenz (88.9% [95% CI 78.4, 95.4] versus Based on Part I week 24 efficacy and safety results, 87.3% [76.5, 94.4], treatment difference 1.6 [-10.4, doravirine 100 mg was selected for enrolment in Part II. 13.7]). Among participants with baseline HIV-1 RNA Participants who received doravirine at 25, 50 and >100,000 copies/ml, the proportion who achieved 200  mg doses were all switched to doravirine 100 mg HIV-1 RNA <40 copies/ml at week 96 was 78.1% after dose selection; however, the data shown below for (60.0, 90.7) for doravirine 100 mg versus 93.1% (77.2, doravirine 100 mg from Parts I and II combined includes 99.2) for efavirenz (difference -15.0 [-33.4, 3.5]). only those Part I participants randomized to 100 mg, plus Over the course of the trial, 43 doravirine recipi- all Part II participants randomized to doravirine, all of ents (26 non-responders [11.2%] and 17 rebounders whom received the 100 mg dose. In Parts I+II, the propor- [7.3%]) and 14 efavirenz recipients (10 non-responders tion of participants with HIV-1 RNA <40 copies/ml at [9.3%] and 4 rebounders [3.7%]) met the criteria for week 24 was 72.9% for doravirine 100 mg versus 73.1% PDVF. In the doravirine 100 mg group, 19 (17.6%) par- for efavirenz (difference [95% CI], -0.5 [-12.3, 11.2]). ticipants met criteria for PDVF, including 16 (14.8%) Similar response rates were observed at subsequent time non-responders. A substantial proportion of the non- points through week  96 (Figure 1A) and were similar responders achieved virological suppression later in the between treatment groups regardless of missing data trial: 12/26 of the doravirine recipients and 5/10 of the approach (Additional file 6). The proportion of partici- efavirenz recipients at week 48; 16/26 and 8/10, respec- pants with HIV-1 RNA <200 copies/ml was 89.7% and tively, at week 96. 79.6% at weeks 24 and 96, respectively, for doravirine In total, 18 participants with PDVF had samples 100 mg compared with 87.0% and 75.9% at weeks 24 with sufficient HIV-1 RNA (> 400 copies/ml) for and 96, respectively, for efavirenz. The mean change in resistance testing. Two participants in the doravirine CD4 T-cell counts increased throughout the study in 25 mg group showed genotypic resistance associ- both treatment groups, reaching 259 cells/mm for dora- ated with NNRTIs (K101K/E, P236P/L mutations in virine 100 mg and 264 cells/mm for efavirenz at week 96 one participant, and V106V/I, F227C mutations in (Figure 1B). one participant), and one participant in the 100 mg Antiviral Therapy 24.6 429 AVT-19-OA-4512_Gatell.indd 429 AVT-19-OA-4512_Gatell.indd 429 22/11/2019 11:48:52 22/11/2019 11:48:52 JM Gatell et al. Figure 1. Primary and secondary end points over time, up to week 96, Parts I+II Difference in percent response versus efavirenz (95% CI) Week 96 n/total n (%) Doravirine 100 mg 81/108 (75.0) -0.8 (-12.4, 10.7) Doravirine combined 160/232 (69.0) -6.6 (-16.2, 3.9) Efavirenz 600 mg 82/108 (75.9) 0 2 4 8 16 24 36 48 60 72 84 96 Week Doravirine 100 mg Doravirine combined Efavirenz 600 mg Mean change Difference in CD4 T-cell from baseline count change versus (95% CI) efavirenz (95% CI) Week 96 Doravirine 100 mg 259 (220, 298) -4 (-64, 55) Doravirine combined 237 (210, 265) -27 (-77, 24) Efavirenz 600 mg 264 (218, 309) 0 2 4 8 16 24 36 48 60 72 84 96 Week Doravirine 100 mg (n=95) Doravirine combined (n=196) Efavirenz 600 mg (n=93) (A) Percent of participants with HIV-1 RNA <40 copies/ml. (B) Mean change from baseline in CD4 T-cell count. Graphical data are presented with 95% CI. group showed mutations associated with resistance to and K103N, N348I in one participant) and pheno- NNRTIs (E138E/G, V179D) and nucleoside reverse typic resistance to efavirenz. transcriptase inhibitors (A62V). Only the virus with The occurrence of pre-specified CNS events by week 8 V106V/I, F227C mutations displayed phenotypic and 24 in Parts I+II was a key safety end point of the resistance to doravirine, with a 66-fold decrease in trial. At week 8, the proportion of participants with susceptibility; this participant also developed resist- CNS events was significantly lower in the doravirine ance to FTC (M184V). Two of the three efavirenz 100 mg group (24.1%) compared with the efavirenz participants with PDVF had virus with efavirenz resist- group (44.4%; P=0.002; difference -20.4%; 95% CI ance mutations (K101K/Q, G190S in one participant, -32.4, -7.8). The difference was also observed through 430 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 430 AVT-19-OA-4512_Gatell.indd 430 22/11/2019 11:48:52 22/11/2019 11:48:52 Mean change from baseline in Percent of participants with + 3 CD4 T-cell count, cells/mm HIV-1 RNA <40 copies/ml Doravirine versus efavirenz Phase IIb trial week 24, with 26.9% and 47.2% of participants who and 96.3% of the efavirenz group and led to discon- received doravirine 100 mg and efavirenz, respectively, tinuation in 4.6% and 10.2%, respectively (Table 3). reporting at least one of the pre-specified CNS events No deaths occurred during the study. The proportion (P=0.002; difference -20.4%; 95% CI -32.6, -7.5). of participants with drug-related AEs in Parts I+II was At both time points, dizziness and abnormal dreams lower for doravirine 100 mg (35.2%) versus efavirenz accounted for most of the difference between dora- (58.3%; difference [95% CI] -23.1 [-35.6, -9.9]). Over- virine 100 mg and efavirenz (Figure 2). all, the most commonly reported drug-related AEs Through week 96 of Parts I+II, one or more AEs were dizziness (7.4% versus 26.9%), abnormal dreams occurred in 89.8% of the doravirine 100 mg group (5.6% versus 14.8%) and nausea (7.4% versus 6.5%) Figure 2. CNS events in Parts I+II at week 8 and week 24 Percent of participants with ≥1 CNS event 0.9 Suicidal ideation Doravirine 100 mg Efavirenz 600 mg Difference (95% CI) 3.7 Disturbance in attention 24.1% 44.4% -20.4 (-32.4, -7.8) 0.9 Somnolence 0.9 Efavirenz 600 mg 2.8 Hallucination 0.9 Doravirine 100 mg 1.9 Depression 0.9 8.3 Nightmare 5.6 16.7 Abnormal dreams 6.5 2.8 Insomnia 7.4 28.7 Dizziness 9.3 0 5 10 15 20 25 30 % of participants with ≥1 event 0.9 Depressed mood Percent of participants with ≥1 CNS event 2.8 Suicidal ideation Doravirine 100 mg Efavirenz 600 mg Difference (95% CI) Depressive symptom 0.9 26.9% 47.2% -20.4 (-32.6, -7.5) 0.9 Somnolence 0.9 2.8 Hallucination Efavirenz 600 mg 0.9 Doravirine 100 mg 3.7 Disturbance in attention 0.9 4.6 Depression 1.9 8.3 Nightmare 6.5 17.6 Abnormal dreams 6.5 2.8 Insomnia 7.4 28.7 Dizziness 9.3 0 5 10 15 20 25 30 % of participants with ≥1 event (A) Week 8. (B) Week 24. CNS, central nervous system. Antiviral Therapy 24.6 431 AVT-19-OA-4512_Gatell.indd 431 AVT-19-OA-4512_Gatell.indd 431 22/11/2019 11:48:53 22/11/2019 11:48:53 JM Gatell et al. Table 3. Summary of clinical AEs up to week 96 (Parts I+II) Doravirine all dose groups (n=232) Doravirine 100 mg (n=108) Efavirenz 600 mg (n=108) a a a All causality Drug-related All causality Drug-related All causality Drug-related Participants with any clinical AE, n (%) 212 (91.4) 96 (41.4) 97 (89.8) 38 (35.2) 104 (96.3) 63 (58.3) Participants with serious clinical AE, n (%) 19 (8.2) 0 (0.0) 11 (10.2) 0 (0.0) 13 (12.0) 3 (2.8) Participants discontinued due to 11 (4.7) 5 (2.2) 5 (4.6) 2 (1.9) 11 (10.2) 10 (9.3) clinical AE, n (%) Most common clinical AEs Diarrhoea, n (%) 35 (15.1) 8 (3.4) 16 (14.8) 1 (0.9) 18 (16.7) 7 (6.5) Nausea, n (%) 32 (13.8) 17 (7.3) 13 (12.0) 8 (7.4) 11 (10.2) 7 (6.5) Bronchitis, n (%) 18 (7.8) 0 (0.0) 5 (4.6) 0 (0.0) 12 (11.1) 0 (0.0) Nasopharyngitis, n (%) 39 (16.8) 1 (0.4) 19 (17.6) 1 (0.9) 13 (12.0) 0 (0.0) Upper respiratory infection, n (%) 19 (8.2) 0 (0.0) 10 (9.3) 0 (0.0) 13 (12.0) 0 (0.0) Dizziness, n (%) 29 (12.5) 13 (5.6) 16 (14.8) 8 (7.4) 32 (29.6) 29 (26.9) Headache, n (%) 32 (13.8) 7 (3.0) 14 (13.0) 3 (2.8) 15 (13.9) 6 (5.6) Abnormal dreams, n (%) 25 (10.8) 21 (9.1) 7 (6.5) 6 (5.6) 19 (17.6) 16 (14.8) Depression, n (%) 8 (3.4) 2 (0.9) 4 (3.7) 0 (0.0) 11 (10.2) 2 (1.9) Note: both doravirine and efavirenz were administered with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). Determined by investigator to be related to blinded therapy or to open label TDF/FTC. Reported by ≥10% participants in any of these groups. AE, adverse event. for doravirine 100 mg and efavirenz, respectively. The in the presence of CYP3A inducers or following a proportion of participants with treatment-emergent missed dose, and providing coverage of a variety of laboratory abnormalities of Grade 2 or higher was sim- NNRTI mutations, including K103N, Y181C and ilar between doravirine 100 mg and efavirenz through G190A mutations and the dual K103N/Y181C muta- week 96 of Parts I+II, with two exceptions: Grade 2 ele- tions [10,26]. Based on all available data, doravirine vations in total cholesterol and low-density lipoprotein 100 mg once daily was selected for Part II of the trial (LDL)-cholesterol were less common with doravirine and the Phase III clinical programme. 100 mg (0.0% and 2.0%, respectively) than with efa- In all participants who received the selected dose, virenz (9.7% and 9.8%, respectively; Additional file 7). doravirine 100 mg once daily demonstrated antiretro- For the overall doravirine group (all dose groups com- viral activity similar to that of efavirenz. In both treat- bined), Grade 2 elevations in total cholesterol and LDL- ment groups, the proportion of participants with HIV-1 cholesterol were also less common (0.9% and 1.4%, RNA <40 copies/ml increased through week 24 and was respectively) than in the efavirenz group. Grade  3 maintained up to week 96. The efficacy observed in par - total cholesterol and Grade 3 LDL-cholesterol events ticipants with baseline HIV-1 RNA >100,000 copies/ml occurred in 2 participants in the efavirenz group only was numerically lower for doravirine 100 mg than for (no Grade 4 events). Grade 2 creatinine elevations were efavirenz at week 96; however, this difference should more common in the overall doravirine group (8.3%) be interpreted in the context of the relatively small than in the efavirenz group (0.9%). No Grade 3 or 4 subgroup size (32 receiving doravirine 100 mg and 29 creatinine elevations and no discontinuations due to receiving efavirenz). In ongoing Phase III trials, dora- renal AEs occurred in any treatment group. virine 100 mg has demonstrated similar efficacy to the comparator regimens among participants with baseline HIV-1 RNA >100,000 copies/ml [27,28]. In this trial, Discussion doravirine 100 mg also demonstrated an immunologi- Doravirine 100 mg in combination with TDF/FTC cal effect similar to that of efavirenz, as measured by demonstrated similar antiretroviral efficacy to efa- the change from baseline in CD4 T-cell counts. virenz and was associated with a significantly lower Doravirine 100 mg was generally safe and well toler- incidence of CNS AEs in ART-naive adults with HIV-1 ated in this trial. In the key safety analyses, the propor- infection. In Part I of the trial, all studied doses of tion of participants who experienced CNS AEs was sig- doravirine were generally well tolerated and dem- nificantly lower for doravirine 100 mg compared with onstrated antiretroviral activity and immunological efavirenz at weeks 8 and 24. Drug-related AEs were effect similar to efavirenz through 24 weeks of treat- also less common with doravirine compared with efa- ment. Therefore, the selection of the dose for further virenz, driven primarily by lower rates of drug-related study included additional considerations, such as CNS AEs, such as dizziness and abnormal dreams, maintaining therapeutic concentrations of doravirine in the doravirine group. The favourable CNS profile 432 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 432 AVT-19-OA-4512_Gatell.indd 432 22/11/2019 11:48:53 22/11/2019 11:48:53 Doravirine versus efavirenz Phase IIb trial of doravirine versus efavirenz has been confirmed by doravirine showing non-inferior efficacy to ritonavir- the week 48 results of the Phase III DRIVE-AHEAD boosted darunavir in the DRIVE-FORWARD trial trial, in which the fixed-dose combination of dora- and to efavirenz in the DRIVE-AHEAD trial [27,28], virine/lamivudine (3TC)/TDF was compared with the supporting the recent approval of doravirine in the fixed-dose combination of efavirenz/FTC/TDF [28]. US [34,35], Europe [36,37] and elsewhere. Doravirine Treatment-emergent Grade 2 creatinine elevations were has the potential to provide another convenient treat- more common in the overall doravirine group (all dose ment option that offers efficacy, good tolerability and groups combined) than in the efavirenz group; however, safety for people living with HIV. this finding was not seen in either of the Phase III trials, where the incidence of Grade 2 creatinine elevations Acknowledgements was low in the doravirine groups (2.6% and 2.2%, respectively) and similar to the comparator groups We thank all the study participants, and the staff of (4.2% and 1.4%, respectively) [29]. all the centres taking part in the study. Medical writ- Across all treatment groups, the rate of participant ing assistance, under the direction of the authors, was discontinuation was relatively high. For example, in provided by Edward Rochford and Annette Smith of Part I, 19% of the participants discontinued due to CMC AFFINITY, a division of McCann Health Medi- protocol violations, loss to follow-up, non-compliance cal Communications Ltd, Macclesfield, UK, and Kim or withdrawal by subject. The high discontinuation Strohmaier of Merck & Co., Inc., Kenilworth, NJ, USA, rate partially accounts for the relatively low response in accordance with Good Publication Practice (GPP3) rates observed compared with other Phase II trials with guidelines. This assistance was funded by Merck Sharp efavirenz [30–32], particularly in Part I, in which 64% & Dohme Corp., a subsidiary of Merck & Co., Inc., of participants in the efavirenz group achieved HIV-1 Kenilworth, NJ, USA. RNA <40 copies/ml at week 24. The relatively compli- JMG, JOM-R, DPH, MT, KA, C Hoffmann, FR, OO, cated dosing strategy and high pill burden may par- RD, AP, DES, JP and SR enrolled the study partici- tially explain the high discontinuation rate; the trial pants and collected the study data. C Harvey, SK, CF, required twice-daily dosing, including both active and C Hwang and HT contributed to the coordination and placebo tablets to maintain blinding (a total of six tab- oversight of the study. XX, HW and AR performed lets per day before and three tablets per day after dose the statistical analysis. All authors participated in data selection). A further limitation was the relatively small interpretation, contributed to the drafting and critical size of the treatment groups precluding a formal non- review of the article, and approved the final version of inferiority comparison of efficacy. However, the subse- the manuscript. quent Phase III DRIVE-AHEAD trial was adequately powered for statistical comparisons, lacked the high Disclosure statement pill burden of this trial, and demonstrated the non- inferior efficacy of doravirine/3TC/TDF versus efa- Funding for this research was provided by Merck Sharp virenz/FTC/TDF at week 48, with 84.3% and 80.8%, & Dohme Corp., a subsidiary of Merck & Co., Inc., respectively, achieving HIV-1 RNA <50 copies/ml [28]. Kenilworth, NJ, USA. C Harvey, XX, SK, CF, HW, AR, The trial population was primarily young male C Hwang and HT are current or former employees of participants with high baseline CD4 T-cell counts, Merck Sharp & Dohme Corp., a subsidiary of Merck potentially limiting the applicability of these results & Co., Inc., Kenilworth, NJ, USA, and may own stock to a more diverse patient population. Ongoing Phase and/or stock options in Merck & Co., Inc., Kenilworth, III trials of doravirine are composed of larger, more NJ, USA. diverse study populations and greater opportunity to Up to 30 April 2018, JMG received honoraria for speak- evaluate the relationships between demographics or ing and advisory boards, and research grants to his insti- baseline characteristics and the efficacy and safety of tution from ViiV Healthcare, Gilead Sciences, MSD and doravirine. Janssen. From 1 May 2018, he is an employee (Senior Overall, this trial showed promising results for Global Medical Director) of ViiV Healthcare. JOM-R has doravirine as initial treatment of adults with HIV-1 received honoraria for advisory panels and lectures from infection. The superior neuropsychiatric profile of MSD, Bristol-Myers Squibb, ViiV Healthcare and AbbVie; doravirine compared with efavirenz and the once- and research grants from MSD, Bristol-Myers Squibb, daily dosing regimen are likely to improve treatment GeneOne, Sanofi Pasteur, GlaxoSmithKline, Sangamo adherence [33]. An important outcome was the selec- Therapeutics and Gilead Sciences. DPH has received hon- tion of doravirine 100 mg as the dose for further clini- oraria for speaker’s bureau and advisory boards for Merck cal development in the Phase III trials. The 48-week & Co., Inc., Kenilworth, NJ, USA, Gilead Sciences, and results of the Phase III trials are favourable, with Bristol-Myers Squibb. MT has received research support Antiviral Therapy 24.6 433 AVT-19-OA-4512_Gatell.indd 433 AVT-19-OA-4512_Gatell.indd 433 22/11/2019 11:48:53 22/11/2019 11:48:53 JM Gatell et al. to AIDS Research Consortium of Atlanta from Bristol- Additional file 6: A table showing proportion of Myers Squibb, CytoDyn Inc., GlaxoSmithKline, Gilead participants with HIV-1 RNA <40 copies/ml at weeks Sciences, MSD, Roche Laboratories, TaiMed Biologics 24 and 96 (Parts I+II) can be found at https://www. Inc. and ViiV Healthcare. KA has received honoraria from intmedpress.com/uploads/documents/4512_Gatell_ lectures and advisory boards for MSD, Bristol-Myers Addfile6.pdf Squibb, GSK/ViiV Healthcare and Boehringer Ingelheim. C Hoffmann has received honoraria for lecturing, advi- Additional file 7: A table showing the most common sory boards, and/or travelling grants from AbbVie, Bris- treatment-emergent laboratory changes, occurring in tol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, ≥4 participants in any treatment group with DAIDS Hexal, Janssen, MSD and ViiV Healthcare; and research Grade ≥2 (based on DAIDS toxicity criteria) through grants from AbbVie, Janssen and Gilead Sciences. FR has week 96 (Parts I+II) can be found at https://www. received research funding or honoraria from, or consulted intmedpress.com/uploads/documents/4512_Gatell_ for, AbbVie, Bristol-Myers Squibb, Gilead Sciences, Jans- Addfile7.pdf sen, MSD and ViiV Healthcare. OO has received research grants from Gilead Sciences and Forest Laboratories, and Additional file 8: A redacted protocol can be found at honoraria for advisory boards from Gilead Sciences, Bris- https://www.intmedpress.com/uploads/documents/4512_ tol-Myers Squibb, ViiV Healthcare and Janssen. RD owns Gatell_Addfile8.pdf stock in Merck & Co., Inc., Kenilworth, NJ, USA. AP has received research and/or congress sponsoring, and/or trav- References elling grants from AbbVie, Bristol-Myers Squibb, Gilead 1. Food and Drug Administration (FDA). Full prescribing Sciences, Hexal, Janssen, MSD and ViiV Healthcare. DES information: SUSTIVA (efavirenz). 2017. (Accessed 29 has received travel sponsorship and research grant sup- April 2019.) Available from https://www.accessdata.fda. gov/drugsatfda_docs/label/2017/021360s044,020972s056 port from MSD, ViiV Healthcare and Gilead Sciences. JP lbl.pdf has received research and/or congress sponsoring, and/or 2. Mollan KR, Smurzynski M, Eron JJ, et al. Association travelling grants from AbbVie, Gilead Sciences, Janssen, between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or MSD and ViiV Healthcare. SR has no conflicts of interest completed suicide: an analysis of trial data. Ann Intern Med to declare. 2014; 161:1–10. 3. British HIV Association. BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015 Additional files (2016 interim update). 2016. (Accessed 29 April 2019.) Available from http://www.bhiva.org/HIV-1-treatment- Additional file 1: A figure showing the study design guidelines.aspx can be found at https://www.intmedpress.com/uploads/ 4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral documents/4512_Gatell_Addfile1.pdf Agents in Adults and Adolescents Living with HIV. 2018. (Accessed 14 May 2019.) Available from https://aidsinfo. nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf Additional file 2: Additional exclusion criteria can 5. Crauwels HM, van Heeswijk RP, Buelens A, Stevens M, be found at https://www.intmedpress.com/uploads/ Boven K, Hoetelmans RM. Impact of food and different documents/4512_Gatell_Addfile2.pdf meal types on the pharmacokinetics of rilpivirine. J Clin Pharmacol 2013; 53:834–840. Additional file 3: A figure showing participant flow 6. Food and Drug Administration (FDA). Full prescribing information: INTELENCE™ (etravirine). 2018. (Accessed through the study at week 96: Part I and Part II can 29 April 2019.) Available from https://www.accessdata.fda. be found at https://www.intmedpress.com/uploads/ gov/drugsatfda_docs/label/2018/022187s023lbl.pdf documents/4512_Gatell_Addfile3.pdf 7. Food and Drug Administration (FDA). Full prescribing information: VIRAMUNE (nevirapine). 2018. (Accessed 29 April 2019.) Available from https://www.accessdata.fda.gov/ Additional file 4: A table showing proportion of drugsatfda_docs/label/2018/020636s050,020933s040lbl.pdf participants with HIV-1 RNA <40 copies/ml at week 8. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 24 (Part I) can be found at https://www.intmedpress. 2018 Recommendations of the International Antiviral com/uploads/documents/4512_Gatell_Addfile4.pdf Society-USA Panel. JAMA 2018; 320:379–396. 9. World Health Organization. Updated recommendations on Additional file 5: A table showing most common first-line and second-line antiretroviral regimens and post- exposure prophylaxis and recommendations on early infant laboratory changes, occurring in ≥4 participants in any diagnosis of HIV: interim guidance. 2018 (WHO/CDS/ treatment group with indicated grade (based on DAIDS HIV/18.18). (Accessed 15 October 2018.) Available from http://www.who.int/hiv/pub/guidelines/ARV2018update/en/ toxicity criteria ) that was also an increase from baseline, 10. Lai MT, Feng M, Falgueyret JP, et al. In vitro through week 24 (Part I) can be found at https://www. characterization of MK-1439, a novel HIV-1 nonnucleoside intmedpress.com/uploads/documents/4512_Gatell_ reverse transcriptase inhibitor. Antimicrob Agents Addfile5.pdf Chemother 2014; 58:1652–1663. 434 ©2019 International Medical Press AVT-19-OA-4512_Gatell.indd 434 AVT-19-OA-4512_Gatell.indd 434 22/11/2019 11:48:53 22/11/2019 11:48:53 Doravirine versus efavirenz Phase IIb trial 11. Anderson MS, Gilmartin J, Cilissen C, et al. Safety, 25. Miettinen O, Nurminen M. Comparative analysis of two tolerability and pharmacokinetics of doravirine, a novel rates. Stat Med 1985; 4:213–226. HIV non-nucleoside reverse transcriptase inhibitor, after 26. Feng M, Sachs NA, Xu M, et al. Doravirine suppresses single and multiple doses in healthy subjects. Antivir Ther common nonnucleoside reverse transcriptase inhibitor- 2015; 20:397–405. associated mutants at clinically relevant concentrations. 12. Behm MO, Yee KL, Liu R, Levine V, Panebianco D, Antimicrob Agents Chemother 2016; 60:2241–2247. Fackler P. The effect of food on doravirine bioavailability: 27. Molina JM, Squires K, Sax PE, et al. Doravirine versus results from two pharmacokinetic studies in healthy ritonavir-boosted darunavir in antiretroviral-naive adults subjects. Clin Drug Investig 2017; 37:571–579. with HIV-1 (DRIVE-FORWARD): 48-week results of a 13. Khalilieh SG, Yee KL, Sanchez RI, et al. A study to evaluate randomised, double-blind, Phase 3, non-inferiority trial. doravirine pharmacokinetics when coadministered with acid- Lancet HIV 2018; 5:e211–e220. reducing agents. J Clin Pharmacol 2019; 59:1093–1098. 28. Orkin C, Squires KE, Molina JM, et al. Doravirine/ 14. Bleasby K, Fillgrove KL, Houle R, et al. In vitro evaluation lamivudine/tenofovir disoproxil fumarate is non-inferior of the drug interaction potential of doravirine. Antimicrob to efavirenz/emtricitabine/tenofovir disoproxil fumarate Agents Chemother 2019; 63:e02492–18. in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD 15. Khalilieh SG, Yee KL, Sanchez RI, et al. Multiple doses of Trial. Clin Infect Dis 2019; 68:535–544. rifabutin reduce exposure of doravirine in healthy subjects. J Clin Pharmacol 2018; 58:1044–1052. 29. European Medicines Agency. Pifeltro public assessment report. 2019. (Accessed 22 May 2019.) Available from 16. Yee KL, Khalilieh SG, Sanchez RI, et al. The effect of single https://www.ema.europa.eu/en/documents/assessment- and multiple doses of rifampin on the pharmacokinetics report/pifeltro-epar-public-assessment-report_en.pdf of doravirine in healthy subjects. Clin Drug Investig 2017; 37:659–667. 30. Cohen C, Elion R, Ruane P, et al. Randomized, Phase 2 evaluation of two single-tablet regimens elvitegravir/ 17. Schürmann D, Sobotha C, Gilmartin J, et al. A randomized, cobicistat/emtricitabine/tenofovir disoproxil fumarate versus double-blind, placebo-controlled, short-term monotherapy efavirenz/emtricitabine/tenofovir disoproxil fumarate for the study of doravirine in treatment-naive HIV-infected initial treatment of HIV infection. AIDS 2011; 25:F7–F12. individuals. AIDS 2016; 30:57–63. 31. Pozniak AL, Morales-Ramirez J, Katabira E, et al. Efficacy 18. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Forty- and safety of TMC278 in antiretroviral-naive HIV-1 eight-week efficacy and safety and early CNS tolerability patients: week 96 results of a Phase IIb randomized trial. of doravirine (MK-1439), a novel NNRTI, with TDF/FTC AIDS 2010; 24:55–65. in ART-naive HIV-positive patients. J Int AIDS Soc 2014; 17:19532. 32. Vernazza P, Wang C, Pozniak A, et al. Efficacy and safety of lersivirine (UK-453,061) versus efavirenz in antiretroviral 19. Gatell JM, Raffi F, Plettenberg A, et al. Efficacy and safety of treatment-naive HIV-1-infected patients: week 48 primary doravirine 100 mg QD vs efavirenz 600 mg QD with TDF/ analysis results from an ongoing, multicenter, randomized, FTC in ART-naive HIV-infected patients: week 24 results. double-blind, Phase IIb trial. J Acquir Immune Defic Syndr J Int AIDS Soc 2015; 18 Suppl 4:36. 2013; 62:171–179. 20. Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety 33. Cohen CJ, Meyers JL, Davis KL. Association between and antiviral effect of MK-1439, a novel NNRTI (+FTC/ daily antiretroviral pill burden and treatment adherence, TDF) in ART-naive HIV-infected patients. Top Antiviral hospitalisation risk, and other healthcare utilisation and Med 2014; 22:46–47. costs in a US medicaid population with HIV. BMJ Open 21. Gatell JM, Raffi F, Plettenberg A, et al. Doravirine 100mg 2013; 3:e003028. QD vs efavirenz +TDF/FTC in ART-naive HIV+ patients: 34. Pifeltro (doravirine) prescribing information. Merck Sharp week 48 results. Top Antivir Med 2016; 24:183. & Dohme Corp., Whitehouse Station, NJ, USA. 2019. 22. Food and Drug Administration (FDA). Full prescribing (Accessed 7 October 2019.) Available from https://www. information: TRUVADA (emtricitabine/tenofovir disoproxil merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_ fumarate). 2018. (Accessed 29 April 2019.) Available pi.pdf from https://www.accessdata.fda.gov/drugsatfda_docs/ 35. Delstrigo (doravirine, lamivudine, and tenofovir disoproxil label/2018/021752s055lbl.pdf fumarate) prescribing information. Merck Sharp & Dohme 23. U.S. Department of Health and Human Services, Corp., Whitehouse Station, NJ, USA. 2019. (Accessed 7 National Institutues of Health, National Institute of October 2019.) Available from https://www.merck.com/ Allergy and Infectious Diseases, Division of AIDS. product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf Division of AIDS (DAIDS) Table for Grading the Severity 36. European Medicines Agency. Delstrigo. 2019. (Accessed 29 of Adult and Pediatric Adverse Events, Version 2.0. 2014. April 2019.) Available from https://www.ema.europa.eu/en/ (Accessed 15 October 2018.) Available from https://rsc. medicines/human/EPAR/delstrigo tech-res.com/clinical-research-sites/safety-reporting/daids- grading-tables 37. European Medicines Agency. Pifeltro. 2019. (Accessed 29 April 2019.) Available from https://www.ema.europa.eu/en/ 24. U.S. Department of Health and Human Services, Food medicines/human/EPAR/pifeltro and Drug Administration, Center for Drug Evaluation and Research. Human immunodeficiency virus-1 infection: developing antiretroviral drugs for treatment. Guidance for industry. 2015. (Accessed 15 October 2018.) Available from www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ ucm355128.pdf Accepted 24 May 2019; published online 29 July 2019 Antiviral Therapy 24.6 435 AVT-19-OA-4512_Gatell.indd 435 AVT-19-OA-4512_Gatell.indd 435 22/11/2019 11:48:53 22/11/2019 11:48:53

Journal

Antiviral Therapy – SAGE

Published: Aug 1, 2019

There are no references for this article.