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    Clinical Trial Results:
    A Phase 2B, Randomized, Double-Blind, Active-Comparator-Controlled, Dose-Ranging Clinical Trial to Evaluate the Safety, Tolerability, Antiretroviral Activity, and Pharmacokinetics of MK-8591 Given in Combination with Doravirine (DOR) and Lamivudine (3TC) in HIV-1-Infected Treatment-Naïve Adults

    Summary
    EudraCT number
    		 2017-000437-32
    Trial protocol
    		 GB   FR  
    Global end of trial date
    09 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Mar 2023
    First version publication date
    17 Mar 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-8591-011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03272347
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the safety, tolerability, antiretroviral activity, and pharmacokinetics of 3 doses of islatravir (MK-8591) in combination with doravirine (DOR) and lamivudine (3TC) administered to antiretroviral treatment-naïve adult participants with human immunodeficiency virus type 1 (HIV-1) infection.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Chile: 40
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 51
    Worldwide total number of subjects
    123
    EEA total number of subjects
    24
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    121
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Treatment-naïve participants ≥18 years of age with human immunodeficiency virus type 1 (HIV-1) were enrolled in this study.

    Pre-assignment
    Screening details
    		 A total of 197 participants were screened and 123 were randomized in the study. All non-randomized participants were screen failures.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Islatravir 0.25 mg
    Arm description
    		 In Part 1, participants were treated once daily (QD) with 0.25 mg islatravir, 100 mg doravirine (DOR), 300 mg lamivudine (3TC), and placebo to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no Protocol-defined Virologic Failure (PDVF) discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doravirine
    Investigational medicinal product code
    Other name
    MK-1439
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks

    Investigational medicinal product name
    Islatravir
    Investigational medicinal product code
    Other name
    MK-8591
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Islatravir at 0.25 mg was orally administered QD in capsule form for up to 52 weeks. After Week 60 a selected open label dose may be administered.

    Investigational medicinal product name
    Doravirine/Islatravir
    Investigational medicinal product code
    Other name
    MK-8591A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks

    Investigational medicinal product name
    Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks

    Investigational medicinal product name
    Lamivudine
    Investigational medicinal product code
    Other name
    3TC
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks

    Arm title
    		 Islatravir 0.75 mg
    Arm description
    		 In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Islatravir
    Investigational medicinal product code
    Other name
    MK-8591
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Islatravir at 0.75 mg was orally administered QD in capsule form for up to 52 weeks. After Week 60 a selected open label dose may be administered.

    Investigational medicinal product name
    Doravirine
    Investigational medicinal product code
    Other name
    MK-1439
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks

    Investigational medicinal product name
    Lamivudine
    Investigational medicinal product code
    Other name
    3TC
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks

    Investigational medicinal product name
    Doravirine/Islatravir
    Investigational medicinal product code
    Other name
    MK-8591A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks

    Investigational medicinal product name
    Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks

    Arm title
    		 Islatravir 2.25 mg
    Arm description
    		 In Part 1, participants were treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 2.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Islatravir
    Investigational medicinal product code
    Other name
    MK-8591
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Islatravir at 2.25 mg was orally administered QD in capsule form for up to 52 weeks. After Week 60 a selected open label dose may be administered.

    Investigational medicinal product name
    Doravirine
    Investigational medicinal product code
    Other name
    MK-1439
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks

    Investigational medicinal product name
    Lamivudine
    Investigational medicinal product code
    Other name
    3TC
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks

    Investigational medicinal product name
    Doravirine/Islatravir
    Investigational medicinal product code
    Other name
    MK-8591A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks

    Investigational medicinal product name
    Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks

    Arm title
    		 DOR/3TC/TDF
    Arm description
    		 In Part 1, participants were treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. In Parts 2 and 3, after a minimum of 24 weeks of treatment, placebo treatments were discontinued and participants received only DOR/3TC/TDF QD open label up to Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate
    Investigational medicinal product code
    Other name
    MK-1439A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fixed dose combination of 100 mg doravirine + 300 mg lamivudine + 300 mg tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 144 weeks.

    Investigational medicinal product name
    Placebo to Islatravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to islatravir is orally administered QD in capsule form for up to 52 weeks

    Investigational medicinal product name
    Doravirine/Islatravir
    Investigational medicinal product code
    Other name
    MK-8591A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks

    Investigational medicinal product name
    Placebo to Lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Lamivudine is orally administered QD in tablet form for up to 52 weeks

    Investigational medicinal product name
    Placebo to Doravirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Doravirine is orally administered QD in tablet form for up to 52 weeks

    Number of subjects in period 1
    		Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Started
    31
    30
    31
    31
    Treated
    29
    30
    31
    31
    Completed
    20
    24
    19
    24
    Not completed
    11
    6
    12
    7
         Adverse event, serious fatal
    -
    -
    -
    1
         Physician decision
    4
    2
    5
    4
         Consent withdrawn by subject
    5
    1
    2
    1
         Screen Failure
    1
    -
    -
    -
         Lost to follow-up
    1
    3
    5
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Islatravir 0.25 mg
    Reporting group description
    		 In Part 1, participants were treated once daily (QD) with 0.25 mg islatravir, 100 mg doravirine (DOR), 300 mg lamivudine (3TC), and placebo to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no Protocol-defined Virologic Failure (PDVF) discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Reporting group title
    Islatravir 0.75 mg
    Reporting group description
    		 In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Reporting group title
    Islatravir 2.25 mg
    Reporting group description
    		 In Part 1, participants were treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 2.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Reporting group title
    DOR/3TC/TDF
    Reporting group description
    		 In Part 1, participants were treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. In Parts 2 and 3, after a minimum of 24 weeks of treatment, placebo treatments were discontinued and participants received only DOR/3TC/TDF QD open label up to Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Reporting group values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF Total
    Number of subjects
    		 31 30 31 31 123
    Age categorical
    Units: Participants
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 30 30 30 31 121
        From 65-84 years
    		 1 0 1 0 2
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 32.3 ± 13.3 30.0 ± 9.0 32.4 ± 11.8 29.4 ± 8.9 -
    Sex: Female, Male
    Units: Participants
        Female
    		 1 3 3 3 10
        Male
    		 30 27 28 28 113
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 6 6 8 5 25
        White
    		 24 24 21 24 93
        More than one race
    		 0 0 2 0 2
        Unknown or Not Reported
    		 1 0 0 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 14 19 12 15 60
        Not Hispanic or Latino
    		 16 11 18 15 60
        Unknown or Not Reported
    		 1 0 1 1 3
    HIV-1 RNA Levels at Screening
    Randomization was stratified by the screening HIV-1 RNA levels (<=100,000 copies/mL or >100,000 copies/mL).
    Units: Subjects
        <=100,000 copies/mL
    		 24 23 23 24 94
        >100,000 copies/mL
    		 7 7 8 7 29
    CD4+ T-Cell Count
    Two untreated participants from the Islatravir 0.25 mg treatment group were not analyzed.
    Units: cells/mm^3
        arithmetic mean (standard deviation)
    		 450.8 ± 170.0 538.5 ± 165.5 469.6 ± 203.3 508.5 ± 206.8 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Islatravir 0.25 mg
    Reporting group description
    		 In Part 1, participants were treated once daily (QD) with 0.25 mg islatravir, 100 mg doravirine (DOR), 300 mg lamivudine (3TC), and placebo to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no Protocol-defined Virologic Failure (PDVF) discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Reporting group title
    Islatravir 0.75 mg
    Reporting group description
    		 In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Reporting group title
    Islatravir 2.25 mg
    Reporting group description
    		 In Part 1, participants were treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 2.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Reporting group title
    DOR/3TC/TDF
    Reporting group description
    		 In Part 1, participants were treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. In Parts 2 and 3, after a minimum of 24 weeks of treatment, placebo treatments were discontinued and participants received only DOR/3TC/TDF QD open label up to Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    DOR/ISL Continued (Part 4)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Part 4, beginning with week 144, participants who received the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label in Part 3 and continued treatment through Week 192.

    Subject analysis set title
    DOR/ISL Switch (Part 4)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Part 4, beginning with week 144, participants who received DOR/3TC/TDF QD open label up to Week 144 were switched to the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and continued treatment until Week 192

    Subject analysis set title
    DOR/ISL Continued (Part 4)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In Part 4, beginning with week 144, participants who received the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label in Part 3 and continued treatment through Week 192.

    Subject analysis set title
    DOR/ISL Switch (Part 4)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In Part 4, beginning with week 144, participants who received DOR/3TC/TDF QD open label up to Week 144 were switched to the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and continued treatment until Week 192

    Subject analysis set title
    Islatravir 0.25 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    Islatravir 0.75 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    Islatravir 2.25 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Part 1, participants were treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 2.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    DOR/3TC/TDF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Part 1, participants were treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. In Parts 2 and 3, after a minimum of 24 weeks of treatment, placebo treatments were discontinued and participants received only DOR/3TC/TDF QD open label up to Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    Islatravir 0.25 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    Islatravir 0.75 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    Islatravir 2.25 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In Part 1, participants were treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 2.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Subject analysis set title
    DOR/3TC/TDF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In Part 1, participants were treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. In Parts 2 and 3, after a minimum of 24 weeks of treatment, placebo treatments were discontinued and participants received only DOR/3TC/TDF QD open label up to Week 144. In Part 4, beginning with Week 144, participants received the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Primary: Percentage of participants with HIV-1 RNA <50 copies/mL at Week 24

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    End point title
    		 Percentage of participants with HIV-1 RNA <50 copies/mL at Week 24
    End point description
    Blood samples were collected and plasma human immunodeficiency virus 1 (HIV-1) ribonucleic acid (RNA) were quantified using a real time polymerase chain reaction (PCR) assay with a lower limit of detection of 40 copies/mL. Missing values were counted as failure. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: Percentage of participants
        number (not applicable)
    93.1
    100.0
    90.3
    90.3
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% confidence intervals (CIs) were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.5
         upper limit
    		 18.3
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16
         upper limit
    		 16.3
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    9.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 23

    Primary: Percentage of participants with HIV-1 RNA <50 copies/mL at Week 48

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    End point title
    		 Percentage of participants with HIV-1 RNA <50 copies/mL at Week 48
    End point description
    Blood samples were collected and plasma HIV-1 RNA were quantified using a real time PCR assay with a lower limit of detection of 40 copies/mL. Missing values were counted as failure. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: Percentage of participants
        number (not applicable)
    89.7
    90.0
    77.4
    83.9
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.2
         upper limit
    		 24.4
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.1
         upper limit
    		 14.8
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.2
         upper limit
    		 24.6

    Primary: Number of participants experiencing adverse events (AEs) up to Week 144

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    End point title
    		 Number of participants experiencing adverse events (AEs) up to Week 144
    End point description
    An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. All randomized participants who received at least 1 dose of study treatment, corresponding to the study treatment they actually received.
    End point type
    Primary
    End point timeframe
    Up to 144 weeks
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: Participants
    26
    27
    24
    27
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.7
         upper limit
    		 20.5
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    -9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.4
         upper limit
    		 10.1
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 20.8

    Primary: Number of participants discontinuing study drug due to AEs up to Week 144

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    End point title
    		 Number of participants discontinuing study drug due to AEs up to Week 144
    End point description
    An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. All randomized participants who received at least 1 dose of study treatment, corresponding to the study treatment they actually received.
    End point type
    Primary
    End point timeframe
    Up to 144 weeks
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: Participants
    1
    0
    2
    1
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 14.5
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in %
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.4
         upper limit
    		 8.5
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.8
         upper limit
    		 18.1

    Secondary: Percentage of participants with HIV-1 RNA <50 copies/mL up to 24 weeks after 3TC and placebo are discontinued from the regimen

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    End point title
    		 Percentage of participants with HIV-1 RNA <50 copies/mL up to 24 weeks after 3TC and placebo are discontinued from the regimen
    End point description
    Blood samples were collected and plasma HIV-1 RNA were quantified using a real time PCR assay with a lower limit of detection of 40 copies/mL, and missing values were counted as failure. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks after 3TC and Placebo are discontinued from the regimen (up to approximately 60 weeks after initiating treatment)
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    27
    28
    Units: Percentage of participants
        number (not applicable)
    86.2
    90.0
    88.9
    96.4
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.1
         upper limit
    		 6.6
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.9
         upper limit
    		 8.8
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.5
         upper limit
    		 9.1

    Secondary: Percentage of participants with HIV-1 RNA <50 copies/mL up to 48 weeks after 3TC and placebo are discontinued from the regimen

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    End point title
    		 Percentage of participants with HIV-1 RNA <50 copies/mL up to 48 weeks after 3TC and placebo are discontinued from the regimen
    End point description
    Blood samples were collected and plasma HIV-1 RNA were quantified using a real time PCR assay with a lower limit of detection of 40 copies/mL, and missing values were counted as failure. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    27
    28
    Units: Percentage of participants
        number (not applicable)
    62.1
    56.7
    59.3
    60.7
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.4
         upper limit
    		 27.7
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.6
         upper limit
    		 22.1
    Statistical analysis title
    		 Treatment difference in percent response
    Statistical analysis description
    The 95% CIs were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA ≤100,000 or >100,000 copies/mL).
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.7
         upper limit
    		 25.2

    Secondary: Percentage of participants with HIV-1 RNA <50 copies/mL up to 48 weeks after starting open-label doravirine/islatravir regimen (Part 4)

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    End point title
    		 Percentage of participants with HIV-1 RNA <50 copies/mL up to 48 weeks after starting open-label doravirine/islatravir regimen (Part 4)
    End point description
    Blood samples were collected and plasma HIV-1 RNA were quantified using a real time PCR assay with a lower limit of detection of 40 copies/mL. Missing values were counted as failure. The percentage of participants with HIV-1 RNA <50 copies in Part 4 are reported. Per protocol, all randomized participants who entered Part 4 and either continued treatment with DOR/ISL from Part 3 or switched from DOR/3TC/TDF in Part 3 to DOR/ISL in Part 4; and received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 192
    End point values
    		 DOR/ISL Continued (Part 4) DOR/ISL Switch (Part 4)
    Number of subjects analysed
    67
    22
    Units: Percentage of participants
        number (not applicable)
    85.1
    95.5
    No statistical analyses for this end point

    Secondary: Change from baseline in mature T-helper (CD4+ T)-cell count at Week 24

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    End point title
    		 Change from baseline in mature T-helper (CD4+ T)-cell count at Week 24
    End point description
    Blood samples were collected and cluster of differentiation (CD4)+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    220.5 (170.3 to 270.8)
    192.8 (117.9 to 267.7)
    142.9 (89.9 to 196.0)
    142.1 (105.7 to 178.5)
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    78.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.8
         upper limit
    		 138.1
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63
         upper limit
    		 64.7
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    50.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.7
         upper limit
    		 133.1

    Secondary: Change from baseline in CD4+ T-cell count at Week 48

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    End point title
    		 Change from baseline in CD4+ T-cell count at Week 48
    End point description
    Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    182.0 (119.6 to 244.5)
    183.0 (124.7 to 241.2)
    100.7 (25.0 to 176.3)
    181.4 (137.2 to 225.6)
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -74.1
         upper limit
    		 75.3
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -70.7
         upper limit
    		 73.8
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -80.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -165.6
         upper limit
    		 4

    Secondary: Change from baseline in CD4+ T-cell count at Week 96

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    End point title
    		 Change from baseline in CD4+ T-cell count at Week 96
    End point description
    Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    243.4 (165.5 to 321.3)
    161.3 (90.2 to 232.4)
    136.5 (57.0 to 216.0)
    268.9 (188.5 to 349.3)
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -25.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -134.8
         upper limit
    		 83.8
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -132.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -242.9
         upper limit
    		 -21.9
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -107.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -212.1
         upper limit
    		 -3.1

    Secondary: Change from baseline in CD4+ T-cell count at Week 144

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    End point title
    		 Change from baseline in CD4+ T-cell count at Week 144
    End point description
    Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication. All randomized participants who received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 144
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    31
    31
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    204.4 (102.0 to 306.7)
    209.0 (111.5 to 306.6)
    162.9 (70.2 to 255.5)
    270.0 (183.2 to 356.8)
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -65.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -195.3
         upper limit
    		 64
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -107.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -231.2
         upper limit
    		 16.9
    Statistical analysis title
    		 Treatment difference in T-cell count
    Statistical analysis description
    The 95% CI for mean difference in CD4 change was based on t-distribution.
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -188.7
         upper limit
    		 66.8

    Secondary: Change from baseline in CD4+ T-cell count at Week 192 (Part 4)

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    End point title
    		 Change from baseline in CD4+ T-cell count at Week 192 (Part 4)
    End point description
    Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Week 144 value. The change from baseline in CD4+ T-cell count at Week 192 (Part 4) are reported. Per protocol, all randomized participants who entered Part 4 and either continued treatment with DOR/ISL from Part 3 or switched from DOR/3TC/TDF in Part 3 to DOR/ISL in Part 4; and received at least 1 dose of study treatment and have baseline data for those analyses that require baseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 192
    End point values
    		 DOR/ISL Continued (Part 4) DOR/ISL Switch (Part 4)
    Number of subjects analysed
    57
    21
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    3.8 (-1.9 to 9.5)
    -3.4 (-12.0 to 5.2)
    No statistical analyses for this end point

    Secondary: Number of participants experiencing AEs through 24 weeks after 3TC and placebo are discontinued from the regimen

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    End point title
    		 Number of participants experiencing AEs through 24 weeks after 3TC and placebo are discontinued from the regimen
    End point description
    An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52. All randomized participants who received at least 1 dose of study treatment, corresponding to the study treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    27
    28
    Units: Participants
    18
    20
    14
    16
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.3
         upper limit
    		 29.6
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    -5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.6
         upper limit
    		 20.7
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    9.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.4
         upper limit
    		 33.5

    Secondary: Number of participants discontinuing study drug due to AEs through 24 weeks after 3TC and placebo are discontinued from the regimen

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    End point title
    		 Number of participants discontinuing study drug due to AEs through 24 weeks after 3TC and placebo are discontinued from the regimen
    End point description
    An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52. All randomized participants who received at least 1 dose of study treatment, corresponding to the study treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF
    Number of subjects analysed
    29
    30
    27
    28
    Units: Participants
    0
    0
    2
    1
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 0.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.9
         upper limit
    		 8.5
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 2.25 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.5
         upper limit
    		 20.6
    Statistical analysis title
    		 Difference in % Islatravir vs Active Comparator
    Statistical analysis description
    Based on Miettinen & Nurminen method.
    Comparison groups
    Islatravir 0.75 mg v DOR/3TC/TDF
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in %
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.9
         upper limit
    		 8.2

    Secondary: Number of participants experiencing AEs from Week 96 through study duration

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    End point title
    		 Number of participants experiencing AEs from Week 96 through study duration
    End point description
    An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. Per protocol, all randomized participants who received at least 1 dose of open label study treatment in Part 3 or Part 4, corresponding to the study treatment they actually received were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 96 up to Week 192
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF DOR/ISL Continued (Part 4) DOR/ISL Switch (Part 4)
    Number of subjects analysed
    29
    30
    31
    31
    67
    22
    Units: Participants
    12
    19
    11
    12
    36
    14
    No statistical analyses for this end point

    Secondary: Number of participants discontinuing study drug due to AEs from Week 96 through study duration

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    End point title
    		 Number of participants discontinuing study drug due to AEs from Week 96 through study duration
    End point description
    An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. Per protocol, all randomized participants who received at least 1 dose of open label study treatment in Part 3 or Part 4, corresponding to the study treatment they actually received were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 96 up to Week 192
    End point values
    		 Islatravir 0.25 mg Islatravir 0.75 mg Islatravir 2.25 mg DOR/3TC/TDF DOR/ISL Continued (Part 4) DOR/ISL Switch (Part 4)
    Number of subjects analysed
    29
    30
    31
    31
    67
    22
    Units: Participants
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants experiencing AEs during open label doravirine/islatravir treatment after week 144 up to week 192 (Part 4)

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    End point title
    		 Number of participants experiencing AEs during open label doravirine/islatravir treatment after week 144 up to week 192 (Part 4)
    End point description
    An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who experienced AEs during Part 4 are reported. Per protocol, all randomized participants who entered Part 4 and either continued treatment with DOR/ISL from Part 3 or switched from DOR/3TC/TDF in Part 3 to DOR/ISL in Part 4; and received at least 1 dose of study treatment, corresponding to the study treatment they actually received were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 144 up to Week 192
    End point values
    		 DOR/ISL Continued (Part 4) DOR/ISL Switch (Part 4)
    Number of subjects analysed
    67
    22
    Units: Participants
    36
    14
    No statistical analyses for this end point

    Secondary: Number of participants discontinuing study drug due to AEs during open label doravirine/islatravir treatment after week 144 up to week 192 (Part 4)

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    End point title
    		 Number of participants discontinuing study drug due to AEs during open label doravirine/islatravir treatment after week 144 up to week 192 (Part 4)
    End point description
    An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who experienced AEs during Part 4 are reported. Per protocol, all randomized participants who entered Part 4 and either continued treatment with DOR/ISL from Part 3 or switched from DOR/3TC/TDF in Part 3 to DOR/ISL in Part 4; and received at least 1 dose of study treatment, corresponding to the study treatment they actually received were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 144 up to Week 192
    End point values
    		 DOR/ISL Continued (Part 4) DOR/ISL Switch (Part 4)
    Number of subjects analysed
    67
    22
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For All-Cause Mortality: from randomization up to 198 weeks. For AEs: from first treatment up to 198 weeks.
    Adverse event reporting additional description
    The population analyzed for All-Cause Mortality was all randomized participants. The population analyzed for AEs was all randomized participants who received at least 1 dose of study treatment, corresponding to the study treatment they actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Islatravir 0.25mg
    Reporting group description
    		 In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144.

    Reporting group title
    Islatravir 0.75mg
    Reporting group description
    		 In Part 1, participants were treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 0.75 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144.

    Reporting group title
    Islatravir 2.25mg
    Reporting group description
    		 In Part 1, participants were treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. In part 2, after receiving at least 24 weeks of study intervention, participants with HIV-1 RNA <50 copies/mL and no PDVF discontinued treatment of 3TC and placebo to DOR/3TC/TDF. Part 2 assessed ISL 2.25 mg (blind maintained) + DOR QD. After all participants had received at least 48 weeks of study intervention and the islatravir dose was selected, all participants in the islatravir group were switched to the selected dose 0.75 mg (between week 60 and week 84). Part 3 assessed Islatravir 0.75 mg + DOR QD open label through Week 144.

    Reporting group title
    DOR/3TC/TDF
    Reporting group description
    		 In Part 1, participants were treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. In Parts 2 and 3, after a minimum of 24 weeks of treatment, placebo treatments were discontinued and participants received only DOR/3TC/TDF QD open label up to Week 144.

    Reporting group title
    DOR/ISL Continued
    Reporting group description
    		 In Part 4, beginning with week 144, participants who received the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label in Part 3 and continued treatment through Week 192.

    Reporting group title
    DOR/ISL Switch
    Reporting group description
    		 In Part 4, beginning with week 144, Participants who received DOR/3TC/TDF QD open label up to Week 144 were switched to the fixed dose combination of doravirine (100 mg)/islatravir (0.75 mg) QD open label and continued treatment until Week 192.

    Serious adverse events
    		 Islatravir 0.25mg Islatravir 0.75mg Islatravir 2.25mg DOR/3TC/TDF DOR/ISL Continued DOR/ISL Switch
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 29 (6.90%)
    6 / 30 (20.00%)
    2 / 31 (6.45%)
    4 / 31 (12.90%)
    2 / 67 (2.99%)
    1 / 22 (4.55%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Burkitt's lymphoma
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Long QT syndrome congenital
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Facial paralysis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysentery
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia chlamydial
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Islatravir 0.25mg Islatravir 0.75mg Islatravir 2.25mg DOR/3TC/TDF DOR/ISL Continued DOR/ISL Switch
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 29 (75.86%)
    26 / 30 (86.67%)
    23 / 31 (74.19%)
    22 / 31 (70.97%)
    21 / 67 (31.34%)
    11 / 22 (50.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    2 / 31 (6.45%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    2
    2
    2
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 29 (3.45%)
    4 / 30 (13.33%)
    2 / 31 (6.45%)
    3 / 31 (9.68%)
    2 / 67 (2.99%)
    0 / 22 (0.00%)
         occurrences all number
    1
    4
    2
    3
    2
    0
    Influenza like illness
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    3
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    4
    0
    1
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    3
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    4
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 30 (10.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    3
    3
    1
    0
    0
    Respiratory disorder
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    1
    3
    1
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Sneezing
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    2 / 31 (6.45%)
    3 / 31 (9.68%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    4
    2
    3
    0
    1
    Anxiety
         subjects affected / exposed
    3 / 29 (10.34%)
    6 / 30 (20.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    3
    7
    0
    1
    0
    2
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    3 / 31 (9.68%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    3
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    2
    1
    0
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 67 (1.49%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    0
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    3 / 31 (9.68%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    4
    1
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Headache
         subjects affected / exposed
    5 / 29 (17.24%)
    2 / 30 (6.67%)
    5 / 31 (16.13%)
    4 / 31 (12.90%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    5
    6
    5
    0
    0
    Syncope
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    3
    2
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    2 / 31 (6.45%)
    3 / 31 (9.68%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    2
    2
    3
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 29 (3.45%)
    6 / 30 (20.00%)
    3 / 31 (9.68%)
    8 / 31 (25.81%)
    0 / 67 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    1
    8
    3
    11
    0
    3
    Aphthous ulcer
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    2 / 67 (2.99%)
    1 / 22 (4.55%)
         occurrences all number
    2
    2
    1
    2
    2
    1
    Nausea
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 30 (16.67%)
    3 / 31 (9.68%)
    3 / 31 (9.68%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    6
    3
    5
    0
    0
    Proctitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 30 (10.00%)
    2 / 31 (6.45%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    3
    2
    5
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    3
    2
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Penile ulceration
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    4 / 31 (12.90%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    4
    3
    0
    0
    Neck pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    Back pain
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    3 / 31 (9.68%)
    4 / 31 (12.90%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    2
    4
    4
    0
    1
    Pain in extremity
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    5
    1
    0
    1
    0
    1
    Osteopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 29 (6.90%)
    7 / 30 (23.33%)
    1 / 31 (3.23%)
    5 / 31 (16.13%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    7
    1
    7
    0
    0
    Anal chlamydia infection
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    2 / 67 (2.99%)
    0 / 22 (0.00%)
         occurrences all number
    2
    3
    1
    2
    2
    0
    COVID-19
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 30 (10.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    2 / 67 (2.99%)
    5 / 22 (22.73%)
         occurrences all number
    0
    3
    1
    1
    2
    5
    Cellulitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    2
    2
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    2
    2
    0
    0
    Fungal skin infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    4 / 31 (12.90%)
    1 / 67 (1.49%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    1
    4
    1
    1
    Influenza
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    3 / 31 (9.68%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    1
    1
    4
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 29 (6.90%)
    9 / 30 (30.00%)
    2 / 31 (6.45%)
    7 / 31 (22.58%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    4
    10
    2
    14
    0
    1
    Oropharyngeal gonococcal infection
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    1
    1
    1
    0
    Oral herpes
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    2
    1
    1
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
    4 / 31 (12.90%)
    2 / 67 (2.99%)
    0 / 22 (0.00%)
         occurrences all number
    1
    3
    0
    5
    2
    0
    Proctitis gonococcal
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    2
    1
    1
    0
    1
    Proctitis chlamydial
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 67 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    4
    0
    0
    2
    0
    1
    Syphilis
         subjects affected / exposed
    6 / 29 (20.69%)
    8 / 30 (26.67%)
    2 / 31 (6.45%)
    6 / 31 (19.35%)
    4 / 67 (5.97%)
    1 / 22 (4.55%)
         occurrences all number
    6
    8
    2
    7
    4
    1
    Tonsillitis
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 30 (10.00%)
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    8
    1
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 30 (10.00%)
    3 / 31 (9.68%)
    3 / 31 (9.68%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    3
    4
    5
    0
    0
    Urethritis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Viral pharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 67 (1.49%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    1 / 29 (3.45%)
    6 / 30 (20.00%)
    4 / 31 (12.90%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    6
    4
    2
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    0 / 67 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2017
    Amendment 1: The primary purpose of the amendment was to incorporate several regulatory requests and correct/add several minor items.
    27 Mar 2018
    Amendment 2: The primary purpose of the amendment was to revise the safety follow-up period from ~14 days (2 weeks) to ~42 days (6 weeks) after the final dose of study treatment due to updated data which indicated the half-life of MK-8591 in plasma was expected to be between 87 and 128 hours after cessation of dosing for the dose range studied in this study. Therefore, a safety follow-up period of ~42 days was allowed for AE/SAE recording and reporting during this time.
    15 Nov 2019
    Amendment 3: The primary purpose of the amendment was to update the terminology in the protocol from “virologic failure” to “clinically significant confirmed viremia,” which is consistent with clinical management of participants with HIV-1 and updated US DHHS guidelines. In addition, the study was extended to allow participants to receive an additional 24 weeks of open-label study treatment, and to collect additional safety and efficacy data. Thus, following Week 120, additional site visits were added at Week 132 and Week 144.
    06 Jul 2020
    Amendment 4: The primary purpose of the amendment was to extend the study for an additional 48 weeks (Part 4: 2-drug dosing with MK-8591A) to allow participants in Part 3 receiving the selected dose of MK-8591 in combination with DOR QD or MK-1439A in the control group to switch to a 2-drug fixed-dose combination (FDC) of MK-8591/DOR (referred to as MK-8591A) QD in Part 4, and to collect additional safety and efficacy data. MK-8591A was provided as open-label supplies. Additional site visits were added at Weeks 148, 156, 168, 180, and 192.
    27 Aug 2020
    Amendment 5: The primary purpose of the amendment was to remove the Week 120 interim analysis and to perform data analysis on an annual basis so that the next analysis would occur at Week 144.
    31 Jan 2022
    Amendment 6: The primary purpose of the amendment was to increase the frequency of monitoring of CD4+ T-cell and total lymphocyte counts and to specify the management of participants who meet protocol-defined decreases in CD4+ T-cell and/or total lymphocyte counts at the Week 192 visit in response to findings of decreases in CD4+ T-cell counts (in studies of participants with HIV) and lymphocytes (in studies of participants with or without HIV) in ISL clinical studies.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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