A Phase 3, Randomized, Active-Controlled, Open-Label Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in Participants With HIV-1 Who Are Virologically Suppressed on Antiretroviral Therapy
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT Number:
NCT05631093
Document Date:           07-Mar-2025
A Phase 3, Randomized, Active-Controlled, Open-
Label Clinical Study to Evaluate a Switch to Doravirine/
Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in 
Participants With HIV-1 Who Are Virologically 
Suppressed on Antiretroviral Therapy

PRODUCT: MK-8591A
1
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Active-Controlled, Open-Label Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in 
Participants With HIV-1 Who Are Virologically Suppressed on Antiretroviral Therapy
Protocol Number: 051-04
Compound Number: MK-8591A
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT05631093
EU CT
2022-502127-22-00
EudraCT
2022-502127-22
JRCT
jRCT2031220698
WHO
Not applicable
UTN
U1111-1283-3894
IND
134,036
Approval Date: 07 March 2025
08WX9K

PRODUCT: MK-8591A
2
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
08WX9K

PRODUCT: MK-8591A
3
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 4
07-MAR-2025
To add ECIs requiring expedited reporting to the 
Sponsor at the request of a health authority.
Amendment 3
08-AUG-2024
To extend the study from Week 96 to Week 144 
(base study) to provide additional safety and 
efficacy data, and to add an optional study 
extension with access to DOR/ISL up to Week 
240 or until commercially accessible (whichever 
comes first).
Amendment 2
27-OCT-2023
To provide for increased HIV-1 RNA 
monitoring during pregnancy (if recommended 
in local guidelines), to clarify the management 
of participants with decreases in total 
lymphocyte and in CD4+ T-cell counts and the 
management of participants with HIV-1 viremia.
Amendment 1
17-FEB-2023
This protocol amendment is applicable only 
to South Africa and participants entering 
study MK-8591A-051 from study MK-8591A-
020 on BIC/FTC/TAF as their ART regimen.
Because BIC/FTC/TAF is registered but not 
commercially available in South Africa, 
participants in South Africa randomized to 
Group 2 in study MK-8591A-051 will continue 
to receive MSD-supplied BIC/FTC/TAF as their 
ART regimen.
Original Protocol
18-OCT-2022
Not applicable
08WX9K

PRODUCT: MK-8591A
4
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendment:
To add ECIs requiring expedited reporting to the Sponsor at the request of a health authority.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 8.4.7 
Events of Clinical 
Interest
Added 2 study-specific ECIs for elevated liver-
related laboratory values for Group 2 
participants during the first 48 weeks of 
DOR/ISL treatment that are to be reported to 
the Sponsor within 24 hours of learning of the 
event.
Health authority/agency feedback requiring these 
changes.
Section Number and Name
Description of Change
Brief Rationale
Additional Changes
Section 8.4.1 Time Period and 
Frequency for Collecting AE, 
SAE, and Other Reportable 
Safety Event Information
Table 5: Updated table to reflect that 
potential or confirmed DILI would be 
reported as SAE with OME criteria in the 
absence of other serious criteria.
To maintain continued regulatory 
reporting compliance in alignment 
with new Health Authority DILI 
reporting requirements
Section 8.4.3 Follow-up of AE, 
SAE, and Other Reportable 
Safety Event Information
Specified that reportable safety events 
include potential DILI or confirmed DILI.
See rationale for Section 8.4.1.
Section 8.4.7 Events of Clinical 
Interest
Initial ECI updated to potential DILI or 
confirmed DILI events, with associated 
reporting requirements.
See rationale for Section 8.4.1.
Section 10.1.6 Compliance with 
Study Registration and Results 
Posting Requirements
Added statement that a summary of the 
study results will be submitted.
For compliance with the EU Clinical 
Trials Regulation 536/2014.
Section 10.3.3 Definition of 
SAE
Added potential DILI or confirmed DILI to 
the definition of SAE with OME criteria in 
the absence of other serious criteria.
See rationale for Section 8.4.1.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
08WX9K

PRODUCT: MK-8591A
5
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................22
1.3.1
Schedule of Activities – Screening Through Week 144 – Open-Label 
Intervention (Base Study) ............................................................................22
1.3.2
Schedule of Activities – Viremia Confirmation and End of Treatment 
for Participants With Viremia (Except Those With Specified Decreases 
in Total Lymphocyte Count and/or CD4+ T-cell Count) ............................34
1.3.3
Schedule of Activities for Participants Who Meet the Discontinuation 
Criteria for Specified Decreases in Total Lymphocyte Count or CD4+ 
T-cell Count .................................................................................................38
1.3.4
Schedule of Activities for Participants Whose Pregnancy or Postpartum 
Visit(s) Extends Beyond Week 144.............................................................46
1.3.5
Schedule of Activities –Week 144 Through Week 240 (Optional Study 
Extension) ....................................................................................................48
2
INTRODUCTION..........................................................................................................51
2.1
Study Rationale....................................................................................................51
2.2
Background ..........................................................................................................51
2.2.1
Islatravir.......................................................................................................51
2.2.2
Doravirine ....................................................................................................52
2.2.3
Doravirine/Islatravir.....................................................................................52
2.2.4
Information on Other Study-related Therapy ..............................................53
2.3
Benefit/Risk Assessment......................................................................................53
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................56
4
STUDY DESIGN............................................................................................................62
4.1
Overall Design......................................................................................................62
4.2
Scientific Rationale for Study Design.................................................................63
4.2.1
Rationale for Endpoints ...............................................................................64
4.2.1.1
Efficacy Endpoints.............................................................................64
4.2.1.1.1
HIV-1 RNA Measurements .....................................................64
4.2.1.1.2
Definition of Clinically Significant Confirmed Viremia.........64
4.2.1.2
Safety Endpoints................................................................................65
4.2.1.3
Weight and Laboratory Markers........................................................65
4.2.1.4
Pharmacokinetic Endpoints ...............................................................66
4.2.1.5
Patient-reported Outcomes.................................................................66
08WX9K

PRODUCT: MK-8591A
6
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
4.2.1.6
Planned Exploratory Biomarker Research.........................................67
4.2.1.6.1
Planned Genetic Analysis ........................................................67
4.2.1.7
Future Biomedical Research..............................................................67
4.2.2
Rationale for the Use of Comparator...........................................................67
4.2.3
Rationale for the Selected Participant Population .......................................68
4.2.4
Rationale for Collecting Race and Ethnicity Data.......................................68
4.2.5
Rationale for Collecting Gender Identity Data ............................................69
4.2.6
Rationale for Infant Safety Data Collection.................................................69
4.2.7
Rationale for Continuing Study Intervention During Pregnancy ................69
4.2.8
Rationale for Collecting Alcohol and Tobacco Use ....................................70
4.3
Justification for Dose...........................................................................................70
4.4
Beginning and End-of-Study Definition ............................................................71
4.4.1
Clinical Criteria for Early Study Termination .............................................71
5
STUDY POPULATION ................................................................................................72
5.1
Inclusion Criteria.................................................................................................72
5.2
Exclusion Criteria................................................................................................73
5.3
Lifestyle Considerations......................................................................................76
5.4
Screen Failures.....................................................................................................76
5.5
Participant Replacement Strategy......................................................................76
6
STUDY INTERVENTION............................................................................................77
6.1
Study Intervention(s) Administered...................................................................77
6.2
Preparation/Handling/Storage/Accountability .................................................80
6.2.1
Dose Preparation..........................................................................................80
6.2.2
Handling, Storage, and Accountability........................................................80
6.3
Measures to Minimize Bias: Randomization and Blinding..............................81
6.3.1
Intervention Assignment..............................................................................81
6.3.2
Stratification.................................................................................................81
6.3.3
Blinding........................................................................................................81
6.4
Study Intervention Compliance..........................................................................81
6.5
Concomitant Therapy..........................................................................................82
6.5.1
Rescue Medications and Supportive Care ...................................................84
6.6
Dose Modification (Escalation/Titration/Other)...............................................84
6.7
Intervention After the End of the Study............................................................84
6.8
Clinical Supplies Disclosure................................................................................84
6.9
Standard Policies..................................................................................................84
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................85
7.1
Discontinuation of Study Intervention...............................................................85
08WX9K

PRODUCT: MK-8591A
7
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
7.2
Participant Withdrawal From the Study...........................................................86
7.3
Lost to Follow-up .................................................................................................87
8
STUDY ASSESSMENTS AND PROCEDURES........................................................88
8.1
Administrative and General Procedures ...........................................................88
8.1.1
Informed Consent.........................................................................................88
8.1.1.1
General Informed Consent.................................................................89
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................89
8.1.1.3
Consent for Continuation of Study Intervention During 
Pregnancy...........................................................................................89
8.1.1.4
Consent for Postnatal Infant Safety Data Collection Through One 
Year of Age........................................................................................90
8.1.1.5
Consent for Optional Study Extension ..............................................90
8.1.2
Inclusion/Exclusion Criteria ........................................................................90
8.1.3
Participant Identification Card.....................................................................90
8.1.4
Medical History ...........................................................................................90
8.1.5
Prior and Concomitant Medications Review...............................................91
8.1.5.1
Prior Medications...............................................................................91
8.1.5.2
Concomitant Medications..................................................................91
8.1.6
Assignment of Screening Number...............................................................91
8.1.7
Assignment of Randomization Number.......................................................91
8.1.8
Study Intervention Administration ..............................................................91
8.1.8.1
Timing of Dose Administration.........................................................92
8.1.9
Discontinuation and Withdrawal .................................................................92
8.1.9.1
Withdrawal From Future Biomedical Research ................................93
8.1.10
Participant Blinding/Unblinding..................................................................93
8.1.11
Calibration of Equipment.............................................................................93
8.2
Efficacy Assessments ...........................................................................................94
8.2.1
HIV-1 RNA..................................................................................................94
8.2.2
Management of Participants With Viremia .................................................94
8.2.2.1
Viremia Confirmation........................................................................94
8.2.2.1.1
Participants With Clinically Significant Confirmed Viremia 
(≥200 Copies/mL)....................................................................94
8.2.2.1.2
HIV-1 Viral Drug Resistance Testing......................................95
8.2.2.1.3
Participants With Low-level Viremia (≥50 and 
<200 Copies/mL) .....................................................................95
8.2.3
T and B Lymphocyte and Natural Killer Cell (TBNK) Profile ...................95
8.3
Safety Assessments...............................................................................................95
8.3.1
Physical Examinations.................................................................................96
08WX9K

PRODUCT: MK-8591A
8
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.3.1.1
Weight................................................................................................96
8.3.2
Vital Signs....................................................................................................96
8.3.3
Electrocardiograms ......................................................................................96
8.3.4
Confirmation of Contraception and Pregnancy Testing ..............................97
8.3.5
Clinical Safety Laboratory Assessments .....................................................97
8.3.6
HBV Assessments........................................................................................98
8.3.7
HCV Assessment .........................................................................................99
8.3.8
Tobacco and Alcohol Assessments..............................................................99
8.3.9
Exploratory Clinical Marker Assessments...................................................99
8.3.9.1
Fasting Lipid and Metabolic Profiles.................................................99
8.3.9.2
Renal Function.................................................................................100
8.3.9.3
Waist and Hip Measurements..........................................................100
8.3.10
Administration of Patient Questionnaires..................................................100
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................100
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................101
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....103
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.103
8.4.4
Regulatory Reporting Requirements for SAE ...........................................104
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................104
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................104
8.4.7
Events of Clinical Interest..........................................................................104
8.5
Treatment of Overdose......................................................................................105
8.6
Pharmacokinetics...............................................................................................106
8.6.1
Blood Collection for Plasma ISL...............................................................106
8.7
Pharmacodynamics............................................................................................107
8.8
Biomarkers .........................................................................................................107
8.8.1
Planned Genetic Analysis Sample Collection............................................107
8.9
Future Biomedical Research Sample Collection.............................................107
8.10
Health Economics and Medical Resource Utilization and Health 
Economics...........................................................................................................107
8.11
Visit Requirements.............................................................................................107
8.11.1
Screening/Rescreening...............................................................................108
8.11.1.1
Screening..........................................................................................108
8.11.1.2
Rescreening......................................................................................108
8.11.2
Treatment Period........................................................................................108
8.11.2.1
Fasting..............................................................................................108
08WX9K

PRODUCT: MK-8591A
9
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.11.2.2
Switch ..............................................................................................109
8.11.2.3
End-of-Base Study Week 144 Visit.................................................109
8.11.2.4
Optional Study Extension (Week 144 up to Week 240)..................109
8.11.3
Participants Who Discontinue Study Intervention.....................................110
8.11.3.1
Discontinuation of Treatment ..........................................................111
8.11.3.2
End of Treatment Follow-up............................................................111
8.11.4
Viremia Confirmation................................................................................111
8.11.5
Management of Participants With Specified Decreases in Total 
Lymphocyte Count or CD4+ T-cell Count................................................111
8.11.6
Clinical Management of Participants Who Become Pregnant...................112
8.11.6.1
Continuing Study Intervention in Pregnancy...................................113
8.11.6.1.1
Collection of Population PK Samples During Pregnancy 
and Postpartum (Participants Continuing DOR/ISL Only) ...114
8.11.6.2
Discontinuing Study Intervention for Pregnancy ............................115
8.11.6.3
Participants Who Choose to Breastfeed...........................................116
8.11.6.4
Infant Safety Data Collection...........................................................116
8.11.6.4.1
Schedule of Activities: Infant Safety Data Collection...........116
9
STATISTICAL ANALYSIS PLAN ...........................................................................117
9.1
Statistical Analysis Plan Summary...................................................................117
9.2
Responsibility for Analyses/In-house Blinding ...............................................119
9.3
Hypotheses/Estimation ......................................................................................119
9.4
Analysis Endpoints.............................................................................................119
9.4.1
Efficacy/Pharmacokinetics Endpoints .......................................................119
9.4.1.1
Efficacy Endpoints...........................................................................119
9.4.1.2
Pharmacokinetic Endpoints .............................................................121
9.4.2
Safety Endpoints........................................................................................121
9.4.3
Patient-reported Outcome Endpoints.........................................................123
9.5
Analysis Populations..........................................................................................123
9.5.1
Efficacy Analysis Populations...................................................................123
9.5.2
Safety Analysis Populations ......................................................................125
9.6
Statistical Methods.............................................................................................125
9.6.1
Statistical Methods for Efficacy Analyses.................................................126
9.6.2
Statistical Methods for Safety Analyses ....................................................134
9.6.2.1
Overall Safety Assessment ..............................................................135
9.6.2.2
Assessment of Safety Topics of Special Interest .............................136
9.6.2.3
Handling of Missing Data and Pregnancies in Safety Analyses......137
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................139
9.6.3.1
Demographic and Baseline Characteristics .....................................139
08WX9K

PRODUCT: MK-8591A
10
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
9.7
Interim Analyses ................................................................................................139
9.8
Multiplicity .........................................................................................................141
9.9
Sample Size and Power Calculations ...............................................................143
9.9.1
Sample Size and Power for Efficacy Analyses..........................................143
9.9.1.1
Evaluation of the Primary Hypothesis.............................................143
9.9.1.2
Evaluation of the Futility Criterion and Non-inferiority at 
Week 48 ...........................................................................................145
9.9.2
Sample Size and Power for Safety Analyses .............................................149
9.9.2.1
Evaluation of Adverse Events..........................................................149
9.9.2.2
Evaluation of Change from Baseline in Lipid Profiles....................151
9.10
Subgroup Analyses.............................................................................................153
9.11
Compliance (Medication Adherence)...............................................................153
9.12
Extent of Exposure.............................................................................................154
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................155
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......155
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................155
10.1.2
Financial Disclosure...................................................................................158
10.1.3
Data Protection...........................................................................................159
10.1.3.1
Confidentiality of Data ....................................................................159
10.1.3.2
Confidentiality of Participant Records.............................................159
10.1.3.3
Confidentiality of IRB/IEC Information..........................................160
10.1.4
Committees Structure.................................................................................160
10.1.4.1
Executive Oversight Committee......................................................160
10.1.4.2
External Data Monitoring Committee .............................................160
10.1.4.3
Scientific Advisory Committee (SAC)............................................160
10.1.5
Publication Policy......................................................................................161
10.1.6
Compliance with Study Registration and Results Posting Requirements .161
10.1.7
Compliance with Law, Audit, and Debarment ..........................................161
10.1.8
Data Quality Assurance .............................................................................162
10.1.9
Source Documents .....................................................................................163
10.1.10
Study and Site Closure...............................................................................163
10.2
Appendix 2: Clinical Laboratory Tests............................................................164
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................173
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................173
10.3.2
Definition of AE ........................................................................................173
10.3.3
Definition of SAE ......................................................................................174
10.3.4
Additional Events Reported.......................................................................175
08WX9K

PRODUCT: MK-8591A
11
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.3.5
Recording AE and SAE .............................................................................176
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................179
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................180
10.5
Appendix 5: Contraceptive Guidance..............................................................181
10.5.1
Definitions..................................................................................................181
10.5.2
Contraceptive Requirements......................................................................182
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................184
10.7
Appendix 7: Country-specific Requirements..................................................188
10.7.1
Country-specific Request for Japan...........................................................188
10.7.2
Country-specific Request for Canada ........................................................188
10.7.3
Country-specific Request for South Africa................................................188
10.8
Appendix 8: Calculation of Creatinine Clearance and eGFR .......................189
10.8.1
Cockcroft-Gault Equations ........................................................................189
10.8.2
MDRD Equations.......................................................................................189
10.9
Appendix 9: AIDS-defining Opportunistic Infections that Require 
Discontinuation of Study Intervention.............................................................190
10.10 Appendix 10: Approved HIV-1 RNA Quantification Assays for Local 
Viral Load Monitoring ......................................................................................191
10.11 Appendix 11: Abbreviations .............................................................................192
11
REFERENCES.............................................................................................................198
08WX9K

PRODUCT: MK-8591A
12
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
LIST OF TABLES
Table 1
Laboratory Exclusion Criteria..........................................................................75
Table 2
Study Interventions..........................................................................................78
Table 3
Prohibited Therapies ........................................................................................83
Table 4
Discontinuation Criteria for Specified Decreases in Total Lymphocyte 
Counts or CD4+ T-cell Counts ........................................................................86
Table 5
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................102
Table 6
Collection of Population PK Samples............................................................106
Table 7
Collection of Population PK Samples During Pregnancy and Postpartum ...115
Table 8
Definitions of Study Time Points ..................................................................127
Table 9
Analysis Strategy for Key Efficacy Variables...............................................134
Table 10
Analysis Strategy for Safety Parameters........................................................138
Table 11
Initial Alpha Allocation Based on PI Stratum Sample Size ..........................143
Table 12
Power (%) to Establish Non-inferiority at Week 48 Under Various 
Response Rate Assumptions..........................................................................144
Table 13
Probability of Not Meeting the Futility Criterion at the Week 24 Interim 
Analysis..........................................................................................................145
Table 14
Probability of Not Meeting the Futility Criterion at the Week 24 Interim 
Analysis and the Conditional Power to Declare Non-inferiority at Week 48 
for Various Underlying True Response Rates ...............................................147
Table 15
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Numbers of Participants With AEs.....................................150
Table 16
Difference in Incidence (Percentage Points) of AEs (Group 1 Minus 
Group 2) That Can Be Ruled Out With 334 Participants in Group 1 and 
167 Participants in Group 2 ...........................................................................151
Table 17
Power to Establish Superiority of Group 1 to Group 2 as Assessed by the 
Mean Change from Baseline in LDL-C/non-HDL-C at Week 48 Under 
Various Assumed Treatment Differences, Standard Deviations, and 
Numbers of Participants in Each Treatment Group.......................................152
Table 18
Protocol-required Laboratory Assessments...................................................165
Table 19
Blood Volumes (Efficacy, Safety, and PK) in the Base Study......................167
Table 20
Blood Volumes (Genetic Analysis and FBR) in the Base Study...................170
Table 21
Blood Volumes (Efficacy, Safety, and PK) in the Optional Study 
Extension........................................................................................................171
Table 22
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) 
Extends Beyond Week 144 (Efficacy, Safety, and PK).................................172
Table 23
Approved HIV-1 RNA Quantification Assays for Local Viral Load 
Monitoring .....................................................................................................191
08WX9K

PRODUCT: MK-8591A
13
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan ..................................................................21
Figure 2
Multiplicity Graph for Type I Error Control of the Secondary Hypothesis ..142
08WX9K

PRODUCT: MK-8591A
14
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Active-Controlled, Open-Label Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in 
Participants With HIV-1 Who Are Virologically Suppressed on Antiretroviral Therapy
Short Title: DOR/ISL 100 mg/0.25 mg QD Open-Label Switch
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants ≥18 years of age with HIV-1 who 
have been virologically suppressed (ie, HIV-1 RNA <50 copies/mL) for ≥3 consecutive 
months on a stable oral 2- or 3-drug combination (± PK booster) ART.
Primary Objective
Primary Endpoint
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48
Hypothesis (H1): DOR/ISL is non-inferior 
to continued baseline ART, as assessed by 
the percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 48. A margin 
of 4 percentage points is used to define 
non-inferiority.
HIV-1 RNA
To evaluate the safety and tolerability of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by 
review of the safety data accumulated 
through Week 48
Adverse events
Adverse events leading to discontinuation
of study intervention
08WX9K

PRODUCT: MK-8591A
15
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Secondary Objectives
Secondary Endpoints
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by the 
percentage of participants with the 
following at Week 48:
•
HIV-1 RNA <200 copies/mL
•
HIV-1 RNA <50 copies/mL
HIV-1 RNA
To evaluate the antiretroviral activity of a 
switch to DOR/ISL in participants who 
switched from baseline ART to DOR/ISL 
on Day 1, as assessed by the percentage of 
participants with the following at Week 96 
and Week 144:
•
HIV-1 RNA ≥50 copies/mL
•
HIV-1 RNA <200 copies/mL
•
HIV-1 RNA <50 copies/mL
HIV-1 RNA
To evaluate the antiretroviral activity of a 
switch to DOR/ISL in participants who 
continued baseline ART and switched to 
DOR/ISL at Week 48, as assessed by the 
percentage of participants with the 
following at Week 96 and Week 144:
•
HIV-1 RNA ≥50 copies/mL
•
HIV-1 RNA <200 copies/mL
•
HIV-1 RNA <50 copies/mL
HIV-1 RNA
To evaluate the immunologic effect of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by the 
mean change from baseline in CD4+ T-cell 
count at Week 48
CD4+ T-cell count
08WX9K

PRODUCT: MK-8591A
16
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
To evaluate the immunologic effect of a 
switch to DOR/ISL, as assessed by the 
mean change in CD4+ T-cell count:
•
From baseline (Day 1) to Week 96 and 
from Week 48 to Week 96 in 
participants who switched from baseline 
ART to DOR/ISL on Day 1
•
From baseline (Day 1) to Week 144 and 
from Week 48 to Week 144 in 
participants who switched from baseline 
ART to DOR/ISL on Day 1
•
From Week 48 to Week 96 in 
participants who continued baseline 
ART and switched to DOR/ISL at 
Week 48 
•
From Week 48 to Week 144 in 
participants who continued baseline 
ART and switched to DOR/ISL at Week 
48 
CD4+ T-cell count
To evaluate the development of viral drug 
resistance to any study intervention at 
Week 48, Week 96, and Week 144
Viral resistance-associated substitutions
To evaluate the effect on fasting LDL-C and 
non-HDL-C of a switch to DOR/ISL 
compared with continued baseline ART by 
baseline ART class (PI- containing
regimens [including PI- + InSTI-containing 
regimens], InSTI-containing regimens [non-
PI-containing regimens], and non-PI- and 
non-InSTI-containing regimens), as 
assessed by the mean change in fasting 
LDL-C and non-HDL-C from baseline to 
Week 48
If non-inferiority of DOR/ISL to continued 
baseline ART at Week 48 (H1) is met, the 
following hypothesis will be tested for each 
parameter within each stratum:
Fasting LDL-C and non-HDL-C
08WX9K

PRODUCT: MK-8591A
17
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Hypothesis (H2): DOR/ISL is superior to 
continued baseline ART in each baseline 
ART stratum (in the order of: PI-containing 
regimens [including PI- + InSTI-containing 
regimens], non-PI- and non-InSTI-
containing regimens, and InSTI-containing 
regimens [non-PI-containing regimens]), as 
assessed by the mean change from baseline 
in fasting LDL-C and non-HDL-C at 
Week 48.
To evaluate the safety and tolerability of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by 
review of the safety data accumulated 
through Week 144:
•
From baseline (Day 1) through Week 96 
and from Week 48 through Week 96 in 
participants who switched from baseline 
ART to DOR/ISL on Day 1
•
From baseline (Day 1) through Week 
144 and from Week 48 through Week 
144 in participants who switched from 
baseline ART to DOR/ISL on Day 1
•
From Week 48 through Week 96 in 
participants who continued baseline 
ART and switched to DOR/ISL at 
Week 48
•
From Week 48 through Week 144 in 
participants who continued baseline 
ART and switched to DOR/ISL at 
Week 48
Adverse events
Adverse events leading to discontinuation 
of study intervention
08WX9K

PRODUCT: MK-8591A
18
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
HIV infection
Population
Participants ≥18 years of age with HIV-1 
who have been virologically suppressed for 
≥3 consecutive months on a stable oral 
2-drug or 3-drug combination (± PK 
booster) ART
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 6 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 501 participants will be randomized.
08WX9K

PRODUCT: MK-8591A
19
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
Group 1
doravirine/
islatravir
100 mg/
0.25 mg
100 mg/
0.25 mg QD
Oral
Day 1 to 
Week 144
Test Product
Group1
doravirine/
islatravir
100 mg/
0.25 mg
100 mg/
0.25 mg QD
Oral
Week 144 
up to Week 
240
Test Product
Group 2
Baseline 
antiretroviral 
therapy 
regimen
Per Approved 
Product Label
Per Approved 
Product Label
Oral
Day 1 to 
Week 48
Comparator
Group 2
Baseline 
antiretroviral 
therapy 
regimen 
(bictegravir/
emtricitabine/
tenofovir 
alafenamide 
only)
Per Approved 
Product Label
Per Approved 
Product Label
Oral
Day 1 to 
Week 48
Comparator
Group 2
doravirine/
islatravir
100 mg/
0.25 mg
100 mg/
0.25 mg QD
Oral
Week 48 to 
Week 144
Test Product
Group 2
doravirine/
islatravir
100 mg/
0.25 mg
100 mg/
0.25 mg QD
Oral
Week 144 
up to Week 
240
Test Product
QD=once-daily
Note: Applicable only to South Africa. The Sponsor will centrally supply 
bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as active comparator for 
participants in South Africa to continue receiving BIC/FTC/TAF as their ART regimen (ie, 
participants receiving BIC/FTC/TAF in study MK-8591A-020 who enroll in studyMK-
8591A-051 and are randomized to Group 2).
Allowed drug classes for baseline ART regimen include NRTIs, NNRTIs, PIs, InSTIs, and 
PK boosters.
The Sponsor will not provide baseline ART medications for participants continuing their 
baseline ART regimens. Participants will provide their own ART medications, in accordance 
with local regulations. Country-specific requirements are noted in Appendix 7.
Study intervention will be extended for participants who become pregnant on-treatment and 
provide documented informed consent to continue their assigned study intervention 
(DOR/ISL or baseline ART), as specified in Sections 1.3.4 and 8.11.6.
08WX9K

PRODUCT: MK-8591A
20
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the base 
study for approximately 3 years from the 
time the participant provides documented 
informed consent through the final contact. 
After a screening phase of up to 45 days, 
each participant will receive assigned open-
label study intervention for approximately 
48 weeks. After 48 weeks of the assigned 
therapy, all participants will receive open-
label DOR/ISL through Week 144. After 
Week 144, participants will be given the 
option to continue in an optional study 
extension and receive DOR/ISL for up to an 
additional 96 weeks or until DOR/ISL is 
commercially accessible (whichever comes 
first). Participants who discontinue study 
intervention or who become pregnant will 
be followed as described in the protocol.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 11.
08WX9K

PRODUCT: MK-8591A
21
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema and Treatment Plan
bART=baseline antiretroviral therapy; DOR=doravirine; ISL=islatravir; N=total number of participants in the 
study; n=number of participants in the intervention group.
a
Participants are expected to enroll as soon as possible after eligibility is confirmed. In cases of unexpected 
delays in receiving repeat screening laboratory results, a screening period of up to 45 days is allowed.
b
For participants who continue optional study extension, study visits will occur every 24 weeks.
08WX9K

PRODUCT: MK-8591A
22
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
1.3
Schedule of Activities
1.3.1
Schedule of Activities – Screening Through Week 144 – Open-Label Intervention (Base Study)
This SoA applies to all participants in the base study. Manage pregnant participants per Section 8.11.6. For the optional study 
extension, see Sections 8.11.2.4 and Section 1.3.5 (SoA).
•
The Early Discontinuation of Treatment Visit applies to any participant who discontinues study intervention prior to Week 144
(Section 8.11.3). 
•
Manage participants with viremia per Section 8.11.4 and Section 1.3.2 (SoA). 
•
Manage participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 and Section 1.3.3 
(SoA). 
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Administrative Procedures
Informed Consent
X
Informed Consent 
for Future 
X
08WX9K

PRODUCT: MK-8591A
23
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Biomedical 
Research
Post-Base Study 
Disposition 
Planning
X
X
X
Proactively discuss prior 
to the Week 144 visit (see 
Section 8.11.2.2)
Informed Consent 
for Optional Study 
Extension
X
Obtain prior to 
dispensing study 
intervention at Week 144.
Informed Consent 
for DOR/ISL During 
Pregnancy
<---------------------------X--------------------------->
Obtain upon confirmation 
of pregnancy. See 
Section 8.1.1.3.
Collect and Enter 
Data From Prenatal 
Care Provider
<---------------------------X--------------------------->
See Section 8.11.6 for 
prenatal safety 
monitoring.
Informed Consent 
for Infant Data 
Safety Collection
<---------------------------X--------------------------->
Obtain after confirmation 
of continuing pregnancy. 
See Sections 8.1.1.4 and 
8.11.6.4.
08WX9K

PRODUCT: MK-8591A
24
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Administration of 
EQ-5D-5L, 
HIVTSQ, and 
HIV-SI/SDM 
Patient 
Questionnaires
X
X
X
X
X
(X)
Administer in the order 
listed, before the 
participant is seen by the 
investigator and before 
discussing medical 
conditions or test results. 
(Do not administer after 
the Week 96 visit).
Inclusion/Exclusion 
Criteria
X
X
Review prior to 
randomization on Day 1 
to confirm eligibility.
Participant 
Identification Card
X
X
Site personnel will add 
treatment/randomization 
number.
Medical History
X
Tobacco and 
Alcohol 
Assessments
X
X
X
X
08WX9K

PRODUCT: MK-8591A
25
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Prior and 
Concomitant 
Medications Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register Study Visit 
in IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Intervention 
Randomization
X
All pretreatment 
procedures should be 
completed prior to 
randomization on Day 1.
Dispense DOR/ISL 
Using IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
(Dispense at Week 144 
for eligible participants 
entering the optional 
study extension and if 
needed for those whose 
pregnancy or Postpartum 
visit(s) extends past 
Week 144.)
08WX9K

PRODUCT: MK-8591A
26
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Study Intervention 
Compliance Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For participants whose 
pregnancy or Postpartum 
visit(s) extends past 
Week 144, see Section 
1.3.4.
Efficacy 
Procedures
Plasma HIV-1 RNA 
Quantification
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.1. See 
Section 8.11.6.1 for 
testing in participants 
who become pregnant.
Blood (Plasma) for 
HIV-1 Drug 
Resistance 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Analysis performed by 
Sponsor if indicated per 
Section 8.2.2.1.2.
Whole Blood for 
HIV-1 Viral Drug 
Resistance Testing
X
Analysis performed by 
Sponsor if indicated per 
Section 8.2.2.1.2.
TBNK Panel/CD4+ 
T-cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
08WX9K

PRODUCT: MK-8591A
27
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Safety Procedures
Full Physical 
Examination
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Local 12-lead ECG
X
Perform up to 7 days 
prior to Day 1 and after 
all other eligibility 
criteria are confirmed.
Contraceptive Use 
Confirmation 
(POCBP Only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception is required 
for 42 days after the last 
dose of study intervention 
(see Section 8.3.4).
Serum Pregnancy 
Test (hCG) 
(POCBP Only)
X
A highly sensitive urine 
pregnancy test may be 
performed instead of 
serum. See Section 5.1.
08WX9K

PRODUCT: MK-8591A
28
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Urine Pregnancy 
Test (hCG) 
(POCBP Only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy must be 
excluded on Day 1 before 
randomization. Confirm 
positive or indeterminant 
urine test with serum. 
HIV-1 and HIV-2 
Serology
X
Hepatitis B Serology 
and HBV DNA
X
X
X
X
Repeat serology and 
HBV DNA testing at 
Weeks 48, 96, and 144. 
Encourage HBV 
vaccination to 
participants who are not 
immune to HBV. 
HBsAg and HBV 
DNA (Group 1)
(X)
(X
)
(X
)
(X
)
(X
)
(X
)
(X
)
(X
)
(X
)
(X
)
(X
)
(X)
(Only anti-HBc-positive 
participants at each visit. 
See Section 8.3.6.)
08WX9K

PRODUCT: MK-8591A
29
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
HBsAg and HBV 
DNA
(Group 2)
(X
)
(X
)
(X)
(X
)
(X
)
(X
)
(X
)
(X
)
(X)
(Only anti-HBc-positive 
participants at each visit 
[starting at Week 36 for 
Group 2]).
Hepatitis B Serology 
and HBV DNA in 
Pregnant 
Participants 
(DOR/ISL only)
<--------------------------------(X)-------------------------------->
Collect once after 
pregnancy is confirmed 
or report local laboratory 
results. See 
Section 8.11.6.1.
Hepatitis C Serology
X
See Section 8.3.7. Repeat 
screening if indicated per 
local standard of care.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting required at Day 1 
and Weeks 24, 48, 96, 
and 144 (see 
Section 8.3.9.1 and 
Appendix 2). Pregnant 
participants should not 
fast. 
08WX9K

PRODUCT: MK-8591A
30
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Manage participants who 
meet the discontinuation 
criteria for total 
lymphocyte count 
(Table 4) per 
Sections 1.3.3 and 8.11.5.
PT/INR
X
Urinalysis
X
X
X
X
X
X
X
X
AE/SAE Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for 
ISL PK
X
X
X
X
X
For Group 1 only. At 
Week 4, if daytime 
dosing, obtain pre- and 
postdose or, if evening 
dosing, collect only 1 
sample irrespective of 
time of last dose. See 
Section 8.6.1 (Table 6).
08WX9K

PRODUCT: MK-8591A
31
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Blood (Plasma) for 
Investigational ISL 
PK (Group 1)
X
X
X
X
X
See Section 8.6.1.
Blood (Plasma) for 
Investigational ISL 
PK (Group 2)
X
X
X
X
X
See Section 8.6.1.
Blood (Plasma) for 
DOR and ISL PK in 
Pregnant 
Participants 
(DOR/ISL only)
<-----------------------------X----------------------------->
X
Collect during the 1st, 
2nd, and 3rd trimesters 
and postpartum. See 
Section 8.11.6.1 
(Table 7).
Exploratory 
Clinical Markers
Waist and Hip 
Measurements
X
X
X
X
Not applicable to 
pregnant participants.
Blood and Urine for 
Renal Markers
X
X
X
X
X
Blood for Energy 
and Metabolism 
Markers
X
X
X
X
X
Do not collect during 
pregnancy.
08WX9K

PRODUCT: MK-8591A
32
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screeninga
DOR/ISL or
Baseline ART 
Regimen 
(Base Study)
DOR/ISL 
(Base Study)
End of Treatment
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14
15
16
Unscheduled
Scheduled 
Day/Week
Screening
Day 1 (Fasting)
Week 4
Week 12
Week 24 (Fasting)
Week 36
Week 48 (Fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96 (Fasting)
Week 108
Week 120 
Week 132
Week 144 (Fasting)
Early 
Discontinu
ation of 
Treatmentb
End of 
Treatment 
Follow-Up
(Base Study)
Visit Window
≤45 
days
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) days 
after end of 
treatment
Biomarkers
Blood for Genetic 
Analysisc
X
Collect predose. See 
Section 8.8.1.
Whole Blood for 
FBR
X
X
X
X
X
X
X
Optional participation; 
requires FBR consent. 
Collect Day 1 sample 
predose; remaining 
samples may be collected 
at any time irrespective of 
last dose.
08WX9K

PRODUCT: MK-8591A
33
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
AE=adverse event; anti-HBc=hepatitis B core antibody; ART=antiretroviral therapy; DNA=deoxyribonucleic acid; DOR=doravirine; ECG=electrocardiogram; EQ-5D-
5L=EuroQol 5-dimensional descriptive system, 5-level version; FBR=future biomedical research; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; hCG=human 
chorionic gonadotropin; HIV-1=human immunodeficiency virus type 1; HIV-2=human immunodeficiency virus type 2; HIV-SI/SDM=Human Immunodeficiency Virus 
Symptom Index/Symptom Distress Module; HIVTSQ=Human Immunodeficiency Virus Treatment Satisfaction Questionnaire; INR=international normalized ratio; 
IRT=Interactive Response Technology; ISL=islatravir; NA=not applicable; PK=pharmacokinetic(s); POCBP=participant/participants of childbearing potential; PT=prothrombin 
time; RNA=ribonucleic acid; SAE=serious adverse event; TBNK=T and B Lymphocyte and Natural Killer Cell.
a Participants are expected to enroll as soon as possible after eligibility is confirmed. In cases of unexpected delays in receiving repeat screening laboratory results, a screening 
period of up to 45 days is allowed.
b Participants discontinued at a Scheduled Visit, should complete the assessments for the Scheduled Visit as well as for the Early Discontinuation of Treatment Visit. Collection 
of laboratory samples should not be duplicated.
c This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if there is 
either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover 
extracted DNA will be stored for FBR if the participant (or their legally acceptable representative) provides documented informed consent for FBR. If the planned genetic 
analyses are not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
08WX9K

PRODUCT: MK-8591A
34
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
1.3.2
Schedule of Activities – Viremia Confirmation and End of Treatment for Participants With Viremia (Except Those 
With Specified Decreases in Total Lymphocyte Count and/or CD4+ T-cell Count)
This SoA only applies to participants requiring viremia confirmation in the base study and/or optional study extension. 
•
Clinically significant confirmed viremia requires discontinuation (Sections 8.2.2.1.1 and 8.11.4). 
•
Manage participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 and Section 1.3.3 
(SoA).
Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of Treatment 
Follow-up
(Optional Study 
Extension)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after 
the end of 
treatment
NA
42 (+7) days after 
the end of 
treatment
Administrative 
Procedures
Prior and 
Concomitant 
Medications 
Review
X
X
X
X
X
Register Study 
Visit in IRT
X
X
X
Study Intervention 
Compliance 
Review
X
X
08WX9K

PRODUCT: MK-8591A
35
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of Treatment 
Follow-up
(Optional Study 
Extension)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after 
the end of 
treatment
NA
42 (+7) days after 
the end of 
treatment
Administration of 
EQ-5D-5L, 
HIVTSQ, and 
HIV-SI/SDM 
Patient 
Questionnaires
(X)
Administer in the order 
listed, before participant is 
seen by the investigator and 
before discussing medical 
conditions or test results. (Do 
not administer after Week 96 
visit.)
Efficacy 
Procedures
Plasma HIV-1 
RNA 
Quantification
X
X
X
X
X
See Section 8.2.1. 
Plasma for HIV-1 
Drug Resistance
X
(X)
(X)
(Do not collect at 
Discontinuation of Treatment 
visit if collected at the 
Viremia Confirmation visit.) 
Analysis performed by 
Sponsor if indicated per 
Section 8.2.2.1.2.
TBNK Panel/CD4+ 
T-cell Count
X
X
Safety Procedures
Full Physical 
Examination
X
08WX9K

PRODUCT: MK-8591A
36
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of Treatment 
Follow-up
(Optional Study 
Extension)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after 
the end of 
treatment
NA
42 (+7) days after 
the end of 
treatment
Directed Physical 
Examination
X
X
X
Weight
X
X
Vital Signs
X
X
Contraceptive Use 
Confirmation 
(POCBP Only)
X
X
X
X
X
Contraception is required 42 
days after the last dose of 
study intervention (Section 
8.3.4).
Urine Pregnancy 
Test (hCG) 
(POCBP Only)
X
X
X
X
X
Confirm positive or 
indeterminant urine test with 
serum. If positive, manage 
participant per 
Section 8.11.6. For 
participants known to be 
pregnant, defer until 6 weeks 
postpartum.
Chemistry
X
Hematology
X
X
Urinalysis
X
AE/SAE Review
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for 
Investigational ISL 
(and DOR, if 
applicable) PK
X
X
Do not collect during 
pregnancy. Analysis 
performed by Sponsor as 
needed. See Section 8.6.1. 
08WX9K

PRODUCT: MK-8591A
37
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of Treatment 
Follow-up
(Optional Study 
Extension)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after 
the end of 
treatment
NA
42 (+7) days after 
the end of 
treatment
Blood (Plasma) for 
DOR and ISL PK
X
X
X
Only for pregnant 
participants on DOR/ISL. 
Collect irrespective of time 
of last dose and record time 
of last dose of study 
intervention in appropriate 
source documentation.
Biomarkers
Whole Blood for 
FBR
X
(X)
Optional participation; 
requires FBR consent. 
Collect irrespective of time 
of last dose. (If collected at 
preceding Viremia 
Confirmation visit, do not 
collect at Early 
Discontinuation of Treatment 
visit.)
AE=adverse event; EQ-5D-5L=EuroQol 5-dimensional descriptive system, 5-level version; FBR=future biomedical research; hCG=human chorionic gonadotropin; HIV-
1=human immunodeficiency virus type 1; HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/Symptom Distress Module; HIVTSQ=Human Immunodeficiency 
Virus Treatment Satisfaction Questionnaire; IRT=Interactive Response Technology; ISL=islatravir; NA=not applicable; PK=pharmacokinetic(s); 
POCBP=participant/participants of childbearing potential; RNA=ribonucleic acid; SAE=serious adverse event; TBNK=T and B Lymphocyte and Natural Killer Cell.
a Participants who discontinue at a Scheduled Visit, should complete the assessments for the Scheduled Visit as well as for the Early Discontinuation of Treatment Visit. 
Collection of laboratory samples should not be duplicated.
08WX9K

PRODUCT: MK-8591A
38
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
1.3.3
Schedule of Activities for Participants Who Meet the Discontinuation Criteria for Specified Decreases in Total 
Lymphocyte Count or CD4+ T-cell Count
This SoA only applies to participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts in the base study and/or 
optional study extension. 
•
Manage participants with Viremia per Sections 8.2.2, Section 8.11.4 and Section 1.3.2 (SoA).
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
Administrative Procedures
Prior and 
Concomitant 
Medications 
Review
X
X
X
X
X
X
Register Study 
Visit in IRT
X
X
X
X
08WX9K

PRODUCT: MK-8591A
39
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
Study Intervention 
Compliance 
Review
X
X
Administration of 
EQ-5D-5L, 
HIVTSQ, and 
HIV-SI/SDM 
Patient 
Questionnaires
(X)
Administer in the 
order listed, before 
the participant is 
seen by the 
investigator and 
before discussing 
medical conditions 
or test results. (Do 
not administer after 
the Week 96 visit.)
08WX9K

PRODUCT: MK-8591A
40
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
Efficacy 
Procedures
Plasma HIV-1 
RNA 
Quantification
X
X
X
X
See Section 8.2.1.
Plasma for HIV-1 
Drug Resistance 
X
X
Analysis performed 
by Sponsor if 
indicated per 
Section 8.2.2.1.2.
TBNK 
Panel/CD4+ T-cell 
Count
X
X
X
X
X
X
Safety 
Procedures
Full Physical 
Examination
X
08WX9K

PRODUCT: MK-8591A
41
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
Directed Physical 
Examination
X
X
X
Weight
X
X
Vital Signs
X
X
Contraceptive Use 
Confirmation 
(POCBP Only)
X
X
X
X
Contraception is 
required for 42 days 
after the last dose of 
study intervention.
08WX9K

PRODUCT: MK-8591A
42
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
Urine Pregnancy 
Test (hCG) 
(POCBP Only)
X
X
X
X
Confirm positive or 
indeterminant urine 
test with serum. If 
positive, manage 
participant per 
Section 8.11.6. For 
participants known 
to be pregnant, defer 
until 6 weeks 
postpartum.
Chemistry
X
Hematology
X
X
X
X
X
X
Urinalysis
X
AE/SAE Review
X
X
X
X
X
X
08WX9K

PRODUCT: MK-8591A
43
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
Pharmacokinetics
Blood (Plasma) for 
Investigational 
ISL PK
X
X
Do not collect during 
pregnancy. Analysis 
performed by 
Sponsor as needed. 
See Section 8.6.1.
08WX9K

PRODUCT: MK-8591A
44
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
Biomarkers
Whole Blood for 
FBR
(X)
Optional 
participation; 
requires FBR 
consent. Collect 
irrespective of time 
of last dose. (If 
collected at 
preceding 
CD4/Lymph 
Confirmation visit, 
do not collect at 
Early 
Discontinuation of 
Treatment visit.)
08WX9K

PRODUCT: MK-8591A
45
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(Optional Study Extension)
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation of 
Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation of 
Treatment
(Optional Study 
Extension)
End of 
Treatment 
Follow-up
(Optional Study 
Extension)
Total Lymphocyte 
Count or CD4+ 
T-cell Count 
Monitoring
See Sections 7.1, 
8.1.9, and 8.11.5 for 
details regarding 
discontinuation and 
monitoring.
Visit Window
Within 
10 to 14 weeks 
after initial 
decrease (or at 
next scheduled 
visit)
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 
10 to 14 weeks 
after discontinuing 
study intervention
AE=adverse event; DOR=doravirine; EQ-5D-5L=EuroQol 5-dimensional descriptive system, 5-level version; FBR=future biomedical research; hCG=human chorionic 
gonadotropin; HIV-1=human immunodeficiency virus type 1; HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/Symptom Distress Module; HIVTSQ=Human 
Immunodeficiency Virus Treatment Satisfaction Questionnaire; IRT=Interactive Response Technology; ISL=islatravir; NA=not applicable; PK=pharmacokinetic(s); 
POCBP=participant/participants of childbearing potential RNA=ribonucleic acid; SAE=serious adverse event; TBNK=T and B Lymphocyte and Natural Killer Cell.
a
Participant discontinued at a Scheduled Visit, should complete the assessments for the Scheduled Visit as well as the Early Discontinuation of Treatment Visit. Collection of 
laboratory samples should not be duplicated. 
08WX9K

PRODUCT: MK-8591A
46
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
1.3.4
Schedule of Activities for Participants Whose Pregnancy or Postpartum Visit(s) Extends Beyond Week 144
This SoA only applies to eligible participants who are pregnant at Week 144 or who become pregnant in the optional study extension 
and consent to continue study intervention during pregnancy. Participants will have visits every 12 weeks during the pregnancy and 
once postpartum. If delivery is premature or the 1st trimester visit is missed, the participant may have ≤3 visits before delivery plus the 
postpartum visit. See Section 8.11.6.
•
Manage participants with viremia per Sections 8.2.2, Section 8.11.4 and Section 1.3.2 (SoA).
•
Participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 and Section 1.3.3 (SoA).
Study Period
Pregnancy
Postpartum
End of 
Treatmenta
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Scheduled Week
Pregnancy 1
Pregnancy 2
(12 weeks from 
Pregnancy 1)
Pregnancy 3
(12 weeks from 
Pregnancy 2)
Pregnancy 4 
(Postpartum 
≤8 weeks after 
delivery)
End of 
Treatment 
Follow-up
Visit Window
±7 days
42 (+7) days 
after the end of 
treatment
Administrative Procedures
Collect and Enter Data 
From Prenatal Care 
Provider
<------------------------------------X------------------------------------>
Obtain relevant prenatal clinical and 
laboratory data to monitor the safety of 
the mother and fetus per Section 8.11.6.
Register Study Visit in 
IRT
X
X
X
X
Dispense DOR/ISL 
Using IRT
X
X
X
X
See Section 1.3.1 or 1.3.5 as applicable. 
Study Intervention 
Compliance Review
X
X
X
X
Prior and Concomitant 
Medications Review
X
X
X
X
X
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification
X
X
X
X
X
See Section 8.2.1. Manage participants 
with viremia per Sections 1.3.2 and 8.2.2.
08WX9K

PRODUCT: MK-8591A
47
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Pregnancy
Postpartum
End of 
Treatmenta
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Scheduled Week
Pregnancy 1
Pregnancy 2
(12 weeks from 
Pregnancy 1)
Pregnancy 3
(12 weeks from 
Pregnancy 2)
Pregnancy 4 
(Postpartum 
≤8 weeks after 
delivery)
End of 
Treatment 
Follow-up
Visit Window
±7 days
42 (+7) days 
after the end of 
treatment
Plasma for HIV-1 Drug 
Resistance 
X
X
X
X
X
Analysis performed by Sponsor if 
indicated per Section 8.2.2.1.2
TBNK Panel/CD4+ T-
cell Count
X
X
X
X
X
Safety Procedures
Weight
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
Vital Signs
X
X
X
X
X
Hepatitis B Serology and 
HBV DNA 
(DOR/ISL only)
<-----------------X----------------------->
Collect once after pregnancy is confirmed 
or report local laboratory results. See 
Section 8.11.6.1.
Chemistry
X
X
X
X
X
Hematology
X
X
X
X
X
Urinalysis
X
X
X
X
X
AE/SAE Review
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for DOR 
and ISL PK
X
X
X
X
X
Collect only for participants on DOR/ISL 
during the 1st, 2nd, and 3rd trimesters and 
postpartum per Section 8.11.6.1 
(Table 7).
AE=adverse event; ART=antiretroviral therapy; DNA=deoxyribonucleic acid; DOR=doravirine; FBR=future biomedical research; HBV=hepatitis B virus; HIV-1= human 
immunodeficiency virus type 1; IRT=Interactive Response Technology; ISL=islatravir; PK=pharmacokinetic(s); RNA=ribonucleic acid; SAE=serious adverse event; TBNK=T 
and B Lymphocyte and Natural Killer Cell.
a The procedures in this End of Treatment Follow-up visit should be followed for those participants not continuing in the optional study extension.
08WX9K

PRODUCT: MK-8591A
48
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
1.3.5
Schedule of Activities –Week 144 Through Week 240 (Optional Study Extension)
This SoA only applies to participants who enter the optional study extension at Week 144. Duration of participation in the optional 
study extension is dependent on when DOR/ISL becomes commercially accessible, with a maximum treatment duration of 96 weeks 
(ie, total study intervention duration of up to 240 weeks). 
•
Manage participants with viremia per Section 8.11.4 and Section 1.3.2 (SoA). 
•
Manage participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 and Section 1.3.3 
(SoA).
•
Manage pregnant participants per Section 8.11.6 and Section 1.3.4 (SoA).
Study Period
Optional Study Extension 
End of Treatment
Notes
Visit Number
17
18
19
20
Unscheduled
Unscheduled
Scheduled Day/Week
Week 168
Week 192
Week 216
Week 240
Discontinuation of Treatment 
(Optional Study Extension)a
End of Treatment Follow-up 
(Optional Study Extension)
Visit Window
±14 days 
(Calculate each visit from 
date of Day 1)
NA
42 (+7) days after end of treatment
Evaluate Local 
Accessibility of 
DOR/ISL
X
X
X
X
Once DOR/ISL is commercially 
accessible, participants should return to 
the study site for the Discontinue of 
Treatment visit and transition to the 
local supply. 
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
Register Study Visit in 
IRT
X
X
X
X
X
Dispense Study 
Intervention Using IRT
X
X
X
(X)
(Dispense at Week 240 if needed for 
pregnant participants, see 
Section 1.3.4).
Study Intervention 
Compliance Review
X
X
X
X
X
08WX9K

PRODUCT: MK-8591A
49
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Optional Study Extension 
End of Treatment
Notes
Visit Number
17
18
19
20
Unscheduled
Unscheduled
Scheduled Day/Week
Week 168
Week 192
Week 216
Week 240
Discontinuation of Treatment 
(Optional Study Extension)a
End of Treatment Follow-up 
(Optional Study Extension)
Visit Window
±14 days 
(Calculate each visit from 
date of Day 1)
NA
42 (+7) days after end of treatment
Plasma HIV-1 RNA 
Quantification
X
X
X
X
X
See Section 8.2.1
TBNK Panel/CD4+ T-
cell Count
X
X
X
X
X
Blood (Plasma) for HIV-
1 Drug Resistance 
X
X
X
X
X
Analysis will be performed by Sponsor 
if indicated per Section 8.2.2.1.2.
Hepatitis B Serology and 
HBV DNA
X
X
Encourage HBV vaccination to 
participants who are not immune to 
HBV. 
HBsAg and HBV DNA
(X)
(X)
(X)
(X)
(Only anti-HBc-positive participants, at 
each visit.) See Section 8.3.6.
Hematology
X
X
X
X
X
Manage participants who meet the 
discontinuation criteria for total 
lymphocyte count per Sections 1.3.3 
and 8.11.5.
Directed Physical 
Examination
X
X
X
X
X
X
AE/SAE Review
X
X
X
X
X
X
Contraceptive Use 
Confirmation
(POCBP Only)
X
X
X
X
X
X
Contraception is required 42 days after 
the last dose of study intervention.
Urine Pregnancy Test 
(hCG) (POCBP Only)
X
X
X
X
X
X
Manage participants who have a 
positive or indeterminant urine test per 
Sections 1.3.4 and 8.11.6. For 
participants known to be pregnant, defer 
until 6 weeks postpartum.
Informed Consent for 
Study Intervention 
During Pregnancy
<------------X---------->
Obtain upon confirmation of pregnancy. 
See Sections 1.3.4 and 8.1.1.3.
08WX9K

PRODUCT: MK-8591A
50
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Optional Study Extension 
End of Treatment
Notes
Visit Number
17
18
19
20
Unscheduled
Unscheduled
Scheduled Day/Week
Week 168
Week 192
Week 216
Week 240
Discontinuation of Treatment 
(Optional Study Extension)a
End of Treatment Follow-up 
(Optional Study Extension)
Visit Window
±14 days 
(Calculate each visit from 
date of Day 1)
NA
42 (+7) days after end of treatment
AE=adverse event; anti-HBc=hepatitis B core antibody ; IC=bictegravir; BP=blood pressure; DNA=deoxyribonucleic acid; DOR=doravirine; ECG=electrocardiogram; ; 
FBR=future biomedical research; FTC=emtricitabine; HBV=hepatitis B virus; hCG=human chorionic gonadotropin; HIV-1=human immunodeficiency virus type 1; HIV-2= 
human immunodeficiency virus type 2; HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/symptom distress module; INR=international normalized ratio; 
IRT=interactive response technology; ISL=islatravir; NA=not applicable; PK=pharmacokinetic(s); POCBP=participant/participants of childbearing potential; PT=prothrombin 
time; RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; TAF=tenofovir alafenamide; TBNK=T and B lymphocyte and natural killer cells; temp=body 
temperature.
a If discontinuation occurs at a Scheduled Visit, perform Discontinuation of Treatment (optional study extension) visit assessments. 
08WX9K

PRODUCT: MK-8591A
51
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
2
INTRODUCTION
DOR/ISL (also known as MK-8591A) is a novel 2-drug FDC of DOR (100 mg) (an approved 
NNRTI) and ISL (0.25 mg) (an investigational NRTTI). DOR/ISL is being developed for QD 
treatment of HIV-1 infection.
2.1
Study Rationale
As treatment regimens have improved, HIV-1 infection has become a chronic, manageable 
condition, and PLWH receiving effective ART regimens can expect to live near-normal 
lifespans. Anticipating that individuals can receive decades of treatment during their lifetime, 
long-term tolerability and safety of antiretrovirals have become increasingly important 
considerations.
The current standard of care for the treatment of HIV-1 is a combination of 2 NRTIs with a 
third agent (eg, InSTI, NNRTI, or PI) [Panel on Antiretroviral Guidelines for Adults and 
Adolescents 2022] [European AIDS Clinical Society 2021] [World Health Organization 
2021]. Although these 3-drug regimens are well tolerated and highly efficacious, the current 
paradigm of lifelong daily treatment is associated with a need for simpler and safer regimens 
that reduce overall drug exposure [Llibre, J. M., et al 2018] [Cahn, P., et al 2019] [Panel on 
Antiretroviral Guidelines for Adults and Adolescents 2022]. As this population ages, there is 
increasing concern about polypharmacy, long-term toxicity, and DDIs related to comorbidity 
and multimorbidity and risks associated with the emergence of HIV-1 variants resistant to 
InSTI, NRTI, and NNRTI treatments.
There is evidence that 2-drug regimens can achieve efficacy comparable to that of 3-drug 
regimens, better tolerability, and improve quality of life; all of which can support adherence 
and help to sustain virologic suppression [Llibre, J. M., et al 2018] [Cahn, P., et al 2019] 
[Panel on Antiretroviral Guidelines for Adults and Adolescents 2022]. The effectiveness of 
2-drug regimens depends on both components having distinct mechanisms of action with at 
least 1 of the components having a relatively high barrier to resistance.
DOR/ISL has the potential to be an effective and well tolerated 2-drug regimen for the 
treatment of HIV-1 infection in the switch setting due to its potent antiretroviral activity 
(including activity against common NRTI- and NNRTI-resistant variants), multiple 
mechanisms of action, lack of food requirements, and favorable DDI profiles observed to 
date (see Section 2.2.3).
2.2
Background
Refer to the approved local labeling for DOR and to the IB for ISL for detailed background 
information.
2.2.1
Islatravir
ISL is a novel and potent NRTTI that blocks HIV-1 reverse transcriptase by novel 
mechanisms of action. It is a nucleoside analog that is converted to the pharmacologically 
active triphosphate (ISL-TP) form via endogenous intracellular kinases. It acts through 
08WX9K

PRODUCT: MK-8591A
52
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
multiple mechanisms, including immediate chain termination by blocking translocation and 
delayed chain termination by preventing nucleotide excision [Michailidis E 2014].
ISL is differentiated from other HIV-1 antiretrovirals by its high potency, long half-life, and 
favorable drug resistance profile. At the proposed dose of 0.25 mg QD, ISL achieves higher 
steady-state IQs (the ratio of drug exposure to viral susceptibility [Ctrough/IC50]) against 
wild-type HIV-1 than any NRTI currently approved for treatment. It also exhibits potent 
activity against the most prevalent NRTI resistance mutations, including M184V.
2.2.2
Doravirine
DOR, a potent NNRTI with demonstrated efficacy and good tolerability, was first approved 
for the treatment of HIV-1 infection by the FDA and EMA in 2018. It is differentiated from 
other NNRTIs by its distinct resistance profile, low likelihood of selection for viral resistance 
in vivo, and low potential for DDIs. It exhibits potent activity against both wild-type HIV-1 
virus and frequently transmitted NNRTI-resistant variants (eg, K103N, Y181C, G190A, and 
E138K) in vitro. The efficacy and safety profiles of DOR have been well characterized in 
Phase 3 studies conducted in treatment-naïve adult participants [Orkin, C., et al 2019] 
[Molina, J. M., et al 2018] and in virologically suppressed adult participants switching from a 
stable antiretroviral regimen [Johnson, M., et al 2019].
2.2.3
Doravirine/Islatravir
DOR/ISL is an FDC containing DOR (100 mg) and ISL (0.25 mg), administered as a single-
tablet QD. DOR and ISL represent 2 distinct antiretroviral agents that inhibit reverse 
transcription by different mechanisms. Based on the profile of each and data available to 
date, the combination DOR/ISL is expected to be well tolerated and highly efficacious, with 
a high barrier to resistance. The combination has demonstrated additive antiretroviral 
activity, with complementary resistance profiles, and suppressed the emergence of resistance 
in vitro at clinically relevant concentrations.
DOR/ISL (100 mg/0.75 mg) has demonstrated antiretroviral activity in Phase 3 studies in 
virologically suppressed (MK-8591A-017 and MK-8591A-018) and TN adults (MK-8591A-
020) with HIV-1. Additional details are available in the IB.
In MK-8591-011 (Phase 2, dose-ranging study) ISL doses of 0.25, 0.75, and 2.25 mg were 
administered to treatment-naïve adults initially in 3-drug regimens (ISL+DOR+3TC) until 
virologic suppression (HIV-1 RNA <50 copies/mL) was achieved, at which point the 
regimen was simplified to a 2-drug regimen (ISL+DOR) for maintenance of suppression. The 
DOR+ISL regimens achieved efficacy (HIV-1 RNA <50 copies/mL) comparable with the 
FDC comparator (DOR/3TC/TDF) used in MK-8591-011. No participant met criteria for 
clinically significant confirmed viremia (HIV-1 RNA ≥200 copies/mL) through Week 144. 
The overall AE profile for ISL+DOR (±3TC) was similar for each dose of ISL and generally 
comparable with DOR/3TC/TDF through Week 144. Differences in changes from baseline in 
total lymphocyte and CD4+ T-cell counts were observed for the different ISL dose groups 
(see Section 2.3).
08WX9K

PRODUCT: MK-8591A
53
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
In MK-8591A-020, DOR/ISL (100 mg/0.75 mg) was noninferior to BIC/FTC/TAF, as 
assessed by the percentage of participants achieving virologic suppression (HIV-1 RNA 
<50 copies/mL) at Week 48 (88.9% vs 88.3%, respectively). Treatment-emergent resistance 
has been observed for 2 participants in the study (DOR/ISL group), which was considered in 
both to be due to nonadherence to treatment as the participants’ ISL levels were BLOQ at the 
time of viremia.
2.2.4
Information on Other Study-related Therapy
For participants in Group 2, refer to local labeling for detailed information for their continued 
baseline ART.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
The totality of available nonclinical and clinical data supports continued evaluation of 
DOR/ISL 100 mg/0.25 mg FDC in Phase 3 studies.
There remains significant unmet need for novel ART as an alternative option for HIV-1 
treatment that is suitable across the population of PLWH, including the elderly and those 
with multiple comorbidities. High in vitro potency against wild-type HIV-1 virus and a high 
barrier to resistance make DOR and ISL suitable candidates for treatment of HIV-1 infection. 
Administration of ISL in doses of 0.25, 0.75, and 2.25 mg with DOR 100 mg and 3TC 
300 mg in MK-8591-011 achieved virological suppression in >90% of treatment-naïve 
participants by Week 24, which was maintained after switching from the 3-drug regimen 
(ISL+DOR+3TC) to the 2-drug regimen (ISL+DOR) through Week 144. The antiviral 
efficacy and overall AE profile through Week 72 (the dose-ranging part of MK-8591-011) 
were not distinguishable among the 3 ISL dose groups (0.25, 0.75, and 2.25 mg).
DOR/ISL (100 mg/0.75 mg QD) was highly efficacious in maintaining virologic suppression 
(>95% and >93% of participants had HIV-1 RNA <50 copies/mL at Week 48) in participants 
who switched from various baseline ARTs, including BIC/FTC/TAF, in 2 Phase 3 studies 
(MK-8591A-017 and MK-8591A-018, respectively). To date, viral resistance was observed 
for 2 participants receiving DOR/ISL across the Phase 2 (MK-8591-011) and the Phase 3 
(MK-8591A-017, MK-8591A-018, and MK-8591A-020) program, in which 1693 TN and 
virologically suppressed participants with HIV-1 infection received DOR/ISL. These 
participants were enrolled in the MK-8591A-020 study. Across the ISL clinical development 
program involving approximately 2300 participants enrolled in Phase 2 and Phase 3 studies, 
there was a low incidence of drug-related AEs, SAEs, and deaths with ISL when 
administered alone or with DOR; decreases in lymphocyte counts were observed.
Comprehensive nonclinical safety evaluation of DOR and ISL as mono-entities has not 
revealed toxicities of concern. Nonclinical developmental and reproductive toxicity studies 
did not identify any clinically relevant concerns that would preclude continued dosing of 
08WX9K

PRODUCT: MK-8591A
54
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
DOR/ISL in participants who become pregnant during the study. Both DOR and ISL may be 
administered without regard to food and have a low potential for DDIs, a favorable attribute 
for those who have multiple chronic comorbidities.
Decreases in total lymphocyte and lymphocyte subset (including CD4+ T-cell counts) have 
been observed in Phase 2 and Phase 3 studies with ISL given QM (60 and 120 mg), QW 
(20 mg in combination with MK-8507, an NNRTI), and QD (0.75 mg in combination with 
DOR 100 mg). As a result, dosing was stopped in December 2021 for ISL 60 mg QM for 
HIV-1 PrEP, ISL QW 20 mg (with MK-8507) for HIV-1 treatment, and DOR/ISL 
(100 mg/0.75 mg) QD for HIV-1 treatment in pediatric participants.
The Sponsor has conducted a comprehensive investigation into ISL-related decreases in 
lymphocyte counts to identify possible mechanism(s) of action and to assess the timing and 
extent of lymphocyte decreases while on-treatment with ISL and the recovery of lymphocyte 
counts when off-treatment with ISL.
Investigations of possible mechanisms for the lymphocyte decreases support the conclusion 
that the preferential accumulation of ISL-TP in lymphocytes can lead to inhibition of cell 
growth and apoptosis at high ISL-TP concentrations. Toxicity due to high TP levels is a 
common mechanism among HIV nucleoside analog drugs. Mitochondrial toxicity is not a 
contributing mechanism to the decrease in lymphocytes.
An overall summary of the comprehensive investigation into ISL-related decreases in 
lymphocyte counts is as follows:
•
No changes in general hematology parameters (including hemoglobin, basophils, 
eosinophils, monocytes, leukocytes, neutrophils, platelets) were observed for participants 
receiving ISL alone or in combination with other ART in any study.
•
ISL dose-dependent decreases from baseline were observed in mean total lymphocyte 
counts and lymphocyte subset (CD4+ T-cell, CD8+ T-cell, B-cell) counts, with greater 
decreases observed at the higher ISL doses administered QW (20 mg) and QM (60 mg) 
compared with QD (0.75 mg) administration.
-
In VS participants in MK-8591A-017 and MK-8591A-018 receiving DOR/ISL 
100 mg/0.75 mg QD, mean percent changes from baseline were observed in total 
lymphocyte (-10.6% and -8.4%, respectively), CD4+ T-cell (-0.68% and +0.87%, 
respectively), CD8+ T-cell (-8.2% and -7.4%, respectively) and B-cell (-4.4% 
and -8.6%, respectively) counts at Week 48.
-
In VS participants in MK-8591-013 receiving ISL 20 mg + MK-8507 100 to 400 mg 
QW, mean percent changes from baseline were observed in total lymphocyte (-15.1% 
to -30.9%), CD4+ T-cell (-7.6% to -28.1%), CD8+ T-cell (-18.1% to -32.8%), and 
B-cell (-36.8% to -46.3%) counts at Week 24.
-
In participants with low risk of HIV-1 infection receiving ISL 60 or 120 mg QM for 
PrEP, the on-treatment mean decreases from baseline in total lymphocyte count 
were -21.3% and -35.6% at Week 24, respectively.
08WX9K

PRODUCT: MK-8591A
55
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
Stabilization of the decreases from baseline in mean total lymphocyte count and 
lymphocyte subset counts observed for the DOR/ISL 100 mg/0.75 mg QD program 
occurred between Weeks 48 and 72, depending on the lymphocyte subset.
•
Decreases from baseline in mean total lymphocyte count and lymphocyte subset counts 
were not associated with increased incidence of infection.
•
A return toward baseline in lymphocyte and lymphocyte subset counts has been observed 
across the ISL clinical development program. However, a full recovery was not observed 
by 24 weeks after stopping ISL. The most robust data on recovery of the lymphocyte 
counts available at this point was from the studies involving administration of ISL QW 
(20 mg) and QM (60-120 mg), as detailed below. Data on recovery to baseline following 
discontinuation of DOR/ISL 100 mg/0.75 mg QD in VS adults (MK-8591A-017 and 
MK-8591A-018) is not yet available.
-
Approximately 6 months after discontinuation of ISL 20 mg QW in adult VS 
participants (MK-8591-013), among those with ≥30% decrease in total lymphocyte or 
CD4+ T-cell counts at their last on-treatment measurement and at least 1 follow-up 
result, 10/40 (25%) and 15/32 (47%) participants demonstrated an increase in total 
lymphocyte and CD4+ T-cell counts, respectively, to within 10% of baseline.
-
Approximately 5 months after discontinuation of ISL 60 mg QM in adults at risk of 
HIV-1 infection, 43 (29.9%) of the 144 participants in MK-8591-022 and 
MK-8591-024 with a ≥30% decrease in total lymphocyte count at the last on-
treatment visit demonstrated an increase in total lymphocyte counts to within 10% of 
baseline.
Overall, the evaluation of data from across the ISL clinical programs to date suggests that the 
decrease in mean total lymphocyte and lymphocyte subset counts is ISL dose-dependent, 
with lower doses less likely to cause decreases. A new FDC of DOR/ISL containing a 
0.25 mg dose of ISL will be evaluated in the current study. In the dose-ranging phase of 
MK-8591-011 (Part 1 and Part 2 through Week 72), participants who received ISL 0.25 mg 
QD had changes in total lymphocyte and CD4+ T-cell counts comparable to those observed 
for participants in the DOR/3TC/TDF comparator group. The results of modeling analyses of 
ISL exposure-effect predict no meaningful decreases in total lymphocyte or CD4+ T-cell 
counts with the 0.25 mg daily dose (see Section 4.3). To mitigate any risk, close monitoring 
and discontinuation criteria (Sections 1.3.3, 7.1, and 8.11.5) for individuals who experience 
significant decreases in lymphocytes are included in this protocol.
Additional details regarding DOR can be found in the local product label. Details regarding 
ISL and DOR/ISL can be found in the accompanying IB.
08WX9K

PRODUCT: MK-8591A
56
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants ≥18 years of age with HIV-1 who 
have been virologically suppressed (ie, HIV-1 RNA <50 copies/mL) for ≥3 consecutive 
months on a stable oral 2- or 3-drug combination (± PK booster) ART.
Primary Objective
Primary Endpoint
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48
Hypothesis (H1): DOR/ISL is non-inferior 
to continued baseline ART, as assessed by 
the percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 48. A margin 
of 4 percentage points is used to define 
non-inferiority.
HIV-1 RNA
To evaluate the safety and tolerability of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by 
review of the safety data accumulated 
through Week 48
Adverse events
Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by the 
percentage of participants with the 
following at Week 48:
•
HIV-1 RNA <200 copies/mL
•
HIV-1 RNA <50 copies/mL
HIV-1 RNA
08WX9K

PRODUCT: MK-8591A
57
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
To evaluate the antiretroviral activity of a 
switch to DOR/ISL in participants who 
switched from baseline ART to DOR/ISL 
on Day 1, as assessed by the percentage of 
participants with the following at Week 96 
and Week 144:
•
HIV-1 RNA ≥50 copies/mL
•
HIV-1 RNA <200 copies/mL
•
HIV-1 RNA <50 copies/mL
HIV-1 RNA
To evaluate the antiretroviral activity of a 
switch to DOR/ISL in participants who 
continued baseline ART and switched to 
DOR/ISL at Week 48, as assessed by the 
percentage of participants with the 
following at Week 96 and Week 144:
•
HIV-1 RNA ≥50 copies/mL
•
HIV-1 RNA <200 copies/mL
•
HIV-1 RNA <50 copies/mL
HIV-1 RNA
To evaluate the immunologic effect of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by the 
mean change from baseline in CD4+ T-cell 
count at Week 48
CD4+ T-cell count
To evaluate the immunologic effect of a 
switch to DOR/ISL, as assessed by the 
mean change in CD4+ T-cell count:
•
From baseline (Day 1) to Week 96 and 
from Week 48 to Week 96 in 
participants who switched from baseline 
ART to DOR/ISL on Day 1
•
From baseline (Day 1) to Week 144 and 
from Week 48 to Week 144 in 
participants who switched from baseline 
ART to DOR/ISL on Day 1
CD4+ T-cell count
08WX9K

PRODUCT: MK-8591A
58
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
From Week 48 to Week 96 in 
participants who continued baseline 
ART and switched to DOR/ISL at 
Week 48 
•
From Week 48 to Week 144 in 
participants who continued baseline 
ART and switched to DOR/ISL at Week 
48 
To evaluate the development of viral drug 
resistance to any study intervention at 
Week 48, Week 96, and Week 144
Viral resistance-associated substitutions
To evaluate the effect on fasting LDL-C and 
non-HDL-C of a switch to DOR/ISL 
compared with continued baseline ART by 
baseline ART class (PI- containing 
regimens [including PI- + InSTI-containing 
regimens], InSTI-containing regimens [non-
PI-containing regimens], and non-PI- and 
non-InSTI-containing regimens), as 
assessed by the mean change in fasting 
LDL-C and non-HDL-C from baseline to 
Week 48
If non-inferiority of DOR/ISL to continued 
baseline ART at Week 48 (H1) is met, the 
following hypothesis will be tested for each 
parameter within each stratum:
Hypothesis (H2): DOR/ISL is superior to 
continued baseline ART in each baseline 
ART stratum (in the order of: PI-containing 
regimens [including PI- + InSTI-containing 
regimens], non-PI- and non-InSTI-
containing regimens, and InSTI-containing 
regimens [non-PI-containing regimens]), as 
assessed by the mean change from baseline 
in fasting LDL-C and non-HDL-C at 
Week 48.
Fasting LDL-C and non-HDL-C
08WX9K

PRODUCT: MK-8591A
59
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
To evaluate the safety and tolerability of a 
switch to DOR/ISL compared with 
continued baseline ART, as assessed by 
review of the safety data accumulated 
through Week 144:
•
From baseline (Day 1) through Week 96 
and from Week 48 through Week 96 in 
participants who switched from baseline 
ART to DOR/ISL on Day 1
•
From baseline (Day 1) through Week 
144 and from Week 48 through Week 
144 in participants who switched from 
baseline ART to DOR/ISL on Day 1
•
From Week 48 through Week 96 in 
participants who continued baseline 
ART and switched to DOR/ISL at 
Week 48
•
From Week 48 through Week 144 in 
participants who continued baseline 
ART and switched to DOR/ISL at 
Week 48
Adverse events
Adverse events leading to discontinuation 
of study intervention
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate the effects on weight, fasting 
lipid and metabolic profiles, and renal 
function of a switch from baseline ART to 
DOR/ISL on Day 1 compared with 
continued baseline ART, as assessed by the 
mean change from baseline in these 
parameters at Week 48
Weight and laboratory markers
To evaluate the effects on weight, fasting 
lipid and metabolic profiles, and renal 
function of a switch from baseline ART to 
DOR/ISL on Day 1 compared with 
continued baseline ART and a switch to 
DOR/ISL at Week 48, as assessed by the 
mean change in these parameters at 
Week 96 and Week 144:
Weight and laboratory markers
08WX9K

PRODUCT: MK-8591A
60
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
From baseline (Day 1) to Week 96 and 
from Week 48 to Week 96 in 
participants who switched to DOR/ISL 
on Day 1
•
From baseline (Day 1) to Week 144 and 
from Week 48 to Week 144 in 
participants who switched to DOR/ISL 
on Day 1
•
From Week 48 to Week 96 in 
participants who continued baseline 
ART and switched to DOR/ISL at
Week 48
•
From Week 48 to Week 144 in 
participants who continued baseline 
ART and switched to DOR/ISL at Week 
48
To evaluate the effects of DOR/ISL on total 
lymphocyte count at Weeks 48, 96, and 144
Total lymphocyte count
To evaluate the pharmacokinetics of ISL 
when administered as a component of 
DOR/ISL
Pharmacokinetic values including AUC, 
Cmax, and C24
To describe PROs (HRQoL, HIV treatment 
satisfaction, and HIV symptoms) after a 
switch to DOR/ISL compared with 
continued baseline ART at Week 48 and 
Week 96
EQ-5D-5L, HIVTSQ, and HIV-SI/SDM
To explore the relationship between genetic 
variation and response to the treatment(s) 
administered and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in this study
Germline genetic variation and association 
to clinical data collected in this study
08WX9K

PRODUCT: MK-8591A
61
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
To evaluate the long-term antiretroviral 
activity of DOR/ISL in participants in 
Group 1 and the antiretroviral activity of a 
switch to DOR/ISL in participants in Group 
2, as assessed by the percentage of 
participants in those enrolled in the optional 
study extension:
•
HIV-1 RNA ≥50 copies/mL
•
HIV-1 RNA <50 copies/mL
•
HIV-1 RNA <200 copies/mL
HIV-1 RNA
To evaluate the long-term immunologic 
effect of DOR/ISL, as assessed by mean 
changes in CD4+ T-cell count over time in 
participants enrolled in the optional study 
extension
CD4+ T-cell count
To evaluate the long-term effects of 
DOR/ISL on total lymphocyte count in 
participants enrolled in the optional study 
extension
Total lymphocyte count
To evaluate the development of viral drug 
resistance to DOR/ISL in the optional study 
extension
Viral resistance-associated substitutions
To evaluate the long-term safety and 
tolerability of DOR/ISL, as assessed by 
review of the safety data accumulated in 
participants enrolled in the optional study 
extension
Adverse events
Adverse events leading to discontinuation 
of study intervention
08WX9K

PRODUCT: MK-8591A
62
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, multisite, open-label study to evaluate a 
switch from any stable oral 2-drug or 3-drug combination (± PK booster) ART regimen to 
DOR/ISL (100 mg/0.25 mg QD) in participants with HIV-1 who have been virologically 
suppressed for ≥3 consecutive months with no history of virologic treatment failure.
The study consists of a screening period of up to 45 days, a 144-week base study, followed 
by an optional study extension period up to Week 240 (Figure 1). 
Base Study
A total of approximately 501 participants will be randomized, stratified by baseline ART 
regimen (PI-containing [including PI- + InSTI-containing] regimens, InSTI-containing 
[non-PI-containing] regimens, and non-PI- and non-InSTI-containing regimens) in a 2:1 ratio 
into 1 of 2 treatment groups (Figure 1):
•
Group 1 (n=approximately 334): Switch from baseline ART to DOR/ISL 
(100 mg/0.25 mg QD) on Day 1 and continue DOR/ISL QD through Week 144
•
Group 2 (n=approximately 167): Continue baseline ART until Week 48 and switch to 
DOR/ISL (100 mg/0.25 mg QD) from Week 48 through Week 144
After 48 weeks of assigned therapy, all participants will receive DOR/ISL (100 mg/0.25 mg 
QD) through Week 144. Participants who complete the last visit will be given an option to 
continue receiving open-label DOR/ISL up to Week 240, or until it is commercially 
accessible (whichever comes first) (Section 6.7). Study intervention will be extended for 
participants who become pregnant on-treatment and provide documented informed consent to 
continue their study intervention (DOR/ISL or baseline ART), as specified in Sections 1.3.4 
and 8.11.6.
Baseline ART regimen allowed drug classes for this study include NRTIs, NNRTIs, PIs, 
InSTIs, and PK boosters. The Sponsor will not provide baseline ART regimens. Participants 
will provide their own ART medications, in accordance with local regulations. Country-
specific requirements for baseline ART categorization in this study are in Appendix 7.
Any participants with clinically significant confirmed viremia (Section 4.2.1.1.2) will be 
assessed for development of viral drug resistance and discontinuation from study intervention 
per the SoA (Section 1.3.2) and Section 7.1.
Participant safety will be monitored by an independent eDMC through periodic review of 
efficacy and safety data throughout the study per the timing specified in the eDMC charter 
(Appendix 1). Additionally, the following IA is planned (see Section 9.7).
08WX9K

PRODUCT: MK-8591A
63
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
Week 24 IA: An IA to assess futility will be performed by the external independent 
statistician when approximately 30% of the total target enrollment has completed the 
Week 24 visit assessments. The nonbinding futility criterion is described in Section 9.7.
Optional Study Extension
At Week 144, participants who meet eligibility criteria and consent to enter the optional 
study extension will continue with DOR/ISL up to Week 240 or until it is commercially 
accessible (whichever comes first). Procedures to be followed upon exiting the study 
extension are outlined in Section 6.7. 
Consistent with global HIV-1 treatment guidelines [Food and Drug Administration (CDER) 
2015] [European AIDS Clinical Society 2021] the optional study extension consists of in-
clinic visits every 6 months to assess maintenance of virologic suppression, CD4+ T-cell and 
total lymphocyte counts, and tolerability. To gain additional data on the effect of long-term 
ISL exposure on lymphocytes, the total lymphocyte count and lymphocyte subsets will also 
be assessed at these visits. Where local treatment guidelines require study visits more 
frequently than every 6 months, these are permitted and should be conducted by the primary 
investigator and/or the treating physician. 
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Base Study
The randomized, active-controlled, non-inferiority study design is consistent with the FDA 
CDER 2015 Guidance for Industry: Human Immunodeficiency Virus-1 Infection: 
Developing Antiretroviral Drugs for Treatment [Food and Drug Administration (CDER) 
2015] and is considered appropriate for a treatment-experienced study population that is 
switching from another stable ART regimen with HIV RNA <50 copies/mL. Small 
differences in virologic efficacy, emergence of resistance, and loss of tolerability or safety 
may be detected prior to 48 weeks of treatment, particularly for therapies with largely 
comparable characteristics. Thus, an efficacy and safety outcome through 48 weeks is 
aligned with current regulatory guidance [Food and Drug Administration (CDER) 2015], and 
the primary efficacy and safety analyses will occur after 48 weeks of treatment with 
DOR/ISL or continued baseline ART regimens. A 2:1 randomization ratio optimizes 
collection of efficacy and safety data on the DOR/ISL investigational product relative to the 
approved baseline ART regimens taken by the Group 2 participants in this study. 
The open-label design allows a broader comparator treatment population to be evaluated in 
this study. All 2- and 3-drug regimens can be included as continued baseline regimens, 
allowing for comparison and analysis closer to what is observed in a real-world population.
08WX9K

PRODUCT: MK-8591A
64
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
It is anticipated that the baseline ART regimens will be heterogeneous and, in some cases, 
may be associated with considerable pill burden. Therefore, after collecting 48 weeks of data, 
switching participants who are on continued baseline ART regimen to DOR/ISL at Week 48 
may simplify regimens for some participants, potentially optimizing the study, including 
improving study retention.
Optional Study Extension 
The optional study extension provides access to DOR/ISL until it is commercially accessible. 
Participation in the study extension is optional and allows eligible participants who are 
deriving benefit from DOR/ISL to continue DOR/ISL and avoid interruption of treatment. 
The study extension will also allow for long-term efficacy and safety data collection for 
DOR/ISL.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
HIV-1 RNA Measurements
The primary efficacy endpoint in this study is plasma HIV-1 RNA ≥50 copies/mL. Eligible 
participants in the switch population being studied are virologically suppressed, with HIV-1 
RNA <50 copies/mL at screening. The assessment of interest is the percentage of participants 
who are unable to maintain virologic suppression after switching to a new antiretroviral 
regimen.
Clinical studies of antiretroviral agents in multiple drug classes have demonstrated that 
virologic suppression of HIV-1 RNA to <50 copies/mL reflects a clinically relevant standard 
used across development programs for antiretroviral therapies and in clinical practice 
[Vandenhende, M. A., et al 2015]. Suppressing HIV-1 RNA to <50 copies/mL preserves the 
immune system and minimizes the risk of opportunistic infections and disease progression.
The secondary efficacy endpoint of plasma HIV-1 RNA <200 copies/mL corresponds to the 
clinically relevant threshold. With values ≥200 copies/mL, there is an increased risk of 
development of resistance.
4.2.1.1.2
Definition of Clinically Significant Confirmed Viremia
For the purpose of managing participants in this study, clinically significant confirmed 
viremia is defined as:
•
Two consecutive occurrences 4 weeks (±1 week) apart of HIV-1 RNA ≥200 copies/mL at 
any time during the study.
There is currently no global standard for the definition of low-level viremia and the 
predictive implication of such low-level viremia is uncertain [Vandenhende, M. A., et al 
2015] [Charpentier, C., et al 2014]. The US Department of Health and Human Services 
08WX9K

PRODUCT: MK-8591A
65
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
guidelines currently define virologic failure as confirmed HIV RNA ≥200 copies/mL and do 
not recommend that low-level viremia (detectable HIV RNA <200 copies/mL) automatically 
results in treatment modification or more frequent virologic monitoring [Panel on 
Antiretroviral Guidelines for Adults and Adolescents 2022]. PLWH with HIV-1 RNA ≥50 
and <200 copies/mL have a lower risk of developing resistance compared with those with 
HIV-1 RNA ≥200 copies/mL. Therefore, study participants with HIV-1 RNA ≥50 and 
<200 copies/mL should continue their current regimen, with HIV-1 RNA levels monitored as 
outlined in Section 8.2.2.
If a participant has an HIV-1 RNA value ≥50 copies/mL, a reflex HIV-1 RNA test will be 
conducted by the central laboratory on the same plasma sample obtained at that visit, if 
available. For management of participants see Section 8.2.2.
4.2.1.2
Safety Endpoints
Safety evaluations will include physical examinations (including vital signs) and laboratory 
tests (eg, hematology, TBNK, chemistry, and urinalysis) performed per the SoA (Section 
1.3). AEs will be evaluated at each visit and assessed according to the guidelines in 
Section 8.4 and Appendix 3. Participants may be asked to return for unscheduled visits to 
perform additional safety monitoring.
Due to decreases in total lymphocyte counts observed in clinical studies with DOR/ISL 
100 mg/0.75 mg, these parameters will be evaluated at Weeks 48, 96, 144, and in the 
optional study extension.
4.2.1.3
Weight and Laboratory Markers
The study will evaluate changes from baseline at Week 48, Week 96, and Week 144 in 
weight, and laboratory markers in the treatment groups to evaluate the impact of DOR/ISL 
on the following outcomes per the SoA (Section 1.3):
Weight
Increases in body weight have been reported in PLWH on long-term ART and have long 
been considered a return-to-health phenomenon. However, evidence suggests that excess 
weight gain may be associated with certain ARV agents, which may have long-term health 
effects [Bailin, S. S., et al 2020] [Shah, S., et al 2021] [Buzon-Martin, L. 2020] [Wood, B. R. 
2021]. In contrast, other ARV drugs, such as TDF and EFV, may have an antiobesogenic 
effect [Hill, A., et al 2019]. The mean change in weight will be compared between 
participants who switch to DOR/ISL and participants who continue taking their baseline 
ART (Sections 8.3.1 and 8.3.9.3). In addition to weight, fat distribution will be measured by 
waist:hip ratio.
Fasting Lipid and Metabolic Profiles
Some antiretrovirals have been associated with lipid abnormalities [U.S. Prescribing 
Information 2017]; thus, key indicators of fasting lipid profiles will be measured 
(Section 8.3.9.1).
08WX9K

PRODUCT: MK-8591A
66
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Insulin resistance has been reported with certain antiretroviral therapies [Carr, A., et al 1998]. 
It is associated with metabolic complications including diabetes, cardiovascular disease, fatty 
liver, and weight gain [Vazquez-Carrera, M. 2016]. Fasting insulin and glucose will be 
measured to calculate HOMA-IR, and HbA1c (fasting or nonfasting) will be measured to 
evaluate glycemic control over time.
The adipokines, leptin and adiponectin, will be measured as exploratory assessments of 
metabolic function and predictors of weight gain [Taylor, E. B. 2021]. These are established 
markers for lipid metabolism and energy utilization to be explored against the various 
baseline ART regimens, particularly as more data emerge about the metabolic effects of 
InSTIs.
Renal Function
Decreases in renal function have been noted with the use of certain NRTIs [U.S. Prescribing 
Information 2019]; thus, key indicators of renal function will be measured (Section 8.3.9.2).
4.2.1.4
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoAs (Section 1.3) and 
Section 8.6 will be used to evaluate PK concentrations of ISL, and as appropriate, 
PK-efficacy, PK-pharmacodynamic, and PK-AE relationships of ISL. PK values including 
AUC, Cmax, and C24 will be explored.
4.2.1.5
Patient-reported Outcomes
PROs can provide unique information on the impact of HIV infection and its treatment from 
the patient’s perspective as some domains are difficult to observe or are subjective and best 
collected through patient report. HIV infection and its treatment can impair HRQoL. 
Symptom burden associated with HIV treatment has decreased with improvements in ART 
regimens but persists despite viral suppression and immunologic recovery. In conjunction 
with efficacy and safety, PRO data may help clinicians and patients in making informed 
decisions on appropriate ART regimens. HTA authorities in many countries recommend 
patient perspectives data and HRQoL measurement as part of their drug benefit evaluations. 
HRQoL data are used to estimate health utility scores, which inform cost-effectiveness model 
analysis.
This study will include 3 self-administered PRO questionnaires (Sections 1.3 SoA, 8.3.10, 
and 9.4.3). The EQ-5D-5L, a generic HRQoL questionnaire, will provide a simple 
descriptive profile and index value for health status used to compute health utilities for health 
economic analyses. The HIVTSQ is a 10-item instrument used to measure satisfaction with 
medications for people with HIV infection. The status version (HIVTSQs) will be used to 
evaluate treatment satisfaction over time. The HIV-SI (also known as the HIV-SDM) is a 
20-item HIV disease-specific questionnaire designed to assess the prevalence and burden of 
adverse effects associated with ART regimens. The PRO questionnaires will be completed up 
to Week 96 at the time points specified in the SoA (Sections 1.3.1, 1.3.2, and 1.3.3.).
08WX9K

PRODUCT: MK-8591A
67
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in 
Appendix 6.
4.2.2
Rationale for the Use of Comparator
This study will evaluate switching from various baseline ART regimens to reflect the diverse 
regimens that are currently used and from which patients might be switched in practice. 
Participants’ baseline antiretroviral combinations have likely been chosen on a case-by-case 
basis, for side effect profile, schedule, pill burden, or any number of other reasons. Allowed 
ART regimens will include stable oral 2-drug or 3-drug combinations (± PK booster) 
(provided a participant meets all other inclusion requirements and does not meet any 
exclusionary criterion). This allows better representation of the real-world use of 
antiretroviral agents and current HIV-1 treatment guidelines. This study will be open-label, 
because blinding of all potential baseline regimens is considered infeasible, not only because 
of the anticipated diversity of the baseline regimens, but also because it could result in a large 
08WX9K

PRODUCT: MK-8591A
68
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
pill burden for the participants who are not on single-tablet regimens QD at baseline. 
Furthermore, the primary efficacy endpoint is based on HIV-1 RNA results, an objective 
laboratory value, which is less susceptible to unblinding bias.
4.2.3
Rationale for the Selected Participant Population
The rationale for the participant population selected for this study is as follows:
•
Participants Switching ART Regimens: Many ART regimens are associated with a 
high likelihood of achieving and maintaining undetectable HIV-1 RNA levels. Although 
70% of all PLWH globally know their HIV status, only 44% are virologically suppressed 
[Joint United Nations Programme on HIV/AIDS 2017]. Drug-associated adverse effects 
and toxicities, food requirements, high pill burdens, frequent dosing, and DDIs with 
concomitant medications are among the reasons that may contribute to lack of adherence 
to prescribed ART regimens. These are the same motivators for patients and prescribers 
to consider switching components of an ART regimen, even in the setting of viral 
suppression before failure can occur.
Furthermore, as the population ages, it is anticipated that switches will become even 
more common in the setting of increasing concern about polypharmacy, long-term 
toxicity, and DDIs related to co- and multimorbidity and risks associated with the 
emergence of HIV-1 variants that are resistant to InSTI, NRTI, and NNRTI treatments.
Life expectancy for PLWH receiving suppressive ART is generally similar to people 
without HIV infection [Farahani, M., et al 2017] [Wandeler, G., et al 2016]. The leading 
cause of mortality in PLWH is no longer attributed to HIV-related complications, but 
rather to comorbid conditions commonly associated with an aging population (eg, 
diabetes, cardiovascular disease, renal disease, cancer).
Participants With Virological Suppression for ≥3 Months: With increasing prevalence of 
early treatment initiation, increasing life expectancy for those who are infected with HIV-1, 
and decreasing incidence rates of new HIV-1 infections in many parts of the world, an 
important population in need of improved treatment regimens is those who are already 
virologically suppressed. Data from the Phase 2 study (MK-8591-011) demonstrate that after 
receiving at least 3 consecutive months of the 3-drug regimen, ISL+DOR+3TC, almost all 
participants with HIV-1 RNA <50 copies/mL maintained virologic suppression on a 2-drug 
regimen, ISL+DOR, through an additional 24 weeks. Based on the results of MK-8591-011, 
enrollment in this study will be open to those who have demonstrated stable suppression with 
HIV-1 RNA <50 copies/mL for ≥3 consecutive months.
4.2.4
Rationale for Collecting Race and Ethnicity Data
The differential effect on efficacy and safety based on any demographic parameter, including 
race or ethnicity, cannot be predicted when evaluating a new investigational drug. Therefore, 
it is important to collect race and ethnicity data to ensure that there is not a differential effect 
based on these parameters and to gain assurance the results observed in the clinical study will 
be representative of the drug’s use in a broader population. As an example, non-Caucasian 
patients were found to have higher plasma concentrations of EFV (an NNRTI) than their 
08WX9K

PRODUCT: MK-8591A
69
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Caucasian counterparts, indicating an increased risk of EFV-induced toxicity in non-
Caucasian persons [Burger, D., et al 2005]. As another example, among PLWH in the US, 
those of African heritage have been found to be less likely to maintain virologic suppression 
compared with other groups, and the factors contributing to this remain to be elucidated 
[Weintrob, A. C., et al 2009] [Ribaudo, H. J., et al 2013]. Thus, subgroup analyses on race 
and ethnicity will be performed to better understand how these parameters may influence 
clinical outcome and toxicity.
4.2.5
Rationale for Collecting Gender Identity Data
Transgender people, defined as those whose gender identities and/or expressions differ from 
the sex assigned to them at birth, have a high prevalence and incidence of HIV infection 
globally [Poteat, T., et al 2016]. When considering HIV treatment, the WHO considers 
transgender people to be a separate key population because of their specific health needs and 
high vulnerability [Department of HIV/AIDS 2015]. Data will be collected in this study to 
assess clinical outcomes in the transgender population.
4.2.6
Rationale for Infant Safety Data Collection
Follow-up through 1 year of age for infants born to participants who become pregnant while 
receiving DOR/ISL provides the ability to monitor growth and development as well as 
potential adverse effects that may be associated with prenatal drug exposure. Growth 
parameters (ie, length, weight, and head circumference) within normal range at 
approximately 1 year of age are key noninvasive indicators that a serious congenital 
malformation caused by in utero drug exposure is unlikely.
4.2.7
Rationale for Continuing Study Intervention During Pregnancy
The US Department of Health and Human Services guidelines currently advise that persons 
who become pregnant while receiving ART for HIV infection should continue their regimen 
provided it is safe, well tolerated, and effective at virologic suppression, because altering the 
regimen could cause an increase in viral load [Panel on Treatment of Pregnant Women with 
HIV Infection and Prev 2018]. Nonclinical developmental and reproductive toxicology 
studies did not identify any teratogenicity or other clinically relevant concerns that would 
preclude continued dosing of DOR/ISL in participants who become pregnant and provide 
documented informed consent to continue study intervention (where allowed by local 
regulations, health authorities, and ethics committees and as appropriate based on available 
data/local standard of care guidelines) (Sections 8.1.1.4 and 8.11.6). For those participants 
continuing on their baseline ART regimens who become pregnant and provide documented 
informed consent to continue study intervention, investigators will need to follow local 
circulars/guidelines for the baseline ART regimen.
There are no clinical data currently available to support breastfeeding by participants who are 
receiving DOR/ISL.
08WX9K

PRODUCT: MK-8591A
70
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
4.2.8
Rationale for Collecting Alcohol and Tobacco Use
Both alcohol use and tobacco use are associated with poor health outcomes. A significant 
number of PLWH across the world die from cardiovascular disease, non-AIDS malignancies, 
and liver disease, which are associated with alcohol and tobacco use [Farahani, M., et al 
2017]. New or worsening existing clinical signs/symptoms, including abnormal laboratory 
results, can be influenced by alcohol and/or tobacco use. The prospective collection of these 
data, occurring once prior to randomization and annually thereafter, is intended to assist in 
the medical management of study participants to help better understand comorbid disease 
outcomes as well as the primary investigators’ determination of the likelihood that the study 
intervention may have caused a potential AE (ie, causality assessment). With smoking and 
alcohol use as known risk factors for cardiovascular disease and liver disease, collection of 
data to monitor these risks among participants is essential to comprehensive safety 
monitoring and better understanding of the safety profile of the IMP(s) against the 
background of comorbid conditions.
4.3
Justification for Dose
IQ (Ctrough/IC50) is the ratio of drug exposure to viral susceptibility. In a Phase 1b proof-of-
concept study (MK-8591-003), single doses as low as 0.5 mg ISL showed robust 
antiretroviral activity at 7 days postdose; this low single-dose provided an IQ threshold of 5 
for wild-type HIV-1 virus. Simulations suggest the ISL-TP trough concentrations achieved 
24 hours after a single-dose of 0.25 mg ISL provide IQs of ~11 for wild-type virus and ~2 for 
M184V virus. After 3 daily doses of 0.25 mg ISL, IQs increase to ~29 for wild-type virus 
and ~6 for M184V/I virus. Steady-state concentrations at later time points will produce even 
higher IQs, as ISL-TP reaches steady-state at ~28 days. These simulations support the 
selection of 0.25 mg ISL in combination with 100 mg DOR to maintain virologic suppression 
in participants who switch from a stable ART regimen at baseline.
In the Phase 2 clinical study (MK-8591-011), 3 daily doses of ISL (0.25, 0.75, and 2.25 mg) 
were evaluated in combination with DOR (100 mg) + 3TC for 24 weeks and subsequently 
with DOR alone through Week 48. All 3 doses of ISL with DOR ± 3TC demonstrated potent 
antiretroviral activity comparable with the comparator (DOR/3TC/TDF) at Week 24 (as a 
3-drug regimen, ISL+DOR+3TC) and at Week 48 (as a 2-drug regimen, ISL+DOR). Overall, 
no ISL dose-response for efficacy was observed. Graphical analysis of steady-state ISL-TP 
trough concentrations and response at Week 48 from MK-8591-011 showed no trends in 
exposure-response. The totality of these efficacy data supports the conclusion that the dose 
range studied (0.25 to 2.25 mg daily) is on the plateau of the dose-response curve. 
MK-8591-011 also demonstrated that all doses of ISL studied, when administered with 
DOR + 3TC or DOR alone, had a favorable AE and tolerability profile through Week 144, 
comparable with that of DOR/3TC/TDF. In the dose-ranging phase of MK-8591-011 (Part 1 
and Part 2 through Week 72), participants who received ISL 0.25 mg QD had similar 
changes in total lymphocyte count and comparable increases in CD4+ T-cell count to those in 
the DOR/3TC/TDF group. See Section 2.2.3 for additional DOR/ISL background 
information.
08WX9K

PRODUCT: MK-8591A
71
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
DOR will be administered at the approved dose of 100 mg. This dose has been studied in 
Phase 1 to Phase 3 studies in treatment-naïve and virologically suppressed participants with 
HIV-1 and was selected based upon favorable efficacy, safety, tolerability, and metabolic 
profiles, as confirmed in Phase 3 studies [Orkin, C., et al 2019] [Molina, J. M., et al 2018] 
[Johnson, M., et al 2019]. Of note, in MK-1439A-024 and MK-1439A-030 [Johnson, M., et 
al 2019] [Wong, A., et al 2019], among 32 participants infected with HIV-1 harboring the 
NNRTI resistance mutations K103N, Y181C, and/or G190A at study entry, all achieved 
virologic suppression following 48 weeks of treatment with DOR/3TC/TDF (24 of 32 
participants had been virologically suppressed on PI or InSTI regimens and 8 had been 
treatment-naïve). Across the Phase 2 and Phase 3 DOR/ISL program, viral resistance was 
observed for 2 TN participants who had received DOR/ISL in study MK-8591A-020.
In summary, a 0.25 mg dose of ISL in combination with 100 mg DOR is predicted to have an 
acceptable safety profile and provide concentrations that will demonstrate potent 
antiretroviral activity against both wild-type virus and most common NRTI- and NNRTI-
resistant variants.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Early study termination may also be considered if the futility criterion is met at the Week 24 
IA (Section 9.7).
08WX9K

PRODUCT: MK-8591A
72
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
5
STUDY POPULATION
Participants ≥18 years of age with HIV-1 who have been virologically suppressed for 
≥3 consecutive months on a stable oral 2-drug or 3-drug combination (± PK booster) ART 
will be enrolled in this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Is HIV-1 positive with plasma HIV-1 RNA <50 copies/mL at screening.
Note: A single repeat of the plasma HIV-1 RNA screening test will be allowed, provided 
results are available within the 45-day screening window.
2. Has been receiving continuous, stable oral 2-drug or 3-drug combination (± PK booster) 
ART with documented viral suppression (HIV-1 RNA <50 copies/mL) for 
≥3 consecutive months prior to providing documented informed consent and has no 
history of prior virologic treatment failure on any past or current regimen.
Notes:
An HIV-1 RNA result above the lower level of detection (ie, transient detectable viremia) 
that is not clinically significant during the 3 months prior to providing documented 
informed consent is acceptable.
Previous regimen switches for tolerability, side effects, dosing convenience, or cost are 
permitted if they occurred >3 months prior to providing documented informed consent.
Demographics
3. Is an individual of any sex/gender, at least 18 years of age, at the time of providing the 
informed consent.
08WX9K

PRODUCT: MK-8591A
73
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Participants Assigned Female Sex at Birth
4. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
-
Uses an acceptable contraceptive method, or is abstinent from penile-vaginal 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 42 days after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
POCBPs should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions are more stringent 
than the requirements above, the local label requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the 
first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive. 
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.4 and Appendix 2.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
5. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Has HIV-2 infection.
2. Has hypersensitivity or other contraindication to any of the components of the study 
interventions as determined by the investigator.
08WX9K

PRODUCT: MK-8591A
74
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
3. Has a diagnosis of an active AIDS-defining opportunistic infection within 30 days prior 
to screening.
4. Has active HBV infection (defined as HBsAg-positive or HBV DNA-positive).
Note: Past HBV infection or previous HBV vaccination (defined as HBsAg-negative and 
anti-HBs-positive) is not an exclusion criterion.
5. Has chronic HCV infection (detectable HCV RNA) with laboratory values consistent 
with cirrhosis (serum albumin <2.8 g/dL or INR >1.7 or platelets <100 × 109 cells/L in 
the absence of another explanation for the abnormal laboratory values).
Note: Treatment with direct-acting antiviral therapies is not exclusionary.
6. Has a history of malignancy ≤5 years prior to providing documented informed consent 
except for adequately treated basal cell or squamous cell skin cancer, in situ cervical 
cancer, or cutaneous Kaposi’s sarcoma.
7. Has a history or current evidence of any condition (including active tuberculosis), 
therapy, laboratory abnormality, or other circumstance (including drug or alcohol use or 
dependence) that might, in the opinion of the investigator, confound the results of the 
study or interfere with the participant’s participation for the full duration of the study, 
such that it is not in the best interest of the participant to participate.
Prior/Concomitant Therapy
8. Is taking or is anticipated to require systemic immunosuppressive therapy, immune 
modulators, or strong and moderate CYP3A inducers (or any other prohibited therapies 
outlined in Section 6.5) from 45 days prior to Day 1 through the study treatment period.
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) are allowed.
9. Has taken long-acting HIV therapy at any time (eg, cabotegravir, lenacapavir).
Prior/Concurrent Clinical Study Experience
10. Is currently participating in or has participated in a clinical study and received (or is 
receiving) an investigational compound or device from 45 days prior to Day 1 through 
the study treatment period.
Notes:
Participants who have had prior exposure to ISL (any duration any time prior to Day 1) 
are excluded.
Baseline ART is not considered investigational in countries where it has received health 
authority approvals, regardless of commercial availability.
08WX9K

PRODUCT: MK-8591A
75
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Participants completing other clinical studies who are receiving placebo or approved 
therapy may be eligible to enroll without waiting 45 days with approval from the 
Sponsor.
Concurrent participation in observational or noninterventional studies may be permitted 
and must be discussed with the Sponsor prior to enrollment and through study duration.
Diagnostic Assessments
11. Has a documented or known virologic resistance to DOR, as demonstrated by any of the 
following DOR resistance substitutions in reverse transcriptase:
V106A/M, V108I, Y188L, H221Y, P225H, F227C/L/V, M230I/L, L234I, P236L, or 
Y318F.
Notes:
Participants who do not have documentation of resistance testing may enroll.
This exclusionary list is for the purpose of this study and includes major (or primary) 
DOR resistance substitutions, but not substitutions that are minor and found as naturally 
occurring polymorphisms.
12. Has exclusionary laboratory values (completed by the central laboratory) within 45 days 
prior to Day 1 as listed in Table 1.
Note: A single repeat of a laboratory screening test will be allowed for test results that 
are unexpected based on documented prior laboratory results, but the repeat test results 
must be available within the 45-day screening window.
Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
ALP
>3 × ULN
AST
>5 × ULN
ALT
>5 × ULN
Calculated CrCl
≤30 mL/min based on the Cockcroft-Gault equation (Appendix 8)
CD4+ T-cell Count
<50 cells/mm3
Hemoglobin
<9.0 g/dL (female) or <10.0 g/dL (male)
Total Lymphocyte Count
<0.650 × 109 cells/L (Grade 1 DAIDS criteria)
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CrCl=creatinine clearance; DAIDS=Division of AIDS; ULN=upper limit of normal.
08WX9K

PRODUCT: MK-8591A
76
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Other Exclusions
None
5.3
Lifestyle Considerations
There are no lifestyle restrictions.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
08WX9K

PRODUCT: MK-8591A
77
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
Country-specific requirements are noted in Appendix 7.
08WX9K

PRODUCT: MK-8591A
78
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Group 
1
Experimental doravirine/
islatravir
Drug
Tablet
100 mg/
0.25 mg
100 mg/
0.25 mg 
QD
Oral
Day 1 to 
Week 144
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Group1 Experimental doravirine/
islatravir
Drug
Tablet
100 mg/
0.25 mg
100 mg/
0.25 mg 
QD
Oral
Week 144 
up to Week 
240
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Group 
2
Active 
Comparator
Baseline 
antiretroviral 
therapy 
regimen
Drug
Unassigned
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
Oral
Day 1 to 
Week 48
Comparator IMP
Local 
country-
level 
sourcing
Group 
2
Active 
Comparator
Baseline 
antiretroviral 
therapy 
regimen 
(bictegravir/
emtricitabine/
tenofovir 
alafenamide 
only)
Drug
Tablet
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
Oral
Day 1 to 
Week 48
Comparator IMP
Provided 
centrally 
by the 
Sponsora
Group 
2
Experimental doravirine/
islatravir
Drug
Tablet
100 mg/
0.25 mg
100 mg/
0.25 mg 
QD
Oral
Week 48 to 
Week 144
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Group 
2
Experimental doravirine/
islatravir
Drug
Tablet
100 mg/
0.25 mg
100 mg/
0.25 mg 
QD
Oral
Week 144 
up to Week 
240
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
08WX9K

PRODUCT: MK-8591A
79
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; QD=once-daily.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note: Applicable only to South Africa. The Sponsor will centrally supply bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as active comparator for participants 
in South Africa to continue receiving BIC/FTC/TAF as their ART regimen (ie, participants receiving BIC/FTC/TAF in study MK-8591A-020 who enroll in study 
MK-8591A-051 and are randomized to Group 2).
08WX9K

PRODUCT: MK-8591A
80
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
Study intervention will be extended for participants who become pregnant on-treatment and 
provide documented informed consent to continue their assigned study intervention 
(DOR/ISL or baseline ART), as specified in Sections 1.3.4 and 8.11.6.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
08WX9K

PRODUCT: MK-8591A
81
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 2:1 ratio to Group 1 or 
Group 2, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factor:
1. Baseline ART Regimen (PI-containing regimens [including PI- + InSTI-containing 
regimens], InSTI-containing regimens [non-PI-containing regimens], and non-PI- and 
non-InSTI-containing regimens)
The stratification factor helps to ensure that the treatment arms will be well balanced and the 
study results will not be confounded by the participants’ baseline ART regimens.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Participants should be instructed to bring the study intervention bottles, whether clinical 
supplies provided by the Sponsor or ART provided by study participants, to their visits. At 
each visit, the number of tablets remaining in the study packaging will be counted, reviewed, 
and recorded. The results will be used to assess participant compliance. If a discrepancy is 
noted, the investigator/study coordinator must discuss the discrepancy with the participant 
and the explanation must be documented. All participants should be reminded of the 
importance of taking their study intervention as instructed for the entire duration of the study.
Decisions to temporarily withhold study intervention because of an AE or other reason(s) 
will be reviewed on a case-by-case basis by the investigator.
Interruptions from the protocol-specified treatment plan that are expected to be 
≥7 consecutive days require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
•
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct 
questioning, counting returned tablets/capsules, etc, during the site visits and documented 
in the source documents and CRF. Deviation(s) from the prescribed dosage regimen 
should be recorded in the CRF.
08WX9K

PRODUCT: MK-8591A
82
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
A record of the number of DOR/ISL tablets dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays will also be 
recorded in the CRF.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medications or vaccinations specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the participant’s primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
The Sponsor Clinical Director should be contacted if there are any questions regarding prior 
or concomitant therapy.
Prior and concomitant therapies listed in Table 3 are not permitted from 45 days prior to 
Day 1 through the study treatment period. Table 3 is not comprehensive, and the investigator 
should use their medical judgment when assessing a participant’s prior and concomitant 
therapy(ies). The Sponsor Clinical Director or designee should be contacted if there are any 
questions about a therapy not on the list below or regarding potential DDIs with a specific 
treatment that the participant may plan to receive.
In instances where the local product information for DOR or baseline ART regimen is more 
restrictive with regard to prohibited (ie, contraindicated or not recommended) therapy(ies), 
the local product information supersedes this section.
08WX9K

PRODUCT: MK-8591A
83
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 3
Prohibited Therapies
Therapy Type
Prohibited Therapy(ies)
Strong and moderate 
CYP3A inducers
Including but not limited to:
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Enzalutamide
Rifabutin
Rifampin
Rifapentine
Mitotane
St. John’s Wort
Herbal remedies (only those that are strong or moderate CYP3A inducers)
Modafinil
Bosentan
Nafcillin
Lumacaftor
Metamizole
Nonstudy ART
All nonstudy antiretrovirals (with the exception of baseline ART during the 
screening period and intrapartum treatment [eg, IV AZT] in the case of 
pregnancy) including treatments for a viral infection other than HIV-1, such as 
hepatitis B, with an agent that is active against HIV-1
Entecavir therapy for HBV infection is permitted.
Long-acting HIV therapy (eg, cabotegravir, lenacapavir) is not permitted at any 
time.
Time-limited course of ritonavir as a pharmacokinetic enhancer is permissible 
(eg, nirmatrelvir/ritonavir for the treatment of COVID-19).
Immunosuppressive 
therapies
Immune therapy agents, immune modulators, or other systemic 
immunosuppressive therapy, including interferon-based treatment for hepatitis
Time-limited courses of corticosteroids (eg, for asthma exacerbation) are 
permitted.
Investigational agents
All nonstudy investigational agents including devices
Any agents (eg, vaccine or therapy for COVID-19) approved locally for 
Emergency Authorized Use, or equivalent, that do not have a known or 
anticipated DDI with study intervention, are permitted.
Additional prohibited 
therapies based on 
baseline ART
Refer to the approved local label
Additional prohibited 
therapies based on 
ISL
Pentostatin
ART=antiretroviral therapy; AZT=zidovudine; COVID-19=coronavirus disease caused by severe acute respiratory 
syndrome coronavirus 2; CYP3A=cytochrome P450 3A; DDI=drug-drug interaction; HBV=hepatitis B virus; 
HIV=human immunodeficiency virus; HIV-1=human immunodeficiency virus type 1; ISL=islatravir; IV=intravenous.
08WX9K

PRODUCT: MK-8591A
84
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
Dose modification of DOR/ISL is not permitted during the study (see Section 4.3 for dose 
justification).
Modifications and/or regimen changes of baseline ART (Group 2) may be permissible, but 
require Sponsor approval (ie, FTC and 3TC substitutions, PI dose escalation during 
pregnancy).
6.7
Intervention After the End of the Study
If DOR/ISL is commercially accessible, participants in both groups who complete the 
Week 144 visit should follow the end of treatment procedures outlined in Section 1.3.1 and 
transition to commercially accessible DOR/ISL or local standard of care, as clinically 
appropriate.
If DOR/ISL is not commercially accessible, participants in both groups who complete the 
Week 144 visit will be provided the option to receive DOR/ISL in an optional study 
extension until Week 240 or until DOR/ISL becomes commercially accessible (whichever 
comes first). Participants who do not enter the optional study extension should follow 
Section 1.3.1 and transition to local standard of care as clinically appropriate.
If DOR/ISL is not commercially accessible when the optional study extension ends at 
Week 240, and provided DOR/ISL clinical development continues, a mechanism will be put 
in place (eg, pre-license patient access program) for participants to continue receiving 
DOR/ISL beyond the end of the study until it becomes commercially accessible. The details 
of this mechanism will vary per local regulations.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable.
08WX9K

PRODUCT: MK-8591A
85
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
Discontinuation of study intervention does not represent withdrawal from the study.
Participants who discontinue study intervention before completion of the protocol-specified
treatment period may continue to be monitored in the study as specified in Section 8.11.3, 
unless the participant has withdrawn from the study (see Section 7.2).
A participant must be discontinued from study intervention for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
After prolonged study intervention interruption that prohibits restarting study intervention 
(per Section 6.4).
•
The participant has a medical condition or personal circumstance (for pregnancy, see 
Section 8.11.6) which, in the opinion of the investigator and/or Sponsor, places the 
participant at unnecessary risk from continued administration of study intervention.
•
The participant chooses to breastfeed.
Note: Study intervention can continue until breastfeeding is initiated.
•
The participant has clinically significant confirmed viremia as defined in 
Section 4.2.1.1.2. Do not discontinue prior to consultation with the Sponsor when 
feasible.
•
The participant has a new AIDS-defining opportunistic infection as listed in Appendix 9, 
ie, a Category C condition according to the CDC 1993 Revised Classification System for 
HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents 
and Adults [Centers for Disease Control (CDC) 1992].
•
The participant has an SAE or Grade 4 laboratory AE assessed by the investigator to be 
related to study intervention AND that is life-threatening or results in prolonged 
hospitalization.
•
A participant must be discontinued from study intervention and managed per 
Section 8.11.5 if any of the criteria in Table 4 are confirmed. If the investigator believes 
there is an alternative explanation for the result (eg, COVID-19), consultation between 
the investigator and Sponsor is required when evaluating the participant for 
discontinuation.
08WX9K

PRODUCT: MK-8591A
86
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 4
Discontinuation Criteria for Specified Decreases in Total Lymphocyte Counts or 
CD4+ T-cell Counts
Laboratory 
Test
Criteriona
Confirmationb,c
Total 
lymphocyte 
count
A new on-treatment value <1.0 × 109 cells/L with a 
≥30% decline from baselinea
Repeat measurement 
10 to 14 weeks later 
(or at the next 
scheduled study visit)
CD4+ T-cell 
count
If at baselinea:
And on-treatment:
Repeat measurement 
10 to 14 weeks later 
(or at the next 
scheduled study visit)
≥500 cells/mm3
<350 cells/mm3
≥350 to ≤499 cells/mm3
≥30% decline from 
baseline and 
<350 cells/mm3
≥200 to ≤349 cells/mm3
≥30% decline from 
baseline and 
<200 cells/mm3
≤199 cells/mm3
≥30% decline from 
baseline
CD4+=cluster of differentiation 4-positive; DOR=doravirine; ISL=islatravir; SoA=Schedule of Activities.
a
Baseline is at Day 1 for participants in Group 1. Baseline is at Week 48 for participants in Group 2. 
Baseline in the optional study extension is at Week 144 for all participants who continue in the extension. 
b
If the on-treatment measurement meets the specified discontinuation criteria, a consecutive, 
confirmatory measurement within 10 to 14 weeks is required. Confirmatory laboratory measurements can be 
conducted at the next clinic visit if the next scheduled visit occurs within the interval required for repeat 
testing. Note: If repeat testing at the next scheduled visit occurs sooner than 10 weeks and shows resolution, 
the results may be used to confirm the resolution, and testing should be resumed per the routine SoA. If 
repeat testing at the next scheduled visit occurs sooner than 10 weeks and does not show resolution, 
discontinuation is not required. Testing is still required in the timeframe of 10 to 14 weeks to confirm 
discontinuation.
c
The time frame for confirmation of decreases in total lymphocyte count or CD4+ T-cell count may be 
extended in the setting of intercurrent illness, immunization, or treatment nonadherence or other treatment 
interruption. Allow approximately 4 weeks following resolution of illness, immunization, or treatment 
nonadherence or other treatment interruption before collecting the confirmation sample.
In addition to this list of discontinuation criteria, Country-specific criteria are in Appendix 7.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
08WX9K

PRODUCT: MK-8591A
87
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
08WX9K

PRODUCT: MK-8591A
88
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The amount of blood collected from each participant over the duration of the study is 
provided in Appendix 2.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
08WX9K

PRODUCT: MK-8591A
89
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.1.3
Consent for Continuation of Study Intervention During Pregnancy
Upon confirming that a participant is pregnant (Section 8.3.4), the investigator or medically 
qualified designee and the participant will discuss the potential benefits and risks of 
continuing (or discontinuing) study intervention (Section 8.11.6). A separate consent is 
required to continue study intervention in participants who become pregnant 
(Section 8.11.6.1). Study intervention (DOR/ISL or baseline ART, depending on study 
intervention assignment at the time of the confirmatory pregnancy test) will be provided for 
participants who consent to continue study intervention during pregnancy. Note, participants 
who become pregnant are not allowed to switch study intervention at any time during the 
pregnancy. The investigator or medically qualified designee will explain the consent to the 
participant, or the participant’s legally acceptable representative, answer all of their 
questions, and obtain documented informed consent before continuing study intervention. A 
copy of the informed consent will be given to the participant.
08WX9K

PRODUCT: MK-8591A
90
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.1.1.4
Consent for Postnatal Infant Safety Data Collection Through One Year of 
Age
Once a pregnancy is confirmed to be continuing, the investigator or medically qualified 
designee will explain the consent for infant safety data collection to the participant, or the 
participant’s legally acceptable representative, answer all questions, and obtain documented 
informed consent to collecting any data related to infant safety. A copy of the informed 
consent will be given to the participant.
8.1.1.5
Consent for Optional Study Extension
The investigator or medically qualified designee will explain the consent for the optional 
study extension to the participant, or the participant’s legally acceptable representative, 
answer all of his/her questions, and obtain documented informed consent before performing 
any procedure related to the optional study extension. A copy of the informed consent will be 
given to the participant. The participant must be informed that once DOR/ISL becomes 
commercially accessible they will discontinue from the study.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history should include information pertaining to the diagnosis of HIV-1 and AIDS (if 
applicable) and year diagnosed. If the participant has been previously diagnosed with any 
AIDS-defining conditions or CD4+ T-cell count <200 cells/mm3, the condition as well as a 
corresponding medical history of AIDS must be recorded. In addition, participants’ history of 
smoking and alcohol consumption should be obtained and recorded on the appropriate eCRF. 
For participants assigned female sex at birth, childbearing potential should be assessed. 
Menstrual history, contraceptive use, and recent sexual activity should be reviewed for 
POCBP to exclude potential or early, undiagnosed pregnancy prior to and on Day 1.
08WX9K

PRODUCT: MK-8591A
91
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication(s) taken by the participant within 45 days before the first dose of study 
intervention.
All prior ARTs taken by the participant from the initiation of their therapy (if available) will 
be recorded before the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
DOR/ISL will be provided per Table 2 and dispensed through the IRT system at visits 
indicated in the SoA (Sections 1.3.1, 1.3.4, and 1.3.5).
The Sponsor will not provide baseline ART regimens. Participants will provide their own
ART medications, in accordance with local regulations (Table 2). Country-specific 
requirements are noted in Appendix 7.
Study intervention should begin within 24 hours of randomization (ie, on the day of 
randomization after all pretreatment assessments, as specified in the SoA, are performed or 
as soon as possible after randomization).
08WX9K

PRODUCT: MK-8591A
92
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.1.8.1
Timing of Dose Administration
Group 1
From Day 1 to Week 144, participants in Group 1 will take 1 tablet of DOR/ISL at 
approximately the same time each day without regard to food. If more than 1 bottle is 
dispensed, the participant is instructed to use all of the medication in the 1 bottle before 
opening another bottle.
Group 2
•
Day 1 to Week 48: Participants will take baseline ART as per approved label.
•
After Week 48 and up to Week 144: Participants will take 1 tablet of DOR/ISL 
(unsupervised at their home) at approximately the same time each day without regard to 
food. If more than 1 bottle is dispensed, the participant is instructed to use all of the 
medication in the 1 bottle before opening another bottle.
Note: Those participants in Group 2 who become pregnant prior to Week 48 and consent to 
continue baseline ART will not switch to DOR/ISL and will discontinue from the study 
(Section 8.11.6).
From Week 144 to 240, all participants will take 1 tablet of study intervention (DOR/ISL) 
QD at the same time each day.
If a participant misses a dose of DOR/ISL, the following guidance should be followed:
•
If ≤12 hours from the missed dose, the missed dose should be taken, and the normal 
dosing schedule resumed.
•
If >12 hours from the missed dose, the missed dose should be skipped, and the normal 
dosing schedule resumed. The participant should not double the next dose to compensate 
for what has been missed.
If a participant misses a dose of baseline ART, guidance in the approved label should be 
followed.
For participants who become pregnant and consent to continue DOR/ISL, see 
Section 8.11.6.1.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the base study should 
have an Early Discontinuation visit performed per SoA (Section 1.3.1) and should be 
encouraged to continue to be followed as outlined in the SoA and Section 8.11.3.1.
Participants who end study intervention while in the optional study extension (after 
Week 144 and prior to Week 240) should have a Discontinuation of Study Treatment 
08WX9K

PRODUCT: MK-8591A
93
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
(optional study extension) visit performed per the SoA (Section 1.3.5) and should be 
followed as outlined in the SoA and Section 8.11.3.2.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Early Discontinuation visit at the time of withdrawal. Any AEs 
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
Participants who discontinue study intervention due to specified decreases in total 
lymphocyte count or CD4+ T-cell count (Table 4) should be managed per Section 8.11.5 
until their counts recover. Participants who become pregnant and discontinue study 
intervention should be managed per Section 8.11.6.2.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
08WX9K

PRODUCT: MK-8591A
94
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.2
Efficacy Assessments
8.2.1
HIV-1 RNA
Plasma HIV-1 RNA quantification will be performed at the central laboratory using a PCR 
assay with a lower limit of detection of <50 copies/mL.
8.2.2
Management of Participants With Viremia
When viremia (HIV-1 RNA ≥50 copies/mL) is detected (Section 4.2.1.1.2), the investigator 
should query the participant regarding adherence to study intervention, intercurrent illness, or 
recent immunization. All cases of viremia must be confirmed, and the participant should 
continue to take the full assigned dosage of study intervention while awaiting confirmation.
If a participant has an on-treatment HIV-1 RNA value ≥50 copies/mL, a reflex HIV-1 RNA 
test will be conducted by the central laboratory on the same plasma sample obtained at that 
visit, if available. Management of participants should be based on reflex HIV-1 RNA results 
if available.
•
If the reflex HIV-1 RNA result is <50 copies/mL, no further action is required.
•
If the reflex HIV-1 RNA result is ≥50 copies/mL or there is insufficient sample available 
for reflex testing, the participant will be asked to return to the clinic in 4 weeks (± 1 
week) for Viremia Confirmation (see Section 8.2.2.1 and the SoA in Section 1.3.2).
8.2.2.1
Viremia Confirmation
At the Viremia Confirmation visit:
•
If the HIV-1 RNA value is ≥50 copies/mL, a reflex HIV-1 RNA test will be conducted by 
the central laboratory on the same plasma sample obtained at that visit, if available.
•
If the reflex HIV-1 RNA result is <50 copies/mL, no further action is required.
•
If HIV-1 RNA result is ≥200 copies/mL (on both primary and reflex tests, if available) on 
consecutive visits 4 weeks (±1 week) apart, then clinically significant viremia is 
confirmed, and the participants will be assessed for potential discontinuation from study 
intervention (Sections 7.1. and 8.2.2.1.1).
Allow approximately 4 weeks after resolution of illness, immunization, or treatment 
nonadherence or other treatment interruption for drawing these confirmation samples.
8.2.2.1.1
Participants With Clinically Significant Confirmed Viremia 
(≥200 Copies/mL)
Participants with confirmed HIV-1 RNA of ≥200 copies/mL (per Section 4.2.1.1.2) will be 
assessed for development of viral drug resistance (Section 8.2.2.1.2) and discontinuation 
from study intervention (Section 7.1).
08WX9K

PRODUCT: MK-8591A
95
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
If it is determined that study intervention discontinuation is appropriate, Early 
Discontinuation of Treatment and End of Treatment Follow-up visit procedures should be 
completed (Sections 1.3.2 and 8.11.3) and the participant managed by the investigator per 
local standard of care.
8.2.2.1.2
HIV-1 Viral Drug Resistance Testing
Participants with confirmed HIV-1 RNA ≥200 copies/mL at any time during the study will 
be assessed for development of viral drug resistance.
Samples will be collected for genotypic and phenotypic HIV-1 viral drug resistance testing 
per the SoA (Section 1.3) and used to assess resistance-associated substitutions and viral 
susceptibility as applicable during the study. If clinically significant viremia is confirmed, the 
plasma sample from the Viremia Confirmation visit will be the primary sample used for 
HIV-1 genotypic and phenotypic testing.
8.2.2.1.3
Participants With Low-level Viremia (≥50 and <200 Copies/mL)
Participants with confirmed HIV-1 RNA ≥50 and <200 copies/mL should continue study 
intervention and all regularly scheduled study visits during which HIV-1 RNA levels will be 
monitored per the SoA (approximately every 3 months). Additional visits may be conducted 
to monitor HIV-1 RNA levels more frequently than every 3 months, if appropriate, after 
discussion with the Sponsor.
Investigators should use their clinical judgment regarding the most appropriate clinical 
management of participants, if more stringent local guidelines apply, and may contact the 
Sponsor’s Clinical Director to discuss questions on clinical management of individual 
participants.
8.2.3
T and B Lymphocyte and Natural Killer Cell (TBNK) Profile
A TBNK panel, including CD4+ T-cell count (Table 18), will be performed as specified in 
Appendix 2. Refer to Section 8.11.5 for guidance on management of participants with 
decreased total lymphocyte count or decreased CD4+ T-cell count. TBNK panel assessments 
that are considered exploratory do not need to be evaluated by the investigator.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in Table 19, Table 20, Table 21, and Table 22 in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
08WX9K

PRODUCT: MK-8591A
96
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard at the visits specified 
in the SoA (Section 1.3). The full physical examination will include examination of body 
systems including, but not limited to, general appearance, skin, neck, eyes, ears, nose, throat, 
breast, lungs, heart, abdomen, back, lymph nodes, extremities, and nervous system.
Height and weight will also be measured and recorded at the visits specified in the SoA 
(Section 1.3.1 for Height and Section 1.3 for Weight). Height measurements should be taken 
using a stadiometer (recommended but not required). Participants should remove their shoes 
and stand as tall and straight as possible. Weight measurements should be taken per 
Section 8.3.1.1.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard at the visits 
specified in the SoA (Section 1.3). This examination will be sign- and symptom-directed and 
based on the participant’s condition and circumstances. The investigator should note any 
changes in the participant’s condition (body systems) since the last examination, not 
precluding examination of any body system(s) as clinically indicated.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Weight
Weight will be measured and recorded at the visits specified in the SoA (Section 1.3). 
Participants should remove their shoes and wear a single layer of clothing at each 
measurement.
8.3.2
Vital Signs
Vital signs will be measured after approximately 5 to 10 minutes rest and will include pulse, 
systolic and diastolic BP, body temperature, and RR.
Note: Oral temperatures are preferred but not required.
8.3.3
Electrocardiograms
A local 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA. Results must be 
available prior to randomization. Sites are to use an ECG machine that automatically 
calculates the HR and measures PR, QRS, QT, and QTc intervals. Clinically significant 
findings must be documented in the source documents and captured in the appropriate eCRF.
If an ECG is performed for any medical reason while the participant is on study intervention 
or during the follow-up period, any clinically significant changes compared with the baseline 
ECG appropriately reported as per requirements of safety reporting.
08WX9K

PRODUCT: MK-8591A
97
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.3.4
Confirmation of Contraception and Pregnancy Testing
POCBP are required to confirm heterosexual abstinence or use of contraception to prevent 
pregnancy during the base study, optional study extension, and for 42 days after the last dose 
of study intervention (base study or optional study extension). POCBP will be tested for 
pregnancy at each visit as outlined in Sections 1.3 and 5.1 and Appendix 5.
Participants who are POCBP should be asked at study visits per the SoA to verbally confirm 
heterosexual abstinence or use of contraception since the prior visit, according to the 
Contraceptive Guidance in Appendix 5. Confirmation should be noted in the source 
documents for each visit.
Urine pregnancy test kits will be provided by the central laboratory to perform locally at each 
visit. In the event of a positive urine or indeterminate pregnancy test result, serum pregnancy 
testing for confirmation of the pregnancy must be performed by the central laboratory. A 
duplicate serum pregnancy test may be sent to a local laboratory to expedite results per 
investigator discretion. Positive urine pregnancy tests (except those from the Screening Visit) 
which have been confirmed by serum testing must be reported to the Sponsor using the 
appropriate eCRF within 24 hours of learning of the event. If a participant becomes pregnant, 
refer to Section 8.11.6.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during participation in the study.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Table 18 in Appendix 2, must 
be conducted in accordance with the Laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 42 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or until a new baseline is established as determined by the investigator.
08WX9K

PRODUCT: MK-8591A
98
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
If laboratory values indicate specified decreases in total lymphocyte count or CD4+ 
T-cell count (Table 4), participants must be managed per Section 8.11.5. TBNK panel 
assessments that are considered exploratory do not need to be evaluated by the 
investigator (Section 8.2.3 and Table 18).
8.3.6
HBV Assessments
Participants coinfected with HIV-1 and HBV who discontinue an antiretroviral medication 
that also has activity against HBV (3TC, FTC, TAF, or TDF) may experience an acute 
exacerbation of HBV. Therefore, participants who have evidence of past HBV exposure 
(anti-HBc-positive) and who meet enrollment criteria will be closely monitored during the 
study.
All eligible participants must be HBsAg-negative and HBV DNA-negative at screening. 
Individuals who are anti-HBc-positive and HBV DNA-positive at screening are excluded. 
Individuals who are anti-HBc-positive but HBV DNA-negative at screening are eligible to 
enroll. All participants will have repeat hepatitis B serology and HBV DNA testing at Weeks 
48, 96, and 144 during the base study (per the SoA Section 1.3.1) and at Week 192 during the 
optional study extension (per the SoA Section 1.3.5).
For the duration of the study (base study and optional study extension), participants who are 
anti-HBc-positive should be monitored for possible HBV reactivation. Samples will be taken 
to monitor for HBsAg and HBV DNA per the SoA (Section 1.3). Investigators should also 
pay close attention to changes from baseline in ALT, AST, bilirubin, and alkaline 
phosphatase.
Participants in Group 1 will be monitored for possible HBV reactivation for the duration of 
the study.
Group 2 participants who were anti-HBc-positive, but HBV DNA-negative at baseline and 
remain so, may continue in the study and switch study intervention at Week 48. Group 2 
participants will be monitored for possible HBV reactivation beginning at Week 36.
Participants in either treatment group who are confirmed to be HBsAg-positive or have 
confirmed quantifiable HBV DNA after randomization will be managed by the investigator 
per local standard of care and/or referred for management of their HBV infection. 
Participants may be allowed to continue study intervention if deemed medically appropriate 
upon consultation with the Sponsor. After Week 144 while in the optional study extension, 
participants who are confirmed to be HBsAg-positive or have confirmed quantifiable HBV 
DNA will be managed by the investigator per local standard of care and/or referred for 
management of their HBV infection. See Appendix 7 for Country-specific requirements.
Therapies indicated for HBV that also have potent activity against HIV (eg, adefovir, TDF, 
TAF, FTC, or 3TC) are prohibited (Section 6.5). Entecavir therapy for HBV infection is 
allowed.
08WX9K

PRODUCT: MK-8591A
99
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.3.7
HCV Assessment
HCV serology will be performed at screening and if the individual is HCV antibody positive, 
reflex testing will be performed for HCV RNA to assess study eligibility. Repeat screening if 
indicated per local standard of care.
8.3.8
Tobacco and Alcohol Assessments
Participants’ use of tobacco/vaping and alcohol will be obtained and recorded as specified in 
the SoA (Section 1.3.1).
8.3.9
Exploratory Clinical Marker Assessments 
The following samples will be collected and assessments performed as specified in the SoA 
(Section 1.3.1) and Appendix 2 (Table 18) for exploratory evaluation of markers of energy 
and metabolism, renal function, and body composition:
•
Blood for fasting lipid and metabolic profiles (Section 8.3.9.1)
•
Blood for renal function markers (Section 8.3.9.2)
•
Urine for renal function markers (Section 8.3.9.2)
•
Waist and hip measurements (Section 8.3.9.3)
8.3.9.1
Fasting Lipid and Metabolic Profiles
Participants will be asked to fast for at least 8 hours prior to visits where blood will be taken 
to measure insulin, glucose, HDL-C, LDL-C, TG, TC, and non-HDL-C as specified in the 
SoA (Section 1.3.1). HOMA-IR will be calculated.
Note: Participants with type 1 diabetes mellitus should not fast and should not have insulin 
levels tested. Participants with type 2 diabetes mellitus taking medications that may result in 
hypoglycemia should delay their morning dose of diabetic medication while fasting and take 
it after the blood draw for testing.
HbA1c should be collected for all nonpregnant participants irrespective of fasting or 
nonfasting status; HgbA1c should not be collected in pregnant participants. 
Blood to evaluate energy and metabolism, as measured by the adipokines, leptin and 
adiponectin, will be collected as indicated in the SoA (Section 1.3.1).
08WX9K

PRODUCT: MK-8591A
100
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.3.9.2
Renal Function
Urine and blood samples will be collected to evaluate renal function as measured by key 
indicators, such as the following potential analytes and calculations, as indicated in the SoA 
(Section 1.3.1) and Appendix 2 (Table 18):
•
Urine: albumin/Cr, eGFR, protein, B-2M/Cr, and RBP/Cr
•
Serum: cystatin-C and Cr
Equations for CrCl and eGFR calculation (Cockcroft-Gault and MDRD equations, 
respectively) are in Appendix 8.
8.3.9.3
Waist and Hip Measurements
Participants should be asked to stand erect, relaxed and should not hold in their stomach 
during measurements. Waist circumference will be measured midway between the iliac crest 
and the lower rib margin. Hip circumference will be measured at the intertrochanteric level. 
Measurements should be taken with a stretch-resistant measuring tape. Waist-to-hip ratios 
will be calculated as waist (cm)/hip (cm) by the Sponsor circumferences.
BMI will be calculated by the Sponsor using weight and height measurements taken as 
specified in the SoA (Section 1.3) and Section 8.3.1.
8.3.10
Administration of Patient Questionnaires
Participants will complete 3 PRO questionnaires to be administered in the following order: 
EQ-5D-5L, HIVTSQ, and HIV-SI/SDM, as specified in the SoA (Sections 1.3.1, 1.3.2, and 
1.3.3). Participants are to complete the questionnaires on their own at the site on paper during 
the appropriate study visit (see SoA) prior to being seen by the investigator, discussing any 
medical conditions with the study personnel, or receiving any medical results. The 
questionnaires should not be administered to participants who are unable to complete 
questionnaires unassisted or for whom native language translations of the questionnaires are 
unavailable.
The participant responses to questionnaires will be entered into the appropriate eCRF by site 
staff according to data entry guidelines.
PROs are not administered after Week 96.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
08WX9K

PRODUCT: MK-8591A
101
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment; if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention randomization through study duration, all AEs, SAEs, and 
other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
For infants born to participants who become pregnant and consent to infant safety data 
collection, SAEs (including perinatal HIV-1 infection) occurring through 1 year of age must 
be reported by the investigator to the Sponsor within 24 hours of learning of the event.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
08WX9K

PRODUCT: MK-8591A
102
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 5
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
AE Collection 
Period
Reporting 
Period:
After the 
Protocol-
specified AE 
Collection 
Period
Time Frame 
to Report 
Events and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout, 
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
Potential or
confirmed DILI 
events (requires 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI/ 
confirmed DILI
– to be reported as 
an ECI and SAE 
with OME 
criteria in the 
absence of other 
serious criteria
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
08WX9K

PRODUCT: MK-8591A
103
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
AE Collection 
Period
Reporting 
Period:
After the 
Protocol-
specified AE 
Collection 
Period
Time Frame 
to Report 
Events and 
Follow-up 
Information to 
Sponsor
ECI (requiring 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report if:
- requiring 
regulatory 
reporting
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (does not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event (unless 
an SAE)
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
an SAE)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
an SAE)
Potential DILI/DILI=drug-induced liver injury; ECI= event of clinical interest; NSAE=nonserious adverse event; 
OME=Other Important Medical Event; SAE=serious adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. SAEs and other reportable safety events, including 
potential or confirmed DILI events, pregnancy and exposure during breastfeeding, ECIs, 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). The 
investigator will also make every attempt to follow nonserious AEs that occur in randomized 
participants for outcome. Further information on follow-up procedures is given in 
Appendix 3.
08WX9K

PRODUCT: MK-8591A
104
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to this study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
08WX9K

PRODUCT: MK-8591A
105
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
ECIs for this study include:
All potential or confirmed DILI events will be reported to the Sponsor as both an ECI and 
SAE, with OME criteria in the absence of other SAE criteria, within 24 hours of learning of 
the event. Potential or confirmed DILI events defined as: 
•
an elevated AST or ALT laboratory value that is greater than or equal to 3 × the ULN,
and
•
an elevated total bilirubin laboratory value that is greater than or equal to 2 × the ULN,
and
•
at the same time, an alkaline phosphatase laboratory value that is less than 2 × the ULN, 
as determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.*
* Note: These criteria are based on available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study-site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
In this study, an overdose of DOR/ISL is any dose higher than twice the prescribed dose of 
study intervention (3 or more tablets of DOR/ISL) in a day.
No specific information is available on the treatment of DOR/ISL overdose.
If a participant experiences an overdose of baseline ART, guidance in the approved label 
should be followed.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
CCI
CCI
08WX9K

PRODUCT: MK-8591A
106
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma ISL
Venous blood samples will be collected for measurement of ISL. The Sponsor may assess 
these samples for DOR as needed. Samples will be collected only from participants in 
Group 1. Sample collection, storage, and shipment instructions for plasma samples will be 
provided in the Operations/Laboratory Manual.
Investigational PK samples will be collected (except during pregnancy) for participants in 
Group 1 at Week 36 and in Group 1 and Group 2 after Week 48 as outlined in the SoA 
(Section 1.3). Investigational ISL PK samples will be collected irrespective of time of last 
dose. The time of last dose of study intervention taken prior to the sample collection will be 
verbally reported to study staff by the participant and recorded in the appropriate source 
documentation. Analysis of these samples will be performed by the Sponsor as needed.
Population PK samples will be collected from all participants in Group 1 as outlined in 
Table 6. The time of dose of study intervention taken prior to the sample collection will be 
verbally reported to study staff by the participant and recorded in the appropriate source 
documentation.
At the Week 4 visit, participants who routinely take their study intervention during the day 
will have a predose and postdose sample collected per Table 6. Participants who routinely 
take their study intervention in the evening should continue to do so, and will have only 
1 sample collected at the Week 4 visit, irrespective of the time of the last dose.
For participants who become pregnant and consent to continue DOR/ISL (base study or 
optional study extension) (Section 8.11.6.1), PK samples will be collected to evaluate DOR 
and ISL concentration levels per Table 7 in Section 8.11.6.1.
Table 6
Collection of Population PK Samples
Study Visit
Sample Time Relative to Dose of Study Interventiona
Day 1
Predose
Week 4
Daytime dosing: Predose AND within 0.5 to 2 hours postdose
OR
Evening dosing: Only 1 sample, irrespective of time of last dose
Week 12
Irrespective of time of last dose
Week 24
Irrespective of time of last dose
Week 48
Irrespective of time of last dose
PK=pharmacokinetic(s).
a
Time of last dose and time of PK sample collection must be documented for all samples.
08WX9K

PRODUCT: MK-8591A
107
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be collected for planned analysis of the 
association between genetic variants in DNA and drug response. This sample will not be 
collected at the site if there is either a local law or regulation prohibiting collection, or if the 
IRB/IEC does not approve the collection of the sample for these purposes. If the sample is 
collected, leftover extracted DNA will be stored for FBR if the participant provides 
documented informed consent for FBR. If the planned genetic analysis is not approved, but 
FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant has provided documented informed consent for FBR, FBR-specific 
specimen collections, including leftover specimens, will be obtained. The following 
specimens will be included for FBR:
•
Whole blood for future biomedical research
•
Leftover extracted DNA for future research
•
Leftover main study plasma from HIV-1 RNA quantification
•
Leftover main study plasma from HIV-1 viral drug resistance samples
8.10
Health Economics and Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
08WX9K

PRODUCT: MK-8591A
108
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.11.1
Screening/Rescreening
8.11.1.1
Screening
Before randomization, potential participants will be evaluated to determine that they fulfill 
the entry requirements as set forth in Section 5. Participants are expected to enroll as soon as 
possible after eligibility is confirmed. In cases of unexpected delays in receiving repeat 
screening laboratory results, a screening period of up to 45 days is allowed.
8.11.1.2
Rescreening
If the screening window has been exceeded, participants are allowed to rescreen one time 
after approval from the Sponsor. Once a participant has started the rescreening process, a 
new screening period (ie, an additional ≤45-day window) will begin, during which time 
screening procedures will be repeated.
The following assessments must be repeated for participants who are rescreened:
•
Vital signs, weight, and directed physical examination
•
Review medical history and prior/concomitant medications for new information
•
All laboratory assessments (includes serum and/or urine hCG pregnancy testing for 
POCBP)
•
Review of AEs
If the informed consent form has been updated, participants should be reconsented before 
rescreening. If no updates have been made, documented informed consent during the original 
screening period should be reviewed with the participant and a verbal reconsent to continue 
in the study should be documented.
If a participant had a Day 1 ECG during the original screening period, it should be repeated 
(at the Day 1 visit or within 7 days prior).
Participants, who were previously considered screen failures because the duration of baseline 
ART was <3 consecutive months, are allowed to rescreen if they have continued to receive a 
stable oral 2-drug or 3-drug combination (± PK booster) with documented viral suppression 
(HIV-1 RNA <50 copies/mL) for ≥3 consecutive months before the rescreening visit and 
have no history of prior virologic treatment failure on any past or current regimen.
8.11.2
Treatment Period
All procedures and their timing should be completed per the SoA (Section 1.3).
8.11.2.1
Fasting
Visits at Day 1, Weeks 24, 48, 96, and 144 require that participants fast (ie, do not consume 
any food or beverages except water) for at least 8 hours prior to the visit. The 
08WX9K

PRODUCT: MK-8591A
109
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
investigator/study coordinator must remind participants to fast prior to these visits and must 
confirm with participants their fasting status and record in the appropriate source 
documentation and laboratory requisition(s).
Note: Participants with type 1 diabetes mellitus and participants who are pregnant should not 
fast and should not have insulin levels or lipids tested. Participants with type 2 diabetes 
mellitus taking medications that may result in hypoglycemia should delay their morning dose 
of diabetic medication while fasting and take it after the blood draw for testing.
8.11.2.2
Switch
At the Week 48 visit, participants in Group 2 will begin receiving DOR/ISL.
Participants in Group 2 who switch to DOR/ISL will have their baseline values for total 
lymphocyte count and CD4+ T-cell count defined as the last nonmissing value at or before 
Week 48. This new baseline will serve as the new baseline for discontinuation criteria 
(Table 4) and participant management per Section 8.11.5.
Those participants in Group 2 who become pregnant prior to Week 48 and consent to 
continue baseline ART will not switch to DOR/ISL and will discontinue from the study 
(Section 8.11.6.1).
8.11.2.3
End-of-Base Study Week 144 Visit
Week 144 represents the end of the base study. Prior to the end of the base study/Week 144 
visit, site staff should proactively discuss the potential plan for treatment to facilitate either a 
transition to locally available ART or DOR/ISL in the optional study extension. For 
participants who are enrolling in the optional study extension, the Week 144 visit serves as 
the start of the study extension, and DOR/ISL will be dispensed, and participants will follow 
procedures outlined in SoA (Section 1.3.5).
Participants who complete Week 144 should follow End of Treatment Follow-Up visit 
assessments per the Week 144 SoA (Section 1.3.1).
Participants who are pregnant at Week 144 will be managed per Section 8.11.6 and SoA 
(Section 1.3.4).
Participants who have laboratory values at the Week 144 visit that meet any of the 
discontinuation criteria for specified decreases in total lymphocyte count or CD4+ T-cell 
count (Section 7.1 and Table 4) must be managed per Section 8.11.5.
8.11.2.4
Optional Study Extension (Week 144 up to Week 240)
If DOR/ISL is not commercially accessible by Week 144, participants will be provided the 
option to enroll in an optional study extension to continue to receive open-label DOR/ISL up 
to Week 240 or until DOR/ISL becomes commercially accessible (whichever comes first) per 
the SoA (Section 1.3.5).
08WX9K

PRODUCT: MK-8591A
110
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
A participant entering the optional study extension must meet all of the following criteria:
•
Is considered, in the opinion of the investigator, to benefit from continued study 
participation.
•
Understands the procedures in study extension and provides documented informed 
consent to enter the study extension.
•
Does not meet any of the discontinuation criteria (See Section 7.1).
Once DOR/ISL becomes commercially accessible, participants should be contacted and 
informed that they will complete the Discontinuation of Treatment (optional study extension) 
visit and transition to DOR/ISL or other commercially accessible ART at their next study 
visit (or sooner at the PIs discretion). In rare circumstances and with permission of the 
Sponsor, study participation may be extended for a limited amount of time to ensure all 
participants are able to secure continued treatment access in the commercial market before 
exiting the study.
The Week 240 Visit represents the end of the optional study extension and the end of the 
study.
Manage participants with viremia per Section 8.11.4 and SoA (Sections 1.3.2). Manage 
participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per 
Section 8.11.5 and SoA (Section 1.3.3). Manage participants who are pregnant per 
Section 8.11.6 and SoA Section 1.3.4).
8.11.3
Participants Who Discontinue Study Intervention
A participant must be discontinued from study intervention for any of the reasons listed in 
Section 7.1.
When it is determined that discontinuation from study intervention is appropriate, the 
participant should have both an Early Discontinuation of Treatment visit (Section 8.11.3.1) 
and an End of Treatment Follow-up visit (Section 8.11.3.2) conducted. After the visit 
procedures are completed, the participant will be withdrawn from the study and managed for 
treatment of their HIV-1 infection per local standard of care.
Participants who discontinue study intervention due to confirmed specified decreases in total 
lymphocyte counts or CD4+ T-cell counts (Table 4) must be managed per Section 8.11.5.
Participants who discontinue study intervention due to other reasons, but have laboratory 
values at the Early Discontinuation of Treatment visit that meet any of the discontinuation 
criteria for specified decreases in total lymphocyte count or CD4+ T-cell count (Table 4) 
must be managed per Section 8.11.5.
08WX9K

PRODUCT: MK-8591A
111
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.11.3.1
Discontinuation of Treatment
Participants who discontinue study intervention due to specified decreases in total 
lymphocyte counts or CD4+ T-cell counts (per Section 7.1) will be managed per 
Section 8.11.5.
Early Discontinuation (Base Study)
Participants who discontinue study intervention prior to Week 144 for any reason(s) should 
have an Early Discontinuation of Treatment visit as outlined in the SoA (Sections 1.3.1, 
1.3.2, or 1.3.3). If discontinuation occurs during the time frame of a scheduled study visit, the 
assessments for the scheduled visit as well as the Early Discontinuation of Treatment visit 
should be conducted, however, collection of laboratory samples should not be duplicated.
Discontinuation (Optional Study Extension)
Participants in the optional study extension who discontinue DOR/ISL prior to Week 240 for 
any reason(s) should have a Discontinuation of Treatment (optional study extension) visit as 
outlined in the SoA (Sections 1.3.2, 1.3.3, or 1.3.5). Participants who complete Week 240 
should follow assessments per the Week 240 SoA (Section 1.3.5).
8.11.3.2
End of Treatment Follow-up
Participants who discontinue study intervention for any reason(s) will have an End of 
Treatment Follow-up visit 42 days (+7 days) after the last dose of study intervention. 
Assessments for this visit are outlined in Sections 1.3.1, 1.3.2, 1.3.3, and 1.3.5, as applicable.
8.11.4
Viremia Confirmation
If a participant has a viral load of ≥50 copies/mL (confirmed as described in Sections 
4.2.1.1.2 and 8.2.2.1) at any time during the study, a Viremia Confirmation visit must be 
conducted within 4 weeks (±1 week) after the initial HIV-1 viremia, as specified in the SoA 
(Section 1.3.2). If a scheduled visit is to occur within the time frame that a participant would 
return for a Viremia Confirmation visit, the assessments for the scheduled visit should be 
conducted, and the HIV-1 viral drug resistance sample must be collected. PK will be assessed 
for both DOR and ISL (from same sample) at the time of viremia confirmation.
8.11.5
Management of Participants With Specified Decreases in Total Lymphocyte 
Count or CD4+ T-cell Count
To meet the protocol-defined discontinuation criteria in the base study or the optional study 
extension, participants must have a confirmed total lymphocyte count or CD4+ T-cell count 
that indicates a specified decrease (Table 4) on 2 consecutive measurements 10 to 14 weeks 
apart. A minimum interval of 10 weeks between consecutive tests is required to meet 
discontinuation criteria. The confirmation visit must occur within 10 to14 weeks after the 
initial decrease (or at the next scheduled visit), as specified in the SoA (Section 1.3.3) and 
Table 4.
08WX9K

PRODUCT: MK-8591A
112
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Management of Participants who Discontinue due to Specified Decreases in Total 
Lymphocyte Count or CD4+ T-cell Count
Participants discontinued from study intervention due to specified decreases in total 
lymphocyte count or CD4+ T-cell count (Section 7.1 and Table 4) should undergo 
assessments for the Discontinuation of Treatment visit and the End of Treatment Follow-up 
visit (regardless of treatment assignment) as specified in the SoA (Sections 1.3.3, 1.3.5). 
After discontinuation from study intervention, participants will be managed for treatment of 
their HIV-1 infection per local standard of care but will continue to be followed in the study. 
Consult with Sponsor prior to discontinuation if the investigator believes there is an 
alternative explanation for the result (eg, COVID-19).
Monitoring for Participants Receiving DOR/ISL 
After completion of the Discontinuation of Treatment visit (base study or optional study 
extension) and the End of Treatment Follow-up visit, participants who discontinued for 
confirmed decreases in CD4+ T-cell or lymphocyte counts (per Table 4) should have 
monitoring visits every 10 to 14 weeks (Section 1.3.3). Participants should be monitored until 
the total lymphocyte counts or CD4+ T-cell counts no longer meet the criteria in Section 7.1 
Table 4 at 2 consecutive visits. If conditions that impact lymphocytes arise during the follow-
up monitoring period and are expected to persist, monitoring may be stopped.
Management of Participants Receiving DOR/ISL Who Discontinue Study Intervention 
Due to Reasons Other Than Decreases in Total Lymphocyte Count or CD4+ T-cell Count
Participants noted to have their first decrease in total lymphocyte count or CD4+ T-cell count 
that meets the criteria for Table 4 at the Discontinuation of Treatment visit (base study or 
optional study extension) or at the Week 144 visit only require monitoring as described 
above if the count declines are confirmed by the End of Treatment Follow-up visit.
8.11.6
Clinical Management of Participants Who Become Pregnant
If a participant becomes pregnant (confirmed by a positive serum pregnancy test), the 
investigator should refer the participant to a local provider for obstetric (prenatal) care per 
local standard of care. The provider should be informed of the participant’s study 
participation by site personnel.
All pregnancies must be followed to completion or termination of the pregnancy by the 
investigator per Section 8.4.5. Severity assessment of AEs that are pregnancy-related 
complications should follow guidance provided as part of the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, July 2017, version 2.1 (Appendix 3) 
“Addendum 1: Female Genital Grading Table for Use in Microbicide Studies,” particularly 
the section “Complications of Pregnancy” [National Institute of Allergy and Infectious 
Diseases 2017].
08WX9K

PRODUCT: MK-8591A
113
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Upon confirmation of pregnancy by serum testing, the investigator or appropriate designee 
should discuss the following with the participant:
•
The appropriateness of continuing study intervention based on available data and local 
standard-of care guidelines (where allowed by local regulations, health authorities, and 
ethics committees). For participants receiving baseline ART, the investigator should refer 
to the local product circular(s) and local guidelines to determine if treatment may be 
continued. Documented informed consent must be obtained to continue study 
intervention regardless of treatment assignment (Section 8.1.1.3)
•
Joining a pregnancy registry (the Antiretroviral Pregnancy Registry), which collects 
information about the outcome of the pregnancy, if applicable
Upon confirming that the pregnancy is continuing, the site will discuss with the participant 
(per timing at the discretion of the Principal Investigator):
•
Intentions for breastfeeding (Section 8.11.6.3)
•
Consenting to infant safety data collection per Sections 8.1.1.3 and 8.11.6.4
8.11.6.1
Continuing Study Intervention in Pregnancy
Participants who become pregnant and consent to continue their assigned study intervention 
(DOR/ISL or baseline ART) should complete all remaining protocol-specified visits and 
procedures per the regular schedule in the applicable SoA (Section 1.3.5), with the following 
exceptions:
•
Only participants in Group 1 will have PK samples collected (per the timing in Table 7). 
Participants in Group 2 will not have PK collection.
•
Participants on DOR/ISL who are pregnant at Week 144 will have the opportunity to 
continue into the optional study extension.
Pregnancy visits are to occur at least every 12 weeks (~1 during each trimester and a 
postpartum visit ≤8 weeks after delivery) in both the base study and the optional study 
extension (Sections 1.3.1 and 1.3.4, as applicable). This applies to participants whose 
pregnancy extends beyond Week 240 (Section 1.3.4). More frequent HIV-1 RNA testing 
should be performed per local guidelines or as determined by the investigator. If HIV-1 RNA 
testing is performed in a local laboratory with an approved assay (Appendix 10), the results 
must be promptly recorded in the appropriate CRF.
For participants receiving baseline ART, the investigator should refer to local product 
circulars and local guidelines to determine if study intervention can be continued or must be 
modified during pregnancy. Modifications (eg, dose adjustment) and/or regimen changes 
may be permitted, but require Sponsor approval (Section 6.6). Those participants in Group 2 
who become pregnant prior to Week 48 and consent to continue baseline ART will not 
switch to DOR/ISL and will discontinue from the study. The participant will continue with 
08WX9K

PRODUCT: MK-8591A
114
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
the protocol-specified visits (with the exception of PK collection) per the schedules in the 
SoA (Section 1.3) for the duration of their pregnancy.
For participants receiving study intervention and continuing their pregnancy, prenatal care 
should be coordinated between the investigator and the local obstetric care provider. The 
investigator (or designee) is responsible for reviewing records from prenatal care at each 
study visit and obtaining relevant clinical and laboratory data from the obstetric care provider 
to monitor the safety and well-being of the mother and fetus. Relevant data obtained by the 
site should be entered into the appropriate CRF and source documentation.
The participant’s medical records will be collected and reviewed by the study site for:
•
Clinical safety laboratory assessments
•
Pregnancy screening laboratory assessments (for participants on DOR/ISL only) for 
hepatitis B serology and HBV DNA; if local laboratory test results are unavailable, 
collect central laboratory sample
•
Plasma HIV-1 RNA level
•
Results of 2nd trimester ultrasound(s) providing gestational age and anatomic survey
•
Any complications associated with the pregnancy
•
Outcome of pregnancy
•
Information that could indicate congenital abnormalities
For participants who are pregnant at the last regularly scheduled study visit (Week 144 [base 
study] or Week 240 [optional study extension]), their visit schedule will be extended through 
the duration of the pregnancy to allow assessments through each trimester and postpartum 
and, as applicable, a 42-day follow-up period with an End of Treatment Follow-up visit 
(Section 1.3.4). After completion of the pregnancy, the participant will have completed the 
study after completing either the postpartum visit (if the participant chooses to breastfeed) or 
the End of Treatment Follow-up visit (if the participant does not choose to breastfeed and 
completed the 42-day follow-up period) (Section 1.3.4). Participants on DOR/ISL at the 
completion of the pregnancy will have continued access to DOR/ISL through the optional 
study extension, until DOR/ISL becomes commercially accessible per Section 6.7. The time 
of last dose of study intervention taken prior to the sample collection will be verbally 
reported to study staff by the participant and recorded in the appropriate source 
documentation.
8.11.6.1.1
Collection of Population PK Samples During Pregnancy and Postpartum 
(Participants Continuing DOR/ISL Only)
For participants who continue DOR/ISL, PK samples will be collected at their scheduled 
visit/pregnancy visit during the 1st, 2nd, and 3rd trimesters and postpartum to evaluate DOR 
and ISL concentration levels per Table 7. These samples will be used to characterize the PK 
profile of DOR/ISL during pregnancy. Participants who do not learn of their pregnancy until 
the 2nd trimester may not have had a PK sample collection during the 1st trimester.
08WX9K

PRODUCT: MK-8591A
115
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Participants who routinely take their DOR/ISL during the day will have a predose and 
2 postdose samples collected per Table 7. Participants who routinely take their DOR/ISL in 
the evening should continue to do so and will have only 1 sample collected at the 
2nd trimester, 3rd trimester, and postpartum visits, irrespective of time of the last dose. Time 
of last dose and time of PK sample collection must be documented for all samples.
Table 7
Collection of Population PK Samples During Pregnancy and Postpartum
Study Visit
Sample Time Relative to Dose of DOR/ISLa
1st Trimesterb
Daytime dosing: Predose
OR
Evening dosing: Irrespective of time of last dose
2nd Trimester
Daytime dosing: Predose AND within 0.5 to 2 hours AND within 4 to 
6 hours postdose
OR
Evening dosing: Only 1 sample irrespective of time of last dose
3rd Trimester
Daytime dosing: Predose AND within 0.5 to 2 hours AND within 4 to 
6 hours postdose
OR
Evening dosing: Only 1 sample irrespective of time of last dose
Postpartumc
Daytime dosing: Predose AND within 0.5 to 2 hours AND within 4 to 
6 hours postdose
OR
Evening dosing: Only 1 sample irrespective of time of last dose
DOR=doravirine; ISL=islatravir; PK=pharmacokinetic(s).
a
Time of last dose and time of PK sample collection must be documented for all samples.
b
Collect at the scheduled 1st Trimester visit after a participant reports gravid status. (May not be collected 
if participant does not learn of their pregnancy until after the first trimester.)
c
Postpartum visit ≤8 weeks after delivery.
8.11.6.2
Discontinuing Study Intervention for Pregnancy
Participants who become pregnant and discontinue study intervention should have a 
Discontinuation of Treatment visit (base study or optional study extension) per the SoA 
(Section 1.3.1 or 1.3.5, as applicable). If the decision to discontinue study intervention occurs 
during the time frame of a scheduled study visit, the assessments for the Scheduled Visit as 
well as for the Discontinuation of Treatment Visit should be completed. Collection of 
laboratory samples should not be duplicated. In addition, these participants will have an End 
of Treatment Follow-up visit 42 days (+7) days after the last dose of study intervention.
The investigator (or local HIV care provider, if not the study site) should develop a new 
treatment plan per local standard of care before discontinuing study intervention to minimize 
the risk of a gap in ART.
08WX9K

PRODUCT: MK-8591A
116
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
8.11.6.3
Participants Who Choose to Breastfeed
A participant who chooses to breastfeed must discontinue study intervention before initiating 
breastfeeding (Section 7.1) and be followed in the study per Section 8.11.6.2. The 
investigator (or local HIV care provider, if not the study site) should make every effort to 
develop a new treatment plan (per local standard of care) within sufficient time prior to 
delivery to minimize the likelihood of a gap in ART.
8.11.6.4
Infant Safety Data Collection
For participants who become pregnant while receiving study intervention, or within 42 days 
after the last dose of study intervention, the data in Section 8.11.6.4.1 should be obtained by 
the site and entered into the appropriate CRF and source documentation.
Infant SAEs, including perinatal HIV-1 infection, will be collected as per Section 8.4.1 and 
should be reviewed at the participant’s scheduled study visits that occur during this time. 
Infant safety data collection will be captured if exposure to study intervention occurs during 
pregnancy.
8.11.6.4.1
Schedule of Activities: Infant Safety Data Collection
Time Point
At Birtha
1 Year After Birtha,b
Visit Name
NA
Infant Follow-up-1
Administrative and Safety Procedures
Infant Informed Consent
Xc
Gestational Age at Birth
X
Apgar Score
X
Length
X
X
Weight
X
X
Head Circumference
X
X
Directed Pediatric Examination
X
Concomitant Medications Reviewd
X
X
Review Infant SAEse
-------------------------------X------------------------------
HIV=human immunodeficiency virus; NA=Not applicable; SAE=serious adverse event.
a
Data to be collected and entered at the site within 12 weeks of each time point.
b
If a participant withdraws from the study, data from 1 year after birth should be collected at the time of withdrawal.
c
Consent for infant safety data collection can be obtained from the mother at any time following confirmation of 
pregnancy.
d
Concomitant medications taken by the infant (for SAEs or HIV postpartum prophylaxis).
e
Collect SAEs, including any congenital anomalies and HIV infection in the infant, per Section 8.4.1 and review at 
participant’s regularly scheduled study visits.
08WX9K

PRODUCT: MK-8591A
117
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to final database lock, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in an sSAP and referenced in the CSR for the study. 
Posthoc exploratory analyses will be clearly identified in the CSR. Other planned analyses 
(eg, those specific to the analyses of PK data, PROs, and FBR) will be documented in 
separate analysis plans. Data collected from the optional study extension for those 
participants who consent to enter the optional study extension, will be summarized separately 
using only descriptive statistics.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Randomized, Active-Controlled, Open-Label Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) 
Once-Daily in Participants With HIV-1 Virologically Suppressed on 
Antiretroviral Therapy
Treatment Assignment
Approximately 501 participants will be randomly assigned in a 2:1 ratio to 
either switch to DOR/ISL on Day 1 (Group 1) or continue baseline ART from 
Day 1 to Week 48 with delayed switch to DOR/ISL at Week 48 (Group 2). 
Randomization will be stratified by baseline ART regimen (PI-containing 
regimens [including PI- + InSTI-containing regimens], InSTI-containing 
regimens [non-PI-containing regimens], and non-PI- and non-InSTI-containing 
regimens).
Analysis Populations
Efficacy: FAS, PP, FAS-E, and Resistance Analysis Subset
Safety: APaT and APaT-E
Primary Endpoints
1.
Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48
2.
Percentage of participants who experience AEs and percentage of 
participants who discontinue study intervention due to AEs through 
Week 48
Secondary Endpoints
1.
Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96 
and Week 144
2.
Percentage of participants with HIV-1 RNA <50 and <200 copies/mL at 
Week 48, Week 96, and Week 144.
3.
Mean change from baseline in CD4+ T-cell count at Week 48, Week 96, 
and Week 144.
4.
Mean change from baseline in fasting LDL-C and non-HDL-C at Week 24 
and Week 48
5.
Viral resistance-associated substitutions
6.
General safety and tolerability through Week 144.
08WX9K

PRODUCT: MK-8591A
118
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Statistical Methods for 
Key Efficacy Analyses
For the primary hypothesis (H1), DOR/ISL will be considered non-inferior to 
continued baseline ART if the upper bound of the 2-sided multiplicity-adjusted 
95% CI for the between-treatment difference in the percentage of participants 
with HIV-1 RNA ≥50 copies/mL at Week 48 (DOR/ISL minus continued 
baseline ART) is less than 4 percentage points (non-inferiority margin). The CI 
will be based on the stratified Miettinen and Nurminen method [Miettinen, O. 
and Nurminen, M. 1985] with Cochran-Mantel-Haenszel weights. The FDA 
snapshot algorithm [Food and Drug Administration (CDER) 2015] will be used 
to handle missing data for the analysis of the primary efficacy hypothesis.
Statistical Methods for 
Key Safety Analyses
For overall safety endpoints, specific AEs, and safety topics of special interest 
that meet predefined threshold rules, point estimates and 2-sided nominal 95% 
CIs for the differences between treatment groups (DOR/ISL minus continued 
baseline ART) in the percentages of participants with events will be provided 
using the unstratified Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985]. Inferential analyses with 2-sided multiplicity-adjusted 
CIs and p-values obtained using ANCOVA models will be provided for the 
differences between groups (DOR/ISL minus continued baseline ART) in the 
mean change from baseline in fasting LDL-C and non-HDL-C at Week 48.
IAs
An IA will be performed when approximately 30% of participants have 
completed the Week 24 visit assessments. Results will be reviewed by an 
eDMC. All available efficacy and safety data for participants enrolled at the 
time of the Week 24 IA will be reviewed, and the data from the first 30% of 
participants who reach Week 24 will be included in the futility assessment. The 
nonbinding futility criterion is if the upper bound of the 2-sided 95% CI for the 
treatment difference (DOR/ISL minus continued baseline ART) in the 
percentage of participants with Week 24 HIV-1 RNA ≥200 copies/mL is 
greater than 8 percentage points, consideration may be given to stop the study. 
Additional details are provided in Section 9.7.
In addition, the eDMC will periodically review efficacy and safety data (per the 
timelines specified in the eDMC charter).
Multiplicity
The Type 1 error rate over the multiple hypothesis tests will be controlled by a 
sequential testing procedure. A formal futility analysis at Week 24 is planned 
as described in section 9.7, a small amount of alpha (α=0.00001) will be 
allocated for this IA, purely for statistical rigor. The trial will not be stopped 
early for positive efficacy at the IA. The following hypotheses will be tested 
sequentially at a 1-sided 2.499% Type 1 error rate in the following order:
1.
Primary efficacy hypothesis (H1) testing non-inferiority of DOR/ISL to 
continued baseline ART, as assessed by the percentage of participants with 
HIV-1 RNA ≥50 copies/mL at Week 48
2.
Secondary safety hypothesis (H2) testing superiority of DOR/ISL to 
continued baseline ART, as assessed by the mean change from baseline in 
fasting LDL-C and non-HDL-C at Week 48
If the first hypothesis test fails to reach statistical significance, the second 
hypothesis test would not be considered for statistical significance. In this way, 
the overall 1-sided 2.5% Type 1 error rate in testing these hypotheses is 
strongly controlled. Additional details are provided in Section 9.8.
08WX9K

PRODUCT: MK-8591A
119
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Sample Size and Power
The planned sample size is 501 participants (334 in the DOR/ISL group and 
167 in the continued baseline ART group). For the primary efficacy endpoint of 
the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48, the 
study has 93.3% power to demonstrate that DOR/ISL is non-inferior to 
continued baseline ART at a 1-sided 2.5% alpha-level if the true rate of 
participants with HIV-1 RNA ≥50 copies/mL at Week 48 is 1.5% in both 
treatment groups. This power calculation does not account for the futility 
assessment at Week 24.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a randomized, open-label study; ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented via an IRT.
The planned IAs are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
Success of this study is predicated only on establishing non-inferiority of DOR/ISL to 
continued baseline ART, as assessed by the percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48 (ie, establishing statistical significance of H1).
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
9.4.1
Efficacy/Pharmacokinetics Endpoints
9.4.1.1
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 4.
Percentage of Participants With HIV-1 RNA ≥50 Copies/mL
A PCR assay with a lower level of detection of <50 copies/mL will be used to measure the 
HIV-1 RNA level in blood samples obtained at each visit. The primary objective will be 
assessed based on the percentage of participants with HIV-1 RNA ≥50 copies/mL at 
Week 48. A secondary objective will assess the sustained antiretroviral suppression of 
08WX9K

PRODUCT: MK-8591A
120
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
DOR/ISL after 96 weeks of treatment in Group 1 and after 48 weeks of treatment in Group 2 
by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96 and Week 
144.
The percentage of participants with HIV-1 RNA ≥50 copies/mL will be summarized over 
time for participants who consent to the optional study extension.
Percentage of Participants With HIV-1 RNA <200 Copies/mL and Percentage of 
Participants With HIV-1 RNA <50 Copies/mL
A secondary objective addressing the antiretroviral activity following a switch to DOR/ISL 
will be assessed based upon the percentage of participants with HIV-1 RNA <200 copies/mL 
at Week 48, as well as the percentage of participants with HIV-1 RNA <50 copies/mL at 
Week 48. 
At Weeks 96 and 144, a secondary objective addressing the antiretroviral activity of 
DOR/ISL after 96 weeks and 144 weeks of treatment in Group 1 and after 48 weeks and 96 
weeks of treatment in Group 2 will be assessed based on the percentage of participants with 
HIV-1 RNA <200 copies/mL and the percentage of participants with HIV-1 RNA 
<50 copies/mL.
The percentage of participants with HIV-1 RNA <50 copies/mL and <200 copies/mL will be 
summarized over time for participants who consent to the optional study extension.
In addition, HIV-1 RNA will be summarized using the following bands: <20 copies/mL (the 
LLOQ of the assay), 20 to <50, 50 to <100, 100 to <200, 200 to <400 and ≥400 copies/mL to 
further characterize efficacy response over time through the end of the study.
Change From Baseline in CD4+ T-cell Count
The mean change from baseline in CD4+ T-cell count will be estimated at each time point at 
which CD4+ T-cell count is collected. A secondary objective will compare the mean change 
from baseline in CD4+ T-cell count between treatment groups at Week 48. In addition, 
change from baseline in the absolute CD4+ T-cell count and change from baseline in 
CD4+ T-cell/lymphocyte ratio will be summarized at each timepoint.
At Week 96, the immunologic effect of DOR/ISL will be assessed via the mean change from 
baseline (Day 1) to Week 96 in CD4+ T-cell count after 96 weeks of treatment in Group 1, 
the mean change from Week 48 to Week 96 in CD4+ T-cell count after an additional 
48 weeks of treatment in Group 1, and the mean change from Week 48 to Week 96 in 
CD4+ T-cell count after 48 weeks of treatment in Group 2.
At Week 144, the immunologic effect of DOR/ISL will be assessed via the mean change 
from baseline (Day 1) to Week 144 in CD4+ T-cell count after 144 weeks of treatment in 
Group 1, the mean change from Week 48 to Week 144 in CD4+ T-cell count after an 
additional 96 weeks of treatment in Group 1, and the mean change from Week 48 to 
Week 144 in CD4+ T-cell count after 96 weeks of treatment in Group 2.
08WX9K

PRODUCT: MK-8591A
121
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
For analyses of the mean change from baseline in CD4+ T-cell count, baseline measurements 
are defined as the Day 1 value for each participant. In the rare event when data for this visit 
are missing, the value obtained at the most recent Screening Visit will be used as baseline, 
when available. For the analyses of the mean change from Week 48 in CD4+ T-cell count, 
for Group 1, baseline measurements are defined as the last nonmissing value obtained at or 
prior to the Week 48 visit; for Group 2, baseline measurements are defined as the last 
nonmissing value obtained prior to the switch to DOR/ISL.
The change from baseline in CD4+ T-cell count during the optional study extension will be 
analyzed over time for participants who consent to the optional extension.
Clinically Significant Confirmed Viremia
Participants with clinically significant confirmed viremia as defined in Section 4.2.1.1.2 will 
be identified.
Viral Resistance-associated Substitutions
Participants who meet the definition of clinically significant confirmed viremia 
(Section 4.2.1.1.2), or who discontinue study intervention for another reason and have 
HIV-1 RNA ≥200 copies/mL at the time of discontinuation, will be assessed for development 
of viral drug resistance. Among such participants, those with HIV-1 RNA ≥400 copies/mL 
will be included in the resistance analyses. In addition, anyone for whom available genotypic 
or phenotypic data show evidence of resistance, irrespective of viral load, will also be 
included in the resistance analyses. The resistance analyses will count the number of 
participants in each treatment group who have evidence of resistance-associated 
substitutions. The data will be summarized with primary interest at Weeks 48, 96, 144, and 
during the optional study extension.
9.4.1.2
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoA (Section 1.3) and 
Section 8.6 will be used to evaluate PK concentrations of ISL, and as appropriate, 
PK-efficacy, PK-pharmacodynamic, and PK-AE relationships of ISL.
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory test values, and vital signs.
Adverse Events
The following clinical and laboratory AEs will be summarized: 1) participants with at least 
1 AE; 2) participants with at least 1 drug-related AE; 3) participants with at least 1 SAE; 
4) participants with at least 1 Grade 3 or 4 AE; 5) participants with at least 1 serious and 
drug-related AE; 6) participants with at least 1 AE which is both Grade 3 or 4 and 
08WX9K

PRODUCT: MK-8591A
122
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
drug-related; 7) participants who discontinued study intervention due to an AE; 
8) participants who discontinued study intervention due to a drug-related AE; and 
9) participants with an AE leading to death.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory test results, participants must have both a baseline and a 
post-randomization, on-treatment measurement to be included. Participants’ laboratory test 
values (based on their most abnormal laboratory test values in the direction of interest while 
on study intervention) will be classified as to whether they fall outside of the PDLC and are 
worse in grade (ie, more abnormal in the direction of interest) than at baseline. The criteria 
are adapted from the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, July 2017, version 2.1 (Appendix 3) [National Institute of Allergy and Infectious 
Diseases 2017].
Weight and Laboratory Markers
The mean change from baseline to Weeks 48, 96, and 144 in select weight and laboratory 
markers of fasting lipid and metabolic profiles and renal function will be summarized.
Change From Baseline in Fasting Lipids
The mean change from baseline in fasting lipids (LDL-C, non-HDL-C, TC, HDL-C, TGs, 
and TC/HDL ratio) will be analyzed with primary interest in LDL-C and non-HDL-C at 
Week 48.
Total Lymphocyte Counts 
The mean change from baseline in total lymphocyte count will be calculated at each time 
point at which lymphocytes are assessed. The comparison of mean change from baseline in 
total lymphocyte count between treatment groups will be conducted at Weeks 48. The mean 
change from Week 48 in total lymphocyte count will be calculated at each time point beyond 
Week 48 at which lymphocytes are assessed.
For analyses of the mean change from baseline in lymphocyte, baseline measurements are 
defined as the Day 1 value for each participant. In the rare event when data for this visit are 
missing, the value obtained at the most recent Screening Visit will be used as baseline, when 
available. For the analyses of the mean change from Week 48 in lymphocyte, for Group 1, 
baseline measurements are defined as the last nonmissing value obtained at or prior to the 
Week 48 visit; for Group 2, baseline measurements are defined as the last nonmissing value 
obtained prior to the switch to DOR/ISL. 
The change from baseline in lymphocytes during the optional study extension period will be 
analyzed over time for participants who consent to the optional extension. 
08WX9K

PRODUCT: MK-8591A
123
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Definition of Baseline Measurements for Safety Analyses
For analyses of changes from baseline in safety parameters (eg, weight, vital signs, and 
laboratory parameters), baseline measurements are defined as the Day 1 value for each 
participant. In the rare event when data for this visit are missing, the value obtained at the 
most recent Screening Visit will be used as baseline, when available. For analyses of changes 
from Week 48, for Group 1, baseline measurements are defined as the last nonmissing value 
obtained at or prior to the Week 48 visit; for Group 2, baseline measurements are defined as 
the last nonmissing value obtained prior to the switch to DOR/ISL.
The change from baseline in safety parameters during the optional study extension period 
will be analyzed over time for participants who consent to the optional study extension.
9.4.3
Patient-reported Outcome Endpoints
An initial description of patient-reported outcome measures is provided in Section 4.2.1.5.
PROs from each questionnaire at Day 1 and Weeks 4, 12, 48, and 96 will be summarized for 
each treatment group.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
FAS
The FAS population will serve as the primary population for the analysis of efficacy data in 
the base study. The FAS population consists of all randomized participants who meet the 
following criteria:
•
Receive at least 1 dose of study intervention
•
Have baseline data for those analyses that require baseline data
Note that the number of participants included in the FAS population may vary across 
endpoints due to the applicability of exclusion criteria to each endpoint (eg, the need for 
baseline data only applies to those endpoints that are derived relative to baseline). 
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using FAS population.
08WX9K

PRODUCT: MK-8591A
124
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
PP Analysis Population
The secondary analysis set for the efficacy analyses is defined as the PP analysis population, 
which will exclude participants in the FAS population who had at least one major deviation 
that may substantially affect the results of the efficacy endpoints. Potential deviations that 
may result in the exclusion of a participant from the Per-Protocol population include:
•
Receipt of any ongoing prohibited therapies listed in Table 3
•
Nonadherence to study intervention: <95% drug compliance rate
•
Pregnancy
The PP analysis will be performed for the percentage of participants with HIV-1 RNA ≥50 
copies/mL at Weeks 48, 96, and 144, the percentage of participants with HIV-1 RNA <50 
copies/mL at Weeks 48, 96, and 144, and the percentage of participants with HIV-1 RNA 
<200 copies/mL at Weeks 48, 96, and 144 (see Table 9)
The final determination of major protocol deviations, and thereby the composition of the 
Per-Protocol population, will be made prior to the Week 48 database lock and will be 
documented. A participant who deviates from the protocol at randomization (eg, violation of 
certain inclusion or exclusion criteria, such as the use of a prohibited prior treatment) will be 
excluded from the Per-Protocol population. For participants who have major deviations from 
the protocol during the study (eg, taking a prohibited concomitant medication), data obtained 
after the deviation will be excluded from analysis. As such, the composition of the 
Per-Protocol population may vary by the analysis time point, based on the number of 
participants who satisfy the Per-Protocol criteria at that time point.
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the Per-Protocol population.
FAS for the Optional Study Extension (FAS-E)
The FAS-E population will be used to analyze efficacy data in the optional study extension. 
It consists of all FAS participants in the base study who entered the optional study extension 
and received at least 1 dose of study intervention during the extension.
Resistance Analysis Subset
The resistance analysis subset will include all participants in the FAS with HIV-1 RNA 
≥400 copies/mL and any participants for whom available genotypic or phenotypic data show 
evidence of resistance, irrespective of viral load.
08WX9K

PRODUCT: MK-8591A
125
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
9.5.2
Safety Analysis Populations
APaT
The APaT population will be used for the analysis of safety data in the base study. The APaT 
population consists of all randomized participants who receive at least 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
For most participants, this will be the treatment group to which they are randomized. 
Participants who take incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received. 
Participants in Group 2 who switch to DOR/ISL at Week 48 and subsequently receive at least 
1 dose of DOR/ISL will be included in summaries and analyses from Week 48 through 
Week 144.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required. The composition of the 
APaT population may vary based on the availability of baseline measurements for the 
relevant safety parameters of interest.
APaT-E
The APaT-E population will be used to analyze safety data from the optional study extension 
period. It consists of all APaT participants in the base study who entered the optional study 
extension and received at least 1 dose of study intervention during the extension.
9.6
Statistical Methods
The statistical methods used to evaluate the primary and secondary objectives are described 
below. Methods related to evaluation of exploratory objectives will be described in the sSAP.
Participants in Group 1 will receive DOR/ISL from Day 1 through end of study. Participants 
in Group 2 will continue their baseline regimen from Day 1 through Week 48 and then 
receive DOR/ISL from Week 48 through end of study. Between-treatment comparisons that 
address key efficacy and safety objectives will be limited to data before the switch. Efficacy
and safety data from Week 48 through Week 144 will be summarized separately. For Group 
2, to evaluate the effects of switching from baseline ART to DOR/ISL on safety data, within 
participant mean changes in safety parameters from Week 48 to Week 144 will be analyzed. 
The safety data from Day 1 through Week 144 for participants in Group 1 will also be 
summarized. Safety data for participants who consent to continue the treatment in the 
optional study extension (from Week 144 to Week 240) will be summarized separately. 
08WX9K

PRODUCT: MK-8591A
126
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Definition of On-treatment Measurements for Efficacy Analyses
For participants who have either discontinued or completed study intervention, all 
measurements within 1 day following the last dose of study intervention will be considered to 
be on-treatment measurements. For participants who are on study intervention (ie, have not 
discontinued or completed study intervention), all measurements will be considered to be 
on-treatment measurements.
Definition of On-treatment Measurements for Safety Analyses
For participants who have either discontinued or completed study intervention, all 
measurements within 42 days following the last dose of study intervention will be considered 
to be on-treatment measurements; the 42-day window was selected to account for the 
half-life of ISL. For participants who are on study intervention (ie, have not discontinued or 
completed study intervention), all measurements will be considered to be on-treatment 
measurements.
9.6.1
Statistical Methods for Efficacy Analyses
Time Windows
Definitions of time windows (day-ranges) and target days for the scheduled study visits, 
which will be used for all statistical analyses by time point, are shown in Table 8. The last 
available on-treatment measurement within a window will be used for analyses at a specific 
time point, unless otherwise specified. Results from additional time points beyond Week 96 
may be summarized, and day-range rules for determining the analysis time windows will 
follow the same pattern where the ranges start and end at the midpoints between target days.
08WX9K

PRODUCT: MK-8591A
127
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 8
Definitions of Study Time Points
Treatment 
Phase
Treatment 
Period
Visit
Day-Rangea
Target 
Daya
Pretreatment
Baseline
Day 1
≤1
1
Treatment
DOR/ISL or 
Baseline 
ART 
Regimen
Week 4
≥2 and ≤56
29
Week 12
≥57 and ≤126
85
Week 24
≥127 and ≤210
169
Week 36
≥211 and ≤294
253
Week 48
Group 1: ≥295 and ≤378
Group 2: ≥295 and ≤last baseline ART 
dose day + 1
Group 1 
and 
Group 2: 
337
DOR/ISL
Week 52b
Group 1: NA
Group 2: >last baseline ART dose 
day+1 and ≤392
Group 1: 
NA
Group 2: 
365
Week 60
Group 1: ≥379 and ≤462
Group 2: ≥393 and ≤462
Group 1 
and 
Group 2: 
421
Week 72
≥463 and ≤546
505
Week 84
≥547 and ≤630
589
Week 96
≥631 and ≤714
673
Week 108
≥715 and ≤798
757
Week 120
≥799 and ≤882
841
Week 132
≥883 and ≤966
925
Week 144
≥967 and ≤1091
1009
Treatment 
Extensionc
DOR/ISL
Week 168
≥1092 and ≤1260
1177
Week 192
1261≥ and ≤1428
1345
Week 216
1429≥ and ≤1596
1513
Week 240
1597≥ and ≤1764
1681
ART=antiretroviral therapy; DOR=doravirine; ISL=islatravir; min=minimum; NA=not applicable.
a
Day-ranges and target days are computed relative to the first day of study intervention.
b
The Week 52 visit applies only to participants in Group 2.
c
The treatment extension phase visits apply only to participants who consent to the optional study 
extension.
08WX9K

PRODUCT: MK-8591A
128
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Missing Data Approaches
Three approaches will be used to handle missing HIV-1 RNA values. The primary approach 
for analysis of the percentage of participants with HIV-1 RNA ≥50 copies/mL is the FDA 
“snapshot” algorithm [Food and Drug Administration (CDER) 2015]. Using this approach, 
for data collected in a given analysis window (see Table 8), the last available measurement 
while the participant is on-treatment is used to define the virologic outcome. Virologic 
outcome is defined according to the following categories:
•
HIV-1 RNA <50 copies/mL: Participants who have the last available on-treatment 
HIV-1 RNA measurement <50 copies/mL within the time point of interest analysis 
window specified in Table 8.
•
HIV-1 RNA ≥50 copies/mL: this includes participants:
-
Who have the last available on-treatment HIV-1 RNA measurement ≥50 copies/mL 
within the time point of interest analysis window specified in Table 8.
-
Who do not have on-treatment HIV-1 RNA data in the time point of interest analysis 
window and:
◦
Who discontinue study intervention prior to or in the time point of interest 
analysis window due to lack of efficacy, or
◦
Who discontinue study intervention prior to or in the time point of interest 
analysis window due to reasons other than lack of efficacy and have the last 
available on-treatment HIV-1 RNA measurement ≥50 copies/mL.
•
No Virologic Data in Specified Analysis Time Window: this includes participants who 
do not have on-treatment HIV-1 RNA data in the time point of interest analysis window 
specified in Table 8 because of the following:
-
Discontinued study intervention due to AE or death: This includes participants who 
discontinued study intervention because of an AE or death at any time point from 
Day 1 through the analysis window if this resulted in no on-treatment HIV-1 RNA 
measurements during the specified window and have the last available on-treatment 
HIV-1 RNA measurement <50 copies/mL. In addition, this category will include 
participants who discontinued study intervention because of an AE or death and had 
no on-treatment HIV-1 RNA measurements during the entirety of the study.
-
Discontinued study intervention for other reasons: This includes participants who 
discontinued study intervention prior to or in the time point of interest analysis 
window due to reasons other than lack of efficacy and AE/death (ie, lost to follow-up, 
noncompliance with study intervention, physician decision, protocol deviation, 
withdrawal by participant, etc) and have the last available on-treatment HIV-1 RNA 
measurement <50 copies/mL. In addition, this category will include participants who 
discontinued study intervention due to reasons other than lack of efficacy and 
AE/death and had no on-treatment HIV-1 RNA measurements during the entirety of 
the study.
08WX9K

PRODUCT: MK-8591A
129
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
-
On study intervention but missing data in window: Only data in the predefined 
analysis window can be used for the statistical analysis at a given time point for 
participants remaining on study intervention. Participants with HIV-1 RNA results 
outside this window will be classified as “on study intervention but missing data in 
window” regardless of the out of window HIV-1 RNA results.
For the primary evaluation of non-inferiority as assessed by the percentage of participants 
with HIV-1 RNA ≥50 copies/mL, the parameter for evaluation is the number of participants 
classified as “HIV-1 RNA ≥50 copies/mL” according to the FDA snapshot algorithm defined 
above, divided by the number of participants in the FAS. For the secondary endpoint 
involving those with HIV-1 RNA <50 copies/mL, the parameter for evaluation is the number 
of participants classified as “HIV-1 RNA <50 copies/mL” according to the FDA snapshot 
algorithm, divided by the number of participants in the FAS. Similar logic will also be used 
to define the percentage of participants with HIV-1 RNA <200 copies/mL in accordance with 
the relevant secondary endpoints.
A second approach, the M=F approach, will be performed as a sensitivity analysis for the 
percentage of participants with HIV-1 RNA <50 copies/mL. Under this approach, 
participants who 1) have the last available on-treatment measurement within the time point of 
interest analysis window specified in Table 8 <50 copies/mL, OR 2) are on study 
intervention and have no HIV-1 RNA measurements within the time point of interest analysis 
window specified in Table 8 and have both the immediately preceding and immediately 
subsequent on-treatment HIV-1 RNA measurements <50 copies/mL, will be classified as a 
virologic success (ie, HIV-1 RNA <50 copies/mL) at the time point of interest. Participants 
with other reasons for missing data will be classified as a virologic failure (ie, HIV-1 RNA 
≥50 copies/mL) at the time point of interest.
A third approach, the OF approach, will also be performed as a sensitivity analysis for the 
percentage of participants with HIV-1 RNA ≥50 copies/mL and for the percentage of 
participants with HIV-1 RNA <50 copies/mL. Under this approach, participants with 
nonintermittent missing data who discontinue study intervention early due to lack of efficacy 
or who discontinue study intervention for other reasons and are failures (HIV-1 RNA 
≥50 copies/mL) at the time of study intervention discontinuation are considered to be failures 
at time points thereafter. Participants who discontinue study intervention for reasons other 
than lack of efficacy and who are not failures at the time of study intervention 
discontinuation will be excluded from the analyses at subsequent time points. Participants 
with intermittent missing data will be considered to be successes (HIV-1 RNA 
<50 copies/mL) if both the immediately preceding and immediately subsequent on-treatment 
HIV-1 RNA values are <50 copies/mL; all other intermittent missing results will be imputed 
as failures.
The same supportive approaches as described above will similarly be used for the analysis of 
the percentage of participants with HIV-1 RNA <200 copies/mL.
08WX9K

PRODUCT: MK-8591A
130
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Percentage of Participants With HIV-1 RNA ≥50 Copies/mL
The snapshot approach will be used as the primary approach to analysis with respect to the 
percentage of participants with HIV-1 RNA ≥50 copies/mL in the base study.
Non-inferiority of a switch to DOR/ISL on Day 1 (Group 1) to continued baseline ART from 
Day 1 to Week 48 (Group 2) with respect to the percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48 will be evaluated using the stratified Miettinen and Nurminen 
method [Miettinen, O. and Nurminen, M. 1985] with Cochran-Mantel-Haenszel weights 
(stratified by baseline ART regimen: PI-containing regimens [including PI- + InSTI-
containing regimens], InSTI-containing regimens [non-PI-containing regimens], and all other 
[non-PI- and non-InSTI-containing] regimens). For the evaluation of the primary efficacy 
hypothesis, a margin of 4 percentage points is used to define the non-inferiority of a switch to 
DOR/ISL on Day 1 to the continuation of baseline ART for 48 weeks; non-inferiority will be 
concluded if the upper bound of the 2-sided 95% CI for the between-group difference in the 
percentage of participants with HIV-1 RNA ≥50 copies/mL (Group 1 minus Group 2) is less 
than 4 percentage points. The choice of non-inferiority margin is based on the amount of 
virologic failure that is clinically acceptable; with an anticipated virologic failure rate of 
approximately 2%, a stringent margin of 4 percentage points is clinically acceptable.
To summarize virologic response over time, the difference in percentages between treatment 
groups at each time point through Week 48 will be estimated and the associated 2-sided 95% 
CI will be derived in a similar fashion to that described for the primary efficacy analysis.
In addition, for participants who become pregnant and consent to continue their assigned 
study intervention (Section 8.11.6.1), a listing of HIV-1 RNA values over time at the 
scheduled visits will be provided.
In the optional study extension, the percentage of participants with HIV-1 RNA ≥50 
copies/mL will be summarized at the scheduled visits using the DAO approach. This analysis 
will be summarized based on number of participants who have reached the timepoint of 
interest. 
Percentage of Participants With HIV-1 RNA <200 Copies/mL and Percentage of 
Participants With HIV-1 RNA <50 Copies/mL
The snapshot approach will be used as the primary approach to analysis with respect to the 
percentage of participants with HIV-1 RNA <200 copies/mL and the percentage of 
participants with HIV-1 RNA <50 copies/mL in the base study. These endpoints will be 
summarized by treatment group at each time point, with primary interest at Week 48 by 
comparing Group 1 and Group 2. For this time point of interest, the difference in percentages 
between treatment groups (Group 1 minus Group 2) and the associated 2-sided 95% CI will 
be calculated using the stratified Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985] with Cochran-Mantel-Haenszel weights (stratified by baseline ART 
regimen). A summary of virologic response over time for Group 1 from Day 1 through 
Week 144 and for Group 2 from Week 48 through Week 144 will be provided separately. 
08WX9K

PRODUCT: MK-8591A
131
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Supportive analyses using the M=F and OF approaches (as defined above) will also be 
presented.
In the optional study extension, the percentage of participants with HIV-1 RNA <50 and 
<200 copies/mL will be summarized in a similar manner as for those with HIV-1 RNA 
≥50 copies/mL.
The percentages of participants with HIV 1 RNA <20 copies/mL (the LLOQ of the assay), 20 
to <50, 50 to <100, 100 to <200, 200 to <400 and ≥400 copies/mL will be summarized by 
treatment groups at all scheduled study visit timepoints.
Change From Baseline in CD4+ T-cell Count
The mean change from baseline in CD4+ T-cell count will be summarized by treatment 
group at each time point at which CD4+ T-cell count is scheduled to be collected in the base 
study. To estimate the treatment difference (Group 1 minus Group 2), and corresponding 2-
sided 95% CI, in mean changes from baseline to Week 48 and from baseline to Week 96 
(where the data collected from Week 48 to Week 144, is temporally compared between 
treatment groups) in CD4+ T-cell count at each time point, a cLDA method proposed by 
Liang and Zeger [Liang, K-Y and Zeger, S. L. 2000] will be used. This model assumes a 
common mean across treatment groups at baseline and a different mean for each treatment at 
each of the post-baseline time points. In this model, the response vector consists of the 
baseline value and the values observed at each post-baseline time point. The analysis model 
will adjust for treatment group, time, stratum (at the time of randomization), the interaction 
of time-by-treatment group, and the interaction of time-by-stratum. This model will allow for 
different baseline means for each stratum, but restrict the baseline mean within each stratum 
to be the same for both treatment groups. Time is treated as a categorical variable so that no 
restriction is imposed on the trajectory of the means over time. An unstructured covariance 
matrix will be used to model the correlation among repeated measurements. The Kenward-
Roger adjustment [Kenward, M. G. and Roger, J. H. 1997] will be used with restricted (or 
residual) maximum likelihood to make proper statistical inference.
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups. Of note, if there are no missing data, the estimated treatment difference 
from the above cLDA model will be identical to that from a traditional longitudinal 
ANCOVA model which uses the baseline value as a covariate. However, unlike longitudinal 
ANCOVA, the cLDA model accounts for variability in the baseline values, thus providing 
more accurate standard errors and CIs for individual treatment effects. Moreover, this model 
allows the inclusion of participants who are missing either the baseline or post-baseline 
measurements, thereby increasing efficiency. Details of the model specification, 
assumptions, and SAS implementation codes will be provided in the sSAP.
The cLDA method assumes that data are MAR. In this study, it is expected that 
MAR/MCAR mechanisms will underlie most of the missingness, and the proportion of data 
MNAR, driven solely by unobserved values of the study endpoints, will be small. Reasons 
for discontinuation from the study may include lack of efficacy, death, withdrawal of 
08WX9K

PRODUCT: MK-8591A
132
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
consent, protocol deviations, lost to follow-up (eg, relocation), etc. Missing data caused by a 
participant’s relocation are likely to be MCAR. Missing data caused by discontinuations due 
to lack of efficacy may belong to MAR because this type of discontinuation may depend on 
the observed efficacy outcomes. The MAR or MNAR mechanisms might each underlie the 
other reasons to some extent. If the assigned study intervention in large part determines the 
loss of data for these other reasons, the mechanism may be close to MAR, because the 
intervention assignment is an observed variable and included in the analysis model.
To estimate the treatment difference (Group 1 minus Group 2), and corresponding 2-sided 
95% CI, in mean changes from baseline to Week 48 in Group 1 and from Week 48 to 
Week 96 in Group 2 (where the data reflects the first 48 weeks of treatment with DOR/ISL in 
each treatment group) in CD4+ T-cell count at each time point, a similar longitudinal model 
as described above will be used. However, because the baseline value in Group 1 (ie, the 
Day 1 value) and the baseline value in Group 2 (ie, the Week 48 value) will likely have 
different distributions (since participants in Group 2 will have had an additional 48 weeks of 
baseline ART experience relative to participants at baseline in Group 1), the constraint of 
equal baseline means across treatment groups will not be imposed. That is, an LDA model, 
rather than a cLDA model, will be used. Other model specifications will be consistent with 
those specified above. The estimates of the between-group differences in the mean change 
from baseline in CD4+ T-cell count will not be subject to an absolute criterion for similarity 
as the clinical interpretation of treatment difference is dependent upon the absolute values at 
baseline and the magnitude and direction of the CD4+ T-cell count changes observed in each 
treatment arm.
In addition to CD4+ T-cell count, the observed mean CD4+ T-cell percentage will also be 
summarized by study intervention groups at each timepoint at which the TBNK panel/CD4+ 
T-cell count is scheduled to be collected.
During the optional study extension, the change from baseline in CD4+ T-cell count will be 
summarized separately using descriptive statistics based on the DAO approach. For 
assessments of change from baseline in Group 2 during the optional study extension, the 
baseline measurement will be taken as the Week 48 measurement (or, if the Week 48 
measurement is not available, the last measurement before the switch to DOR/ISL)
Clinically Significant Confirmed Viremia
The number of participants with clinically significant confirmed viremia, as defined in 
Section 4.2.1.1.2, will be summarized for each treatment group.
Viral Resistance-associated Substitutions
The number of participants in the resistance analysis subset with genotypic and/or phenotypic 
resistance to each study intervention will be summarized for each treatment group with 
primary interest at Weeks 48, 96, 144, and timepoints of interest during the optional study 
extension.
08WX9K

PRODUCT: MK-8591A
133
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
HBV Acute Infection/Reactivation
If the clinical management of HBV acute infection/reactivation requires the addition of a
concomitant therapy that is also active against HIV-1, efficacy assessments in these 
participants from that point forward will be handled in a similar manner as the FDA snapshot 
algorithm classification rules for participants with missing data due to discontinuation of 
study intervention in the base study. During the optional study extension, efficacy 
assessments from that point forward in these participants will be reported separately.
Participants Who Discontinue Due to Pregnancy or Breastfeeding
For participants who become pregnant and choose to discontinue study intervention, or 
participants who choose to breastfeed and must discontinue study intervention in the base 
study, efficacy assessments from that point forward will be handled in a similar manner as 
the FDA snapshot algorithm classification rules for participants with missing data due to 
discontinuation of study intervention. Results for participants who become pregnant during 
the study will be reported separately.
Participants in Group 2 who become pregnant prior to the Week 48 visit are not eligible for a 
switch to DOR/ISL, but may consent to remain in the study on their baseline ART 
(Section 8.11.6.1). For such participants, efficacy assessments from that point forward will 
be handled in a similar manner as the FDA snapshot algorithm classification rules for 
participants with missing data due to discontinuation of study intervention.
Table 9 summarizes the key efficacy analyses of the base study.
The strategy to address multiplicity issues with regard to multiple treatment comparisons, 
multiple endpoints, multiple time points, and/or IAs is described in Sections 9.7 and 9.8.
08WX9K

PRODUCT: MK-8591A
134
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 9
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable 
(Description, Time Point)
Primary vs 
Supportive 
Approacha
Statistical 
Method
Analysis 
Population
Missing 
Data 
Approach
Primary Hypothesis H1
Percentage of participants with 
HIV-1 RNA ≥50 copies/mL at 
Week 48
P
M&N with 
CMH 
weightsb
FAS
Snapshot
S
M&N with 
CMH 
weightsb
PP
OF
Secondary Endpoints
Percentage of participants with 
HIV-1 RNA <200 and 
<50 copies/mL at Weeks 48, 96, 
and 144
P
M&N with 
CMH 
weightsb
FAS
Snapshot
S
M&N with 
CMH 
weightsb
FAS
M=F
S
M&N with 
CMH 
weightsb
PP
OF
Mean change from baseline in 
CD4+ T-cell count at Weeks 48, 
96, and 144
P
cLDAc
FAS
Model-based
cLDA=constrained longitudinal data analysis; CMH=Cochran-Mantel-Haenszel; FAS=Full Analysis Set; 
HIV-1=human immunodeficiency virus type 1; InSTI=integrase strand transfer inhibitor; M=F=missing 
equal to failure; M&N=Miettinen and Nurminen; OF=Observed Failure; PI=protease inhibitor; 
PP=Per-Protocol; RNA=ribonucleic acid.
a
P=primary approach; S=supportive approach.
b
The M&N method with CMH weights will be stratified by baseline ART regimen: PI-containing 
regimens (including PI- + InSTI-containing regimens), InSTI-containing regimens (non-PI-containing 
regimens), and non-PI- and non-InSTI-containing regimens [Miettinen, O. and Nurminen, M. 1985].
c
The cLDA model will include terms for treatment group, time, stratum, the interaction of time-by-
treatment group, and the interaction of time-by-stratum.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory test results and vital signs. For analyses of safety by time 
point, the same analysis windows as specified in Table 8 will be used, unless otherwise 
specified.
08WX9K

PRODUCT: MK-8591A
135
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Safety summaries will be presented by treatment arm for data collected up to Week 48 (ie, 
data collected from Day 1 to prior to the switch to DOR/ISL in Group 2). The post-Week 48 
safety data (ie, data collected from Week 48 through Week 144) in both treatment arms will 
be summarized. In addition, for Group 1, the safety data from Day 1 through Week 144 will 
be summarized. All between-group comparisons of safety endpoints will only be conducted 
up to Week 48 (prior to the switch to DOR/ISL in Group 2).
9.6.2.1
Overall Safety Assessment
The overall safety evaluation in the base study will include a summary by treatment group of 
the number and percentage of participants with any AE, with a drug-related AE, with an 
SAE, with a Grade 3 or 4 AE, with an AE that is both serious and drug-related, with an AE 
that is both Grade 3 or 4 and drug-related, who discontinued study intervention due to an AE, 
who discontinued study intervention due to a drug-related AE, and with an AE resulting in 
death. Point estimates and 2-sided 95% CIs for the differences between treatment groups 
(Group 1 minus Group 2) in the percentages of participants with the event will be provided.
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 2-sided 95% CIs for the differences between treatment groups in the 
percentages of participants with specific AEs will be provided for AEs that occur in at least 
8 participants in the DOR/ISL treatment group or at least 2 participants in the baseline ART 
group. These thresholds for the numbers of events were chosen because the 95% CI for the 
between-group difference in percent incidence will always include 0 when fewer participants 
per group have events and thus would add little to the interpretation of potentially meaningful 
differences.
CIs for between-treatment group differences will be provided using the unstratified Miettinen 
and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. CIs that are not adjusted for 
multiplicity should only be regarded as helpful descriptive measures for the review of the 
safety profile and not as a formal method for assessing statistical significance of between-
group differences. Point estimates and 2-sided 95% CIs for the differences between treatment 
groups in the percentages of participants with safety parameters that meet predefined limits 
of change will be provided based on the same criteria used above for specific AEs.
For continuous safety measures, such as change from baseline in laboratory and vital signs 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group. For participants who become pregnant during the study, 
measurements collected after the estimated date of conception will be excluded from the 
analyses. Missing data will not be imputed.
To evaluate the effect on weight of a switch to DOR/ISL at Day 1 compared with continued 
baseline ART, the treatment difference (Group 1 minus Group 2) and corresponding 2-sided 
95% CI for the mean change from baseline to Week 48 in weight will be estimated using an 
ANCOVA model adjusted by baseline weight, sex at birth, race, stratum, presence of EFV or 
TDF in the baseline ART regimen, and treatment group. Presence of EFV or TDF in the 
baseline ART regimen will be adjusted for in the ANCOVA models as these are 
antiobesogenic ARTs. Additional ANCOVA models may be run within each stratum to 
08WX9K

PRODUCT: MK-8591A
136
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
estimate the treatment difference among participants with PI-containing baseline ART 
regimens (including PI- + InSTI-containing regimens), among participants with 
InSTI-containing baseline ART regimens (non-PI-containing regimens), and among 
participants with non-PI- and non-InSTI-containing baseline ART regimens; therefore, these 
ANCOVA models will not adjust for stratum. 
For the mean change from baseline to Week 48 in lymphocyte, the treatment difference 
(Group 1 minus Group 2) and corresponding 2-sided 95% CI will be estimated using 
ANCOVA models adjusted by baseline value and treatment group. 
Safety data for participants who consent to continue the treatment in the optional study 
extension (from Week 144 to Week 240) will be summarized separately. Additional details 
are provided in the sSAP.
9.6.2.2
Assessment of Safety Topics of Special Interest
Opportunistic infections and lipid profiles are considered safety topics of special interest in 
the base study.
The number and percentage of participants with any opportunistic infection will be 
summarized by treatment group. The point estimate and 2-sided 95% CI for the difference 
between treatment groups (Group 1 minus Group 2) in the percentage of participants with 
any opportunistic infection will be provided. The number and percentage of participants with 
specific opportunistic infections will also be summarized by treatment group. Point estimates 
and 2-sided 95% CIs for the differences between treatment groups (Group 1 minus Group 2) 
in the percentages of participants with these events will be provided based on the criteria 
described above for specific AEs. CIs for between-treatment group differences will be 
provided using the unstratified Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985]. Opportunistic infections will be identified through SMQs using the 
MedDRA dictionary. SMQs on both broad and narrow PTs will be performed and will be 
summarized separately.
The effect on LDL-C and non-HDL-C at Week 48 of a switch to DOR/ISL on Day 1 
compared with the continuation of baseline ART for each baseline ART class will be 
evaluated. Of particular interest is assessing the superiority of a switch to DOR/ISL on Day 1 
compared with the continuation of baseline ART for those in each stratum at Week 48.
For the evaluation of the secondary objective to assess the effect on lipid profiles of a switch 
to DOR/ISL at Day 1 compared with continued baseline ART, the treatment difference 
(Group 1 minus Group 2) and 2-sided 95% CI for all lipid parameters will be estimated using 
ANCOVA models adjusted by baseline lipid level and treatment group. Separate ANCOVA 
models will be constructed for each baseline ART stratum. Participants who receive 
lipid-lowering therapy at baseline will be excluded from the lipid-related analyses. For 
participants who initiate lipid-lowering therapy during the study, the last lipid measurement 
before initiating the lipid-lowering therapy will be carried forward. For participants who 
become pregnant, lipid data collected after the estimated date of conception will be excluded. 
Missing lipid data will not be imputed; as such, any participant with a missing value will be 
08WX9K

PRODUCT: MK-8591A
137
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
excluded from the analyses. The percentages of participants who initiate or modify lipid-
lowering therapy prior to Week 48 will be summarized by treatment group. Additional details 
will be provided in the sSAP.
The same ANCOVA models used to estimate the between-group differences in lipid profiles 
for each stratum will be used to evaluate the secondary composite hypothesis regarding the 
effect on LDL-C and non-HDL-C of a switch to DOR/ISL at Day 1 compared with the 
continuation of baseline ART for each stratum at Week 48. In accordance with the 
multiplicity strategy (Section 9.8), the hypothesis will be tested for each stratum sequentially 
(ie, statistical significance for the first stratum must be established before testing the next 
stratum, and so forth) in the order of PI-containing regimens (including PI- + 
InSTI-containing regimens), non-PI- and non-InSTI-containing regimens, and 
InSTI-containing regimens (non-PI-containing regimens). The superiority of a switch to 
DOR/ISL on Day 1 compared with continuation of baseline ART as assessed by having a 
lower mean increase from baseline in LDL-C and/or non-HDL-C at Week 48 will be 
concluded if the upper bound of the 2-sided multiplicity-adjusted 95% CI for the estimate of 
the between-group difference (Group 1 minus Group 2) is less than 0. P-values for the 
comparisons will also be provided.
9.6.2.3
Handling of Missing Data and Pregnancies in Safety Analyses
Missing safety parameters, unless otherwise specified, will not be imputed; as such, any 
participant with a missing value will be excluded from the analysis. Change from baseline 
summaries require a baseline value. Baseline measurements are defined as the Day 1 value 
for each participant. In the rare event when data for this visit are missing, the value obtained 
at the most recent Screening Visit will be used as baseline, when available. If no baseline 
result is available for a given analysis, that participant will not be included in the analysis. 
Safety data for participants who consent to enter the optional study extension at Week 144 
will be summarized from Week 144 to Week 240.
For participants who become pregnant during the study, all safety data collected on or after 
the estimated date of conception will be summarized separately from the primary and 
secondary safety analyses. Data collected for participants whose pregnancy or Postpartum 
visit(s) extends beyond Week 144 will be reported separately. Infant safety data will also be 
reported separately.
Table 10 summarizes the analysis strategy for safety endpoints in the base study.
08WX9K

PRODUCT: MK-8591A
138
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 10
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% 
Between-group 
CI
Inferential 
Analysis
Overall Safety 
Assessment
Any AE
X
X
Any drug-related AE
X
X
Any SAE
X
X
Any Grade 3 or 4 AE
X
X
Any serious drug-related AE
X
X
Any Grade 3 or 4 drug-related AE
X
X
Discontinued study intervention due 
to an AE
X
X
Discontinued study intervention due 
to a drug-related AE
X
X
AE resulting in death
X
X
Specific AEs
X
Xa
SOCs, PDLCs
X
Xa
Mean Change from Baseline 
(Laboratory, Vital Signs Parameters, 
and Lymphocyte Parameters)
X
X
Assessment of 
Safety Topics 
of Special 
Interest
Any Opportunistic Infection
X
X
Specific Opportunistic Infections and 
Corresponding SOCs
X
Xa
Lipid Profiles (Mean Change from 
Baseline in LDL-C, non-HDL-C, TC, 
HDL-C, TGs, and TC/HDL-C Ratio)
X
X
Xb
AE=adverse event; CI=confidence interval; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-
density lipoprotein cholesterol; non-HDL-C=non-high-density lipoprotein cholesterol; PDLC=predefined 
limit of change; SAE=serious adverse event; SOC=system organ class; TC=total cholesterol; 
TG=triglyceride.
a
The between-group 95% CI will only be provided for events that occur in at least 8 participants in 
Group 1 or at least 2 participants in Group 2.
b
Inferential analysis will only be performed for the mean change from baseline in the LDL-C and non-
HDL-C lipid parameters at Week 48 in accordance with the relevant secondary hypothesis, H2. P-values 
will be provided for the mean change from baseline in LCDL-C and non-HIDL-C at Week 48.
08WX9K

PRODUCT: MK-8591A
139
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, race, region, etc), baseline characteristics, 
primary and secondary diagnoses, and prior and concomitant therapies will be summarized 
by treatment either by descriptive statistics or categorical tables.
9.7
Interim Analyses
Study enrollment is likely to be ongoing at the time of the IA. The IA results will not be 
shared with the investigators prior to the completion of the study.
An eDMC will serve as the primary reviewer of the interim efficacy and safety review results 
and may make recommendations for discontinuation of the study or for protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) will review results at the 
treatment-level to act on these recommendations. Additional logistical details will be 
provided in the DMC charter.
Once approximately 30% of target enrollment (n=150 participants) have completed the 
Week 24 visit assessments, the Week 24 IA will be conducted by the external statistician to 
assess futility. This analysis will be reviewed by the eDMC. All available efficacy and safety 
data for all participants enrolled at the time of the Week 24 IA will be reviewed. The futility 
analysis will include the first approximately 30% of study participants who complete the 
Week 24 visit assessments. The nonbinding futility criterion is as follows:
Nonbinding Futility Criterion: If the upper bound of the 2-sided 95% CI for the 
between-group difference (Group 1 minus Group 2) in the percentage of participants with 
HIV-1 RNA ≥200 copies/mL at Week 24 is greater than 8 percentage points, consideration 
may be given to stop the study. The CI will be based on the unstratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985].
For the purpose of the futility assessment, those classified as HIV-1 RNA ≥200 copies/mL 
will include participants:

Who have the last available on-treatment HIV-1 RNA measurement within the Week 24 
analysis visit window specified in Table 8 ≥200 copies/mL.
08WX9K

PRODUCT: MK-8591A
140
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Note: For such participants, if the HIV-1 RNA value of ≥200 copies/mL is not confirmed 
at the subsequent assessment (ie, the participant does not meet the criteria for clinically 
significant confirmed viremia [Section 4.2.1.1.2]), their virologic outcome will be 
reassessed for the primary efficacy analysis (Section 9.6.1).
•
Who do not have on-treatment HIV-1 RNA data in the Week 24 analysis visit window 
specified in Table 8 and
-
Discontinued study intervention prior to or in the Week 24 analysis visit window due 
to lack of efficacy or clinically significant confirmed viremia (Section 4.2.1.1.2), or
-
Discontinued study intervention prior to or in the Week 24 analysis visit window due 
to reasons other than lack of efficacy/clinically significant confirmed viremia and 
have their last on-treatment HIV-1 RNA measurement ≥50 copies/mL.
Note: Such participants will be classified as virologic failures (ie, HIV-1 RNA 
≥50 copies/mL) in the primary efficacy analysis (Section 9.6.1) in accordance with 
the FDA snapshot approach.
The endpoint of HIV-1 RNA ≥200 copies/mL for the futility assessment is clinically 
meaningful as it is a threshold associated with increased likelihood of development of viral 
drug resistance and subsequently a potential need to switch to a new regimen, while values 
<200 copies/mL do not necessarily indicate the need for a change in therapy. Furthermore, 
use of this endpoint protects against over-interpretation of transient viremia (ie, an HIV-1 
RNA measurement ≥50 copies/mL in a previously suppressed person that quickly resolves to 
<50 copies/mL); a single value of HIV-1 RNA ≥200 copies/mL is more likely to indicate a 
true treatment failure than a single value ≥50 copies/mL and is thus a useful measure for 
assessing futility at the Week 24 IA.
Given the anticipated small number of participants with HIV-1 RNA ≥200 copies/mL at 
Week 24 and the expected sample sizes of 100 participants in Group 1 and 50 participants in 
Group 2 included in the futility assessment, the specified futility criterion is sensitive to 
imbalances in the number of failures (ie, HIV-1 RNA ≥200 copies/mL) between the 
treatment groups. For example, if there are 2 failures out of 100 participants in Group 1 and 
0 failures out of 50 participants in Group 2, the estimated treatment difference is 2% and the 
upper bound of the between-group 95% CI is 7.03, which would not meet the futility 
criterion. However, if there are 3 failures in Group 1 and 0 failures in Group 2, then the 
treatment difference is 3% and the upper bound of the between-group 95% CI is 8.48, thus 
meeting the futility criterion and leading to consideration to stop the study. If there are 3 
failures in Group 1 and 1 failure in Group 2, then the treatment difference is 1% and the 
upper bound of the between-group 95% CI is 6.84, which would not meet the futility 
criterion. However, with 4 failures in Group 1 and 1 failure in Group 2, the treatment 
difference is 2% and the upper bound of the between-group 95% CI is 8.25, which meets the 
futility criterion. Additional details on the operational characteristics of the futility criterion 
are provided in Section 9.9.1.
The eDMC will review accumulating efficacy and safety data at regular intervals throughout 
the study duration, or at modified intervals based on the recommendation of the eDMC. The 
08WX9K

PRODUCT: MK-8591A
141
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
eDMC will recommend steps to ensure the safety of study participants and the integrity of 
the study as needed.
An analysis will be conducted to test the primary non-inferiority efficacy hypothesis once all 
participants have completed the Week 48 visit assessments. This will be the formal 
evaluation of the primary non-inferiority efficacy hypothesis. All available efficacy and 
safety data will be reviewed at this interim time point. Treatment-level results from this 
analysis will be provided to the eDMC.
Since the hypotheses listed in Section 3 will be tested only at Week 48 (and not at the 
Week 24 IA nor any periodic review of data by the eDMC) and as there is no plan to stop the 
study early for a positive efficacy finding, testing of H1 and H2 will not be adjusted for 
multiplicity on account of any eDMC reviews. The multiplicity strategy for hypothesis 
testing is described in Section 9.8.
At least until the Week 48 database lock, treatment-level results from all IAs will be provided 
to the eDMC by the external statistician. The external statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts after the IAs.
If the study is stopped early, the CSR will include all available data up to and including the 
close-out visits. This approach to include all available information is in line with the ICH-E9 
guideline.
9.8
Multiplicity
As noted in Section 9.7, an eDMC will convene at routine intervals to monitor efficacy and 
safety. A formal futility analysis at Week 24 is planned as described in Section 9.7; a small 
among of alpha (α=0.00001) will be allocated for this IA, purely for statistical rigor. The trial 
will not be stopped early for positive efficacy at the IA.
In order to have strong control of the overall Type I error rate across the primary and 
secondary hypotheses, the following hypotheses will be tested sequentially at a 1-sided 
2.499% Type 1 error rate in the following order:
1. Primary efficacy hypothesis (H1) testing non-inferiority of Group 1 to Group 2 as 
assessed by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48.
2. Secondary safety hypothesis (H2) testing superiority of Group 1 to Group 2 as assessed 
by the mean change from baseline in LDL-C and non-HDL-C at Week 48. It is noted that 
H2 is really a composite hypothesis involving 6 statistical tests (2 cholesterol parameters 
and 3 randomization strata). These 6 tests will be evaluated following the graphical 
approach of Maurer and Bretz [Maurer, W., et al 2011] to strongly control the overall 1-
sided Type 1 error rate at 2.499%.
Figure 2 shows the hierarchical testing procedure in H2 between LDL-C and non-HDL-C 
endpoints in the 3 strata. In each stratum, testing will stop with the first of these tests failing 
to reach statistical significance. The testing in a given stratum is considered a success if 
superiority is established for both the hypotheses in that stratum. The weight ω is defined 
08WX9K

PRODUCT: MK-8591A
142
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
based on the sample size of the PI stratum. Here, “a” denotes the sample size of the PI 
stratum and “N” denotes the total sample size. The assumptions on “a” and weight ω, as 
described below, are based on clinical judgment from historical data and the prevalence of 
the ARTs from the PI stratum and also from observed data at Week 48 in the MK-8591A-017 
study. Specifically, from historical data, the PI stratum is most likely to show a significant 
treatment difference but the sample size in this stratum is uncertain as PI use is diminishing 
in some regions. Therefore, contingent on a sufficient sample size, a large fraction of alpha 
(α) is initially allocated to the PI stratum with the rest distributed equally to the other 2 strata.
Figure 2
Multiplicity Graph for Type I Error Control of the Secondary Hypothesis
Insti=integrase strand transfer inhibitor; LDL-C=low-density lipoprotein cholesterol; 
non-HDL-C=non-high-density lipoprotein cholesterol; PI= protease inhibitor; ω=weight
Table 11 illustrates the initial Type 1 error (α) allocation to all the hypotheses in the 3 strata 
for different hypothetical sample sizes observed in the PI stratum.
08WX9K

PRODUCT: MK-8591A
143
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 11
Initial Alpha Allocation Based on PI Stratum Sample Size
PI 
Sample 
Size
ω
PI -
LDL-C
PI -
Non-
HDL-C
Other -
LDL-C
Other -
Non-
HDL-C
InSTI -
LDL-C
InSTI -
Non-
HDL-C
Total 
Type I 
Error 
(α)
200
0.60079
0.01501
0
0.00499
0
0.00499
0
0.02499
180
0.64072
0.01601
0
0.00449
0
0.00449
0
0.02499
130
0.74052
0.01815
0
0.00324
0
0.00324
0
0.02499
100
0.5
0.01249
0
0.00625
0
0.00625
0
0.02499
70
0.01
0.000249
0
0.01237
0
0.01237
0
0.02499
50
0.01
0.000249
0
0.01237
0
0.01237
0
0.02499
InSTI=integrase strand transfer inhibitor; LDL-C=low-density lipoprotein cholesterol; 
non-HDL-C=non-high-density lipoprotein cholesterol; PI=protease inhibitor; ω=weight.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
9.9.1.1
Evaluation of the Primary Hypothesis
This section presents power calculations for the primary efficacy analysis of demonstrating 
non-inferiority of a switch to DOR/ISL on Day 1 to continued baseline ART at Week 48. The 
power calculations provided in this section do not account for the futility assessment at the 
Week 24 IA or the sequential testing strategy described in Section 9.8.
For efficacy analyses using the FDA snapshot algorithm, missing data (eg, due to study 
intervention discontinuation) are classified as either HIV-1 RNA ≥50 copies/mL (which will 
contribute to both the numerator and denominator in the calculation of the percentage of 
participants with HIV-1 RNA ≥50 copies/mL) or as No Virologic Data in Specified Analysis 
Time Window (which will contribute only to the denominator in the calculation of the 
percentage of participants with HIV-1 RNA ≥50 copies/mL). Therefore, the impact of 
missing data on study power is subsumed within the rates of HIV-1 RNA ≥50 copies/mL 
assumed in the power calculations throughout Section 9.9.1.
Non-inferiority will be concluded if the upper bound of the 2-sided 95% CI for the 
between-group difference in the percentage of participants with HIV-1 RNA ≥50 copies/mL 
at Week 48 (Group 1 minus Group 2) is less than 4 percentage points. The choice of 
non-inferiority margin is based on the amount of virologic failure that is clinically 
acceptable; with an anticipated virologic failure rate of approximately 1.5% to 2%, a 
stringent margin of 4 percentage points is clinically acceptable. The observed percentages of 
participants with HIV-1 RNA ≥50 copies/mL at Week 48 are based on experience with 
MK-8591A-017 and MK-8591A-018. They are 0.0% in DOR/ISL group and 1.5% in 
Baseline ART group in MK-8591A-017 and 0.6% in DOR/ISL group and 0.3% in 
BIC/FTC/TAF group in MK-8591A-018.
08WX9K

PRODUCT: MK-8591A
144
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 12 summarizes the power to declare a switch to DOR/ISL on Day 1 non-inferior to 
continued baseline ART at Week 48 under various assumptions for the response rate (ie, the 
percentage of participants with HIV-1 RNA ≥50 copies/mL) in Group 2 and the underlying 
between-group difference in response rates. For example, if the true rate of participants with 
HIV-1 RNA ≥50 copies/mL is 1.5% in both groups, this study has approximately 93.3% 
power to demonstrate non-inferiority. If the true rates are 2.0% in both groups, this study has 
approximately 87.0% power to demonstrate non-inferiority.
Table 12
Power (%) to Establish Non-inferiority at Week 48 Under Various Response Rate 
Assumptions
True Response Rate 
in Group 2
True Difference in Response Rates (Group 1 Minus Group 2)
-1.0 
Percentage 
Points
-0.5 
Percentage 
Points
0.0 
Percentage 
Points
0.5 
Percentage 
Points
1.0 
Percentage 
Points
0.5%
NA
100
99.9
96.9
83.8
0.75%
NA
100
99.4
93.5
77.7
1.0%
100
100
98.2
89.4
72.1
1.25%
100
99.7
96.1
84.9
67.2
1.5%
100
99.0
93.3
80.6
63.1
1.75%
99.8
97.7
90.2
76.6
59.5
2.0%
99.4
95.9
87.0
72.9
56.3
2.25%
98.7
93.8
83.8
69.5
53.3
2.5%
97.5
91.5
80.7
66.3
50.5
2.75%
96.2
89.1
77.6
63.2
48.0
3.0%
94.6
86.6
74.6
60.3
45.6
CI=confidence interval; HIV-1=human immunodeficiency virus type 1; NA=not applicable; 
PASS=power analysis and sample size; RNA=ribonucleic acid.
334 participants in Group 1 and 167 participants in Group 2
The response rate is the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48.
The non-inferiority margin is 4 percentage points. To establish non-inferiority, the upper bound of the 
2-sided 95% CI for the difference between groups (Group 1 minus Group 2) in the percentage of participants 
with HIV-1 RNA ≥50 copies/mL must be <4 percentage points. The 95% CI is based on the unstratified 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The 1-sided Type 1 error is 
0.02499. Calculations were performed using PASS 16.
The observed percentages of participants with HIV-1 RNA ≥50 copies/mL at Week 48 are based on 
experience with MK-8591A-017 and MK-8591A-018. They are 0.0% in DOR/ISL group and 1.5% in 
Baseline ART group in MK-8591A-017 and 0.6% in DOR/ISL group and 0.3% in BIC/FTC/TAF group in 
MK-8591A-018.
08WX9K

PRODUCT: MK-8591A
145
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
9.9.1.2
Evaluation of the Futility Criterion and Non-inferiority at Week 48
The futility assessment will be conducted on the first approximately 30% of the total planned 
study enrollment (approximately 100 participants in Group 1 and 50 participants in Group 2) 
who complete the Week 24 visit assessments. The study may be stopped if the upper bound 
of the 2-sided 95% CI for the difference in the percentage of participants with HIV-1 RNA 
≥200 copies/mL at Week 24 (Group 1 minus Group 2) is greater than 8 percentage points.
Table 13 summarizes the probability of not meeting the futility criterion at Week 24 under 
various assumptions for the response rate (ie, the percentage of participants with HIV-1 RNA 
≥200 copies/mL) in Group 2 and the underlying between-group difference in response rates. 
For example, if the true rate of participants with HIV-1 RNA ≥200 copies/mL at Week 24 
among 100 participants in Group 1 and 50 participants in Group 2 is 0.75% in both groups, 
then the probability of not meeting the futility criterion is 0.971. If the true rates are 1.0% in 
both groups, then the probability of not meeting the futility criterion is 0.946. If the true rate 
in Group 1 is 2.0% and the true rate in Group 2 is 1.0%, then the probability of not meeting 
the futility criterion is 0.757.
Table 13
Probability of Not Meeting the Futility Criterion at the Week 24 Interim Analysis
True Response Rate in 
Group 2
True Difference in Response Rates (Group 1 Minus Group 2)
-1.0 
Percentage 
Points
-0.5 
Percentage 
Points
0.0 
Percentage 
Points
0.5 
Percentage 
Points
1.0 
Percentage 
Points
0.50%
NA
1.000
0.989
0.935
0.839
0.75%
NA
0.999
0.971
0.900
0.797
1.0%
1
0.991
0.946
0.864
0.757
1.25%
0.999
0.976
0.917
0.827
0.720
1.5%
0.993
0.956
0.885
0.791
0.684
1.75%
0.981
0.931
0.853
0.756
0.652
2.0%
0.964
0.904
0.820
0.723
0.622
2.25%
0.943
0.875
0.789
0.692
0.595
2.5%
0.919
0.846
0.758
0.664
0.570
2.75%
0.894
0.817
0.730
0.638
0.549
3.0%
0.868
0.790
0.704
0.615
0.529
CI=confidence interval; HIV-1=human immunodeficiency virus type 1; NA=not applicable; PASS=power 
analysis and sample size; RNA=ribonucleic acid.
100 participants in Group 1 and 50 participants in Group 2
The response rate is the percentage of participants with HIV-1 RNA ≥200 copies/mL at Week 24.
Futility Criterion: Upper bound of the 2-sided 95% CI for the between-group difference in the percentage of 
participants with HIV-1 RNA ≥200 copies/mL at Week 24 (Group 1 minus Group 2) is greater than 8 
percentage points.
The 95% CI is based on the unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 
1985]. The 1-sided Type 1 error is 0.02499. Calculations were performed using PASS 16.
08WX9K

PRODUCT: MK-8591A
146
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
The probability of not meeting the futility criterion at the Week 24 IA and the power to 
demonstrate non-inferiority at Week 48 under a variety of assumptions is presented in 
Table 14.
The power calculations shown in Table 14 incorporate the futility assessment stopping rules. 
Of interest is the likelihood that the study would not meet the futility criterion at Week 24 for 
a variety of assumed Week 24 response rates and also whether the non-inferiority criterion at 
Week 48 would be subsequently met (ie, the conditional power of declaring DOR/ISL 
non-inferior to baseline ART at Week 48).
For example, if the true rate of participants with HIV-1 RNA ≥200 copies/mL at Week 24 is 
0.5% in both groups, the rate of HIV-1 RNA ≥50 copies/mL at Week 48 among participants 
who had HIV-1 RNA ≥200 copies/mL at Week 24 is 95% in both groups, and the rate of 
HIV-1 RNA ≥50 copies/mL at Week 48 among participants who had HIV-1 RNA 
<200 copies/mL at Week 24 is 1% in both groups, then the probability of not meeting the 
futility criterion at the Week 24 IA is 98.9% and the subsequent power to declare non-
inferiority of DOR/ISL to baseline ART at Week 48 is 93.8%.
Additional power calculations are provided in the sSAP.
08WX9K

PRODUCT: MK-8591A
147
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 14
Probability of Not Meeting the Futility Criterion at the Week 24 Interim Analysis and the Conditional Power to Declare 
Non-inferiority at Week 48 for Various Underlying True Response Rates
Parameter
Base Case
More 
Conservative 
Base Case
Most 
Conservative 
Base Case
Low Efficacy for 
DOR/ISL; Low 
Efficacy for 
Baseline ART
Low Efficacy for 
DOR/ISL; High 
Efficacy for 
Baseline ART
High Efficacy 
for DOR/ISL; 
Low Efficacy for 
Baseline ART
High Efficacy 
for DOR/ISL; 
High Efficacy 
for Baseline 
ART
Lowest Efficacy 
for DOR/ISL; 
High Efficacy 
for Baseline 
ART
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Assumptionsa
% with Week 24 HIV-1 
RNA ≥200 copies/mL
0.5%
0.5%
0.75%
0.75%
1.0%
1.0%
1.5%
1.0%
1.5%
0%
0%
1.0%
0%
0%
3%
0%
% with Week 48 HIV-1 
RNA ≥50 copies/mL if 
Week 24 HIV-1 RNA
≥200 copies/mL
95%
95%
100%
100%
100%
100%
100%
100%
100%
92%
92%
100%
92%
92%
100%
92%
% with Week 48 HIV-1 
RNA ≥50 copies/mL if 
Week 24 HIV-1 RNA 
<200 copies/mL
1%
1%
1.25%
1.25%
1.5%
1.5%
3%
2%
3%
0.5%
0.5%
2%
0.5%
0.5%
3%
0.5%
% with Week 48 HIV-1 
RNA ≥50 copies/mL
1.5%
1.5%
2.0%
2.0%
2.5%
2.5%
4.5%
3.0%
4.5%
0.5%
0.5%
3.0%
0.5%
0.5%
5.9%
0.5%
Study Power
Probability of Not 
Meeting the Futility 
Criterionb
98.9%
97.0%
94.7%
86.5%
81.1%
~100%
~100%
42.4%
Conditional Power to 
Establish Non-inferiority 
at Week 48c
93.8%
87.8%
82.4%
35.9%
2.4%
~100%
99.9%
0.2%
ART=antiretroviral therapy; BIC=bictegravir; CI=confidence interval; COVID-19=coronavirus disease 2019; DOR=doravirine; FTC=emtricitabine; 
HIV-1=human immunodeficiency virus type 1; ISL=islatravir; RNA=ribonucleic acid; TAF=tenofovir alafenamide.
The calculations assume 100 participants in Group 1 and 50 participants in Group 2 for the assessment of futility at Week 24 and 334 participants in Group 1 and 167 participants 
in Group 2 for the assessment of non-inferiority at Week 48.
08WX9K

PRODUCT: MK-8591A
148
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Parameter
Base Case
More 
Conservative 
Base Case
Most 
Conservative 
Base Case
Low Efficacy for 
DOR/ISL; Low 
Efficacy for 
Baseline ART
Low Efficacy for 
DOR/ISL; High 
Efficacy for 
Baseline ART
High Efficacy 
for DOR/ISL; 
Low Efficacy for 
Baseline ART
High Efficacy 
for DOR/ISL; 
High Efficacy 
for Baseline 
ART
Lowest Efficacy 
for DOR/ISL; 
High Efficacy 
for Baseline 
ART
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
a
The assumptions for calculating power are based on observed rates in the MK-8591A-017 and MK-8591A-018 switch studies. Specifically, MK-8591A-017 showed a rate 
≥50 copies/mL at Week 48 of 0.0% in the DOR/ISL arm and 1.5% in the continued baseline ART arm; MK-8591A-018 showed a rate ≥50 copies/mL at Week 48 of 0.6%
in the DOR/ISL arm and 0.3% in the BIC/FTC/TAF arm. For the 3 base cases, the assumed percentages of participants with HIV-1 RNA ≥50 copies/mL at Week 48 are 
generally higher than the rates observed across the MK-8591A-017 and MK-8591A-018 study arms and, therefore, are considered to be conservative. The conservative rates 
were selected in recognition that MK-8591A-017 and MK-8591A-018 were conducted during the global COVID-19 pandemic, during which time participants may have 
been restricted to home stay or limited travel, potentially leading to higher adherence to study intervention and subsequently lower rates of virologic failure than would be 
otherwise expected.
b
Futility Criterion: Upper bound of the 2-sided 95% CI for the between-group difference in the percentage of participants with HIV-1 RNA ≥200 copies/mL at Week 24 
(Group 1 minus Group 2) is greater than 8 percentage points. Values for the probability of not meeting the futility criterion were calculated via simulation.
c
Each value was calculated via 10,000 simulations to evaluate first whether the futility criterion was met and if not, evaluate non-inferiority between groups using the 
unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The non-inferiority margin is 4 percentage points and the Type 1 error is 0.0249 (1-
sided). Calculations were performed in R 3.5.0.
08WX9K

PRODUCT: MK-8591A
149
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
9.9.2
Sample Size and Power for Safety Analyses
9.9.2.1
Evaluation of Adverse Events
The probability of observing at least 1 of a particular type of AE in this study depends on the 
number of participants treated and the underlying percentage of participants with that AE in 
the study population.
If the underlying incidence of a particular AE is 1%, there is a 96.5% chance of observing at 
least 1 AE among 334 participants in a treatment group and an 81.3% chance of observing at 
least 1 AE among 167 participants in a treatment group. If no AE of that type is observed 
among 334 participants in a treatment group, this study will provide 97.5% confidence that 
the underlying percentage of participants with that particular AE is <1.10% (1 in every 
91 participants) in the treatment group; if no AE of that type is observed among 
167 participants in a treatment group, this study will provide 97.5% confidence that the 
underlying percentage of participants with that particular AE is <2.18% (1 in every 
45 participants) in the treatment group.
The point estimate and the upper bound of the corresponding 2-sided 95% CI for the 
underlying percentage of participants with an AE given various hypothetical observed 
numbers of participants with the AE within each treatment group are provided in Table 15. 
These calculations are based on the exact binomial method proposed by Clopper and Pearson 
[Clopper, C. J. and Pearson, E. S. 1934].
08WX9K

PRODUCT: MK-8591A
150
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 15
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants With AEs
Number of 
Participants in the 
Treatment Group
Number of 
Participants With 
Adverse Event
Estimate of 
Incidence
95% Upper 
Confidence Bounda
334
0
0%
0.9%
167
0
0%
1.8%
334
1
0.3%
1.7%
167
1
0.6%
3.3%
334
2
0.6%
2.1%
167
2
1.2%
4.3%
334
5
1.5%
3.5%
167
5
3.0%
6.8%
334
10
3.0%
5.4%
167
10
6.0%
10.7%
334
15
4.5%
7.3%
167
15
9.0%
14.4%
334
20
6.0%
9.1%
167
20
12.0%
17.9%
334
25
7.5%
10.9%
167
25
15.0%
21.3%
334
30
9.0%
12.6%
167
30
18.0%
24.6%
AE=adverse event; CI=confidence interval.
a
Based on the 2-sided exact 95% CI for a binomial proportion (Clopper and Pearson method [Clopper, C. 
J. and Pearson, E. S. 1934]). In the 0-event case, the CI is 1-sided (α=0.05 all in the upper tail).
Table 16 gives the difference in the incidence of an AE (Group 1 minus Group 2) that can be 
ruled out with different power levels and 95% confidence when there are 334 participants in 
Group 1 and 167 participants in Group 2. The underlying incidence of the AE is assumed to 
be the same for the 2 treatment groups. For example, for a reasonably common AE which 
occurs in 20% of participants in both groups, the study has 80% power to declare with 95% 
confidence that the true difference between the treatment groups is no more than 
11.7 percentage points. The calculations are based on an asymptotic method proposed by 
Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
08WX9K

PRODUCT: MK-8591A
151
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 16
Difference in Incidence (Percentage Points) of AEs (Group 1 Minus Group 2) 
That Can Be Ruled Out With 334 Participants in Group 1 and 167 Participants in Group 2
Target Power
Underlying AE Incidence Rate
1%
5%
10%
20%
30%
40%
50%
80%
5.1
7.7
9.6
11.7
12.8
13.2
13.1
85%
5.5
8.3
10.3
12.5
13.7
14.1
14.0
90%
6.1
9.1
11.2
13.6
14.8
15.3
15.1
95%
7.1
10.3
12.6
15.2
16.5
17.0
16.7
AE=adverse event; CI=confidence interval.
Values represent the upper bound of the 2-sided 95% CI (unstratified Miettinen and Nurminen [Miettinen, O. 
and Nurminen, M. 1985]) for the difference in AE incidences (Group 1 minus Group 2) assuming the 
incidences are the same.
9.9.2.2
Evaluation of Change from Baseline in Lipid Profiles
Because it is unknown in advance how many participants will be enrolled into each baseline 
ART stratum, and among those, how many will be on lipid-lowering therapy at baseline or 
initiate lipid-lowering therapy prior to Week 48 and thus be excluded from the lipid-related 
analyses, it is unknown how many participants will be available for the evaluation of the 
lipid-related hypothesis. As such, Table 17 summarizes the power to declare Group 1 
superior to Group 2 in the PI stratum as assessed by the mean change from baseline in 
LDL-C and non-HDL-C at Week 48 under various assumed treatment differences, standard 
deviations, and numbers of participants in each treatment group. The graphical approach will 
be used to test the LDL-C and non-HDL-C parameters within the PI stratum; the PI stratum 
sample sizes and corresponding 1-sided Type 1 error is used in Table 17 for illustrative 
purposes.
For example, if the between-treatment difference (Group 1 minus Group 2) in the mean 
change in fasting LDL-C/non-HDL-C is 10 mg/dL with a standard deviation of 15 mg/dL in 
both treatment groups, 80 participants in Group 1 and 40 participants in Group 2 in the PI 
stratum, and a 1-sided Type 1 error of 0.0125 for that stratum, then this study has 
approximately 87.8% power to demonstrate that Group 1 is superior to Group 2 with respect 
to having a lower mean increase from baseline in LDL-C/non-HDL-C at Week 48.
08WX9K

PRODUCT: MK-8591A
152
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 17
Power to Establish Superiority of Group 1 to Group 2 as Assessed by the Mean 
Change from Baseline in LDL-C/non-HDL-C at Week 48 Under Various Assumed 
Treatment Differences, Standard Deviations, and Numbers of Participants in Each
Treatment Group
Number of 
Participants in 
Group 1
Number of 
Participants in 
Group 2
Type I 
Error (α)
Standard Deviation of Mean Change from 
Baseline
15 mg/dL
17 mg/dL
20 mg/dL
25 mg/dL
Assumed Between-group Difference in the Mean Change from Baseline=10 mg/dL
46
24
0.00025
17.1%
10.6%
5.7%
2.5%
60
30
0.0125
75.7%
63.7%
48.5%
31.6%
80
40
0.0125
87.8%
77.8%
62.3%
42.2%
100
50
0.0125
94.2%
87.0%
73.3%
51.9%
120
60
0.016
98.0%
94.0%
84.1%
64.4%
Assumed Between-group Difference in the Mean Change from Baseline=13 mg/dL
46
24
0.00025
42.4%
28.2%
15.6%
6.6%
60
30
0.0125
94.3%
87.1%
73.4%
52.0%
80
40
0.0125
98.6%
95.2%
86.0%
66.1%
100
50
0.0125
99.7%
98.4%
93.0%
76.9%
120
60
0.016
~100%
99.6%
97.4%
86.9%
Assumed Between-group Difference in the Mean Change from Baseline=16 mg/dL
46
24
0.00025
71.4%
53.6%
32.8%
14.7%
60
30
0.0125
99.3%
97.2%
90.1%
71.9%
80
40
0.0125
99.9%
99.5%
96.8%
84.8%
100
50
0.0125
~100%
99.9%
99.0%
92.3%
120
60
0.016
~100%
~100%
99.8%
97.0%
LDL-C=low-density lipoprotein cholesterol; non-HDL-C=non-high-density lipoprotein cholesterol; 
PASS=power analysis and sample size.
Power was calculated for each scenario using the 2-sample t-test assuming equal variance. Calculations were 
performed using PASS 16.
Observations from MK-8591A-017 Week 48 data: Sample Size in PI Stratum: 29 in Group 1, 35 in Group 2. 
Difference in the Mean Change from Baseline in PI Stratum (Group 1 – Group 2)=-14.12 mg/dL. Pooled 
SD=24.56 mg/dL
08WX9K

PRODUCT: MK-8591A
153
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
9.10
Subgroup Analyses
To assess whether the treatment effect with respect to the primary efficacy endpoint of the 
percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 and the secondary 
efficacy endpoint of the percentage of participants with HIV-1 RNA <50 copies/mL at 
Week 48 is consistent across various subgroups of the study population, the between-
treatment group effect (with a nominal 95% CI based on the unstratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985]) will be estimated within each 
subgroup of the following classification variables:
•
Age category (<50 years of age, ≥50 years of age)
•
Sex at birth (female, male)
•
Gender identity (boy/man, girl/woman, transgender boy/man, transgender girl/woman, 
genderqueer/non-binary/gender non-conforming, other)
•
Region (North America, South America, Europe, Asia, Africa, etc)
•
Race (White, Black, Asian, Other)
•
Ethnicity (Hispanic/Latino, not Hispanic/Latino)
•
Chronic hepatitis C status (HCV-infected, HCV-uninfected)
•
Baseline NRTI backbone (TAF, TDF, Other)
•
ART class used in the baseline regimen (PI-containing regimens [including PI- + 
InSTI-containing regimens], InSTI-containing regimens [non-PI-containing regimens], 
non-PI- and non-InSTI-containing regimens)
•
Duration of baseline ART therapy prior to enrollment (≥1 year, <1 year)
The snapshot approach will be used to handle missing values in these subgroup analyses.
9.11
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study intervention taken by 
each participant, the number of tablets remaining in study packaging will be counted, 
reviewed, and recorded at regular intervals. These results will be used to calculate participant 
compliance.
A day within the study will be considered an “On Therapy” day if the participant takes at 
least 1 tablet from any bottle provided for this study.
In the base study, the “Number of Days Should be On Therapy” is the total number of days 
from Day 1 to the date of the last dose of study intervention for each participant. As such, the 
“Number of Days Should be On Therapy” will be the number of days from Day 1 to the time 
point of interest (ie, Weeks 48, 96, or 144) for those participants who are on study 
intervention for the entire study period of interest. For participants who discontinue study 
intervention prior to or within the study period of interest, the “Number of Days Should be 
08WX9K

PRODUCT: MK-8591A
154
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
On Therapy” will be the number of days from Day 1 to the date of discontinuation of study 
intervention.
For each participant and each study period of interest, percent compliance will be calculated 
using the following formula:
Summary statistics will be provided for percent compliance by treatment group for the FAS 
population.
9.12
Extent of Exposure
The extent of exposure to study intervention for all randomized and treated participants will 
be summarized for participants in Group 1 only in the base study. The number of participants 
exposed to various doses (actual total daily dose) for defined periods of time will be 
tabulated, along with a summary of the mean (range) duration participants were exposed to 
various doses.
08WX9K

PRODUCT: MK-8591A
155
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
08WX9K

PRODUCT: MK-8591A
156
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
08WX9K

PRODUCT: MK-8591A
157
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
08WX9K

PRODUCT: MK-8591A
158
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
08WX9K

PRODUCT: MK-8591A
159
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
08WX9K

PRODUCT: MK-8591A
160
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with an SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
08WX9K

PRODUCT: MK-8591A
161
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. For studies conducted under the EMA Clinical Trials Regulation 
536/2014, a summary of the study results will be submitted in compliance with the 
regulation. MSD entries are not limited to FDAAA or the EMA clinical trials Regulation 
536/2014 mandated trials. Information posted will allow participants to identify potentially 
appropriate studies for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate study locations and study-site contact 
information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
08WX9K

PRODUCT: MK-8591A
162
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
08WX9K

PRODUCT: MK-8591A
163
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
08WX9K

PRODUCT: MK-8591A
164
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 18 will be performed by a central laboratory.
Note: In rare instances, if central laboratory use is not feasible, local laboratory tests 
may be used at scheduled study visits after consultation with the Sponsor. Plasma HIV-1 
RNA quantification requires use of a validated PCR assay with a lower limit of detection 
of <50 copies/mL (see Appendix 10).
•
Unscheduled local laboratory results are only required in the event that the central 
laboratory results are not available in time for either study intervention administration 
and/or response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time, if feasible. Additionally, if the local 
laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
The amount of blood collected from each participant over the duration of the study is 
provided in Table 19, Table 20, Table 21, and Table 22. Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples.
08WX9K

PRODUCT: MK-8591A
165
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 18
Protocol-required Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
MCH Concentration
RDW
WBC count with 
Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
TBNK Panel/
CD4+ T-cell Count
TBNK Cell profile includes the following assessments:
CD3+CD4+ Percent
CD3+CD4+ Value/Absolute Count
CD3+CD8+ Percent
CD3+CD8+ Value/Absolute Count
CD4/CD8 Ratio
and the following exploratory assessments (which do not need to be 
evaluated by the investigator):
CD3+ Percent
CD3+ Value/Absolute Count
CD3-CD19+ Percent
CD3-CD19+ Value/Absolute Count
CD16+CD56+ Percent
CD16+CD56+ Value/Absolute Count
CD3+CD4+CD8+ Percent
CD3+CD4+CD8+ Value/Absolute Count
Coagulation
PT/INR
Chemistry
(nonfasting)
BUN
Potassium
AST/SGOT
Total bilirubin
Direct bilirubin
Indirect bilirubin
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose 
(nonfasting)
Calcium
ALP
CrCl
eGFR by MDRD 
equation (Appendix 8)
CK
Lipase
Amylase
Mg
Additional Chemistry at 
Fasting Visits
(fasting for at least 8 h)
Glucose
HbA1c (collected regardless of participant’s fasting status)
HDL-C
LDL-C
TGs
TC
Non-HDL-C
Insulinb
HOMA-IR (calculation)
Routine Urinalysis (with 
microscopic exam as needed)
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick
Pregnancy Testing
Serum and highly sensitive urine hCG (as needed for POCBP)
Hepatitis B Serologyc
HBsAg
Anti-HBs
Anti-HBc
HBV DNAc
HBV DNA
08WX9K

PRODUCT: MK-8591A
166
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Laboratory Assessments
Parameters
Hepatitis C Serologyc
Hepatitis C antibody (if positive perform plasma HCV quantitative test) (at 
screening only)
HIV-1 and HIV-2 Serology
HIV-1 and HIV-2 antibody test
Virology
HIV-1 viral RNA quantification
HIV-1 viral drug resistance
PK
Plasma ISL PK (For Group 1 participants only)
Plasma Investigational ISL PK (Samples will be collected for participants in 
Group 1 at Week 36 and for all participants after Week 48. Analysis of these 
samples will be performed by the Sponsor as needed)
Plasma ISL and DOR PK (Only participants on DOR/ISL who become 
pregnant during the study)
Renal Markers
Urine analysis:
Albumin/Cr
Protein
B-2M/Cr
RBP/Cr
Serum analysis:
Cystatin-C
Cr
Creatinine Clearance by Cockcroft-Gault equation (Appendix 8)
eGFR by MDRD equation (Appendix 8)
Energy and Metabolism 
Markers
Adipokines:
Leptin
Adiponectin
ALP=alkaline phosphatase; ALT=alanine aminotransferase; anti-HBc=hepatitis B core antibody; anti-HBs=hepatitis B 
surface antibody; AST=aspartate aminotransferase; B-2M/Cr=beta-2-microglobulin/creatinine ratio; BUN=blood urea 
nitrogen; CK=creatine kinase; Cr=creatinine; CrCl=creatinine clearance; DNA=deoxyribonucleic acid; DOR=doravirine; 
eGFR=estimated glomerular filtration rate; HbA1c=hemoglobin A1c; HBsAg=hepatitis B surface antigen; 
HBV=hepatitis B virus; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; HDL-C=high-density lipoprotein 
cholesterol; HIV-1=human immune-deficiency virus type 1; HIV-2=human immune-deficiency virus type 2; 
HOMA-IR=Homeostatic Model Assessment of Insulin Resistance; INR=international normalized ratio; ISL=islatravir; 
LDL-C=low-density lipoprotein cholesterol; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
MDRD=Modification of Diet in Renal Disease; Mg=magnesium; non-HDL-C=non-high-density lipoprotein cholesterol; 
PK=pharmacokinetic(s); POCBP=participant(s) of childbearing potential; PT=prothrombin time; RBC=red blood cell; 
RBP/Cr=retinol-binding protein/creatinine ratio; RDW=red cell distribution width; RNA=ribonucleic acid; SGOT=serum 
glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; TBNK=T and B Lymphocyte and 
Natural Killer Cell; TC=total cholesterol; TG=triglyceride; WBC=white blood cell.
Notes:
a
The central laboratory may reflex to manual differential to further identify atypical or immature forms of 
leukocytes.
b
Participants with type 1 diabetes mellitus should not fast and should not have insulin levels tested. Participants with 
type 2 diabetes mellitus taking medications that may result in hypoglycemia should delay their morning dose of 
diabetic medication while fasting and take it after the blood draw for testing.
c
All participants will be screened for HBsAg, anti-HBs, anti-HBc, and HBV DNA. Repeat serology and HBV DNA 
testing at Weeks 48, 96, 144, and 192 is to be performed for all participants. Participants who are anti-HBc-positive 
but HBV DNA-negative will have HBsAg and HBV DNA monitored for the duration of the study. Pregnant 
participants (on DOR/ISL only) will have a sample collected once after pregnancy is confirmed or local laboratory 
results reported for hepatitis B serology and HBV DNA.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
08WX9K

PRODUCT: MK-8591A
167
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 19
Blood Volumes (Efficacy, Safety, and PK) in the Base Study
Study Period
Screen
Intervention (Base Study)
Viremia Confirm
Total Lymphocyte/
CD4+ T-cell Confirm
Early Discon of 
Treatment
Total Lymphocyte/
CD4+ T-cell Monitor 
(DOR/ISL only)h
EoT Follow-upi
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting) 
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA 
Quantificationa
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Blood (Plasma) for HIV-
1 Drug Resistanceb
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
(12)
Whole Blood for HIV-1 
Drug Resistance
4
HIV-1 and HIV-2 
Serology
1
TBNK Panel/CD4+ T-
cell Count
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
(6)
Hepatitis B and Hepatitis 
C (Screening only) 
Serologyc
4
(4)
(4)
(4)
(4)
(4)
4
(4)
(4)
(4)
(4)
4
(4)
(4)
(4)
4
HBV DNAc
6
(6)
(6)
(6)
(6)
(6)
6
(6)
(6)
(6)
(6)
6
(6)
(6)
(6)
6
Hepatitis B Serology for
Pregnant Participants (D
OR/ISL only)d
<-----------------------------------(4)---------------------------------->
HBV DNA for Pregnant 
Participants (DOR/ISL 
only)d
<-----------------------------------(6)---------------------------------->
Plasma HCV 
Quantitative Testc
6
08WX9K

PRODUCT: MK-8591A
168
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screen
Intervention (Base Study)
Viremia Confirm
Total Lymphocyte/
CD4+ T-cell Confirm
Early Discon of 
Treatment
Total Lymphocyte/
CD4+ T-cell Monitor 
(DOR/ISL only)h
EoT Follow-upi
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting) 
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Chemistry (includes 
Serum Pregnancy Test at 
Screening)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Hematology
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
(4)
HbA1c
2
2
2
2
2
Fasting Lipids
2
2
2
2
2
Fasting Insuline
1
1
1
1
1
PT/INR
3
Cystatin-C
2
2
2
2
2
Blood for Energy and 
Metabolism Markers
6
6
6
6
6
Blood (Plasma) for ISL 
PK (Group 1 only)
4
8
4
4
4
4
4
Blood (Plasma) for 
Investigational ISL (and 
DOR, if applicable) PKf
4
4
4
4
4
4
4
4
4
4
Blood (Plasma) for DOR 
and ISL PK During 
Pregnancyg
<-------(4 or 12, as indicated)-------->
08WX9K

PRODUCT: MK-8591A
169
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Study Period
Screen
Intervention (Base Study)
Viremia Confirm
Total Lymphocyte/
CD4+ T-cell Confirm
Early Discon of 
Treatment
Total Lymphocyte/
CD4+ T-cell Monitor 
(DOR/ISL only)h
EoT Follow-upi
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting) 
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Approximate Total 
Blood Volume per Visit 
(mL)
42
65
52
48
61
48
61
48
48
48
48
61
44
44
44
57
26
14
42
14
20
anti-HBc=hepatitis B core antibody; anti-HBs=hepatitis B surface antibody; Confirm=Confirmation; Discon=discontinuation; DNA=deoxyribonucleic acid; DOR=doravirine; EoT=End of 
Treatment; HbA1c=hemoglobin A1c; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV-1=human immunodeficiency virus type 1; HIV-2=human 
immunodeficiency virus type 2; INR=international normalized ratio; ISL=islatravir; Monitor=Monitoring; PK=pharmacokinetic(s); PT=prothrombin time; RNA=ribonucleic acid; TBNK=T and B 
Lymphocyte and Natural Killer Cell.
a
Not included in total blood volume per visit: Pregnant participants who require more frequent HIV-1 RNA testing performed per local guidelines or as determined by the investigator.
b
Do not collect at Early Discon if collected at previous Viremia Confirm.
c
All participants will be screened for HBsAg, anti-HBs, anti-HBc, and HBV DNA as well as hepatitis C antibody (with reflex plasma HCV quantitative test if indicated) at screening. Repeat
serology and reflex HBV testing at Weeks 48, 96, and 144 is required. Only participants who are anti-HBc-positive but HBV DNA-negative will have HBsAg and HBV DNA monitored for the 
duration of the study (participants in Group 2 will begin HBsAg monitoring at Week 36).
d
Not included in total blood volume at each visit: Pregnant participants (DOR/ISL only) will have 1 sample collected once after pregnancy is confirmed or local laboratory results reported for 
HBsAg, anti-HBs, anti-HBc, and HBV DNA during pregnancy.
e
Participants with type 1 diabetes mellitus and those who are pregnant should not fast and should not have insulin levels or lipids tested. Participants with type 2 diabetes mellitus taking 
medications that may result in hypoglycemia should delay their morning dose of diabetic medication while fasting and take it after the blood draw for testing.
f
Investigational ISL PK samples will be collected from Group 1 participants at Week 36 and from Group 1 and Group 2 participants at Weeks 60, 72, 84, and 96. Analysis of these samples will 
be performed by the Sponsor as needed. See Section 8.6.1.
g
Not included in total blood volume at each visit: During pregnancy, blood samples will be collected for PK sampling per Section 8.11.6.1 during the 1st trimester (4 mL), 2nd trimester (12 mL), 
3rd trimester (12 mL), and Postpartum (4 mL) study visits. For participants whose pregnancy or Postpartum visit(s) extends beyond Week 144, see Table 21 and Table 22.
h
Blood volumes collected at the Total Lymphocyte Count/CD4+ T-cell Count Monitoring visit (DOR/ISL participants only) represent single monitoring visits every 10 to 14 weeks after 
discontinuing study intervention.
i
For the EoT Follow-up visit, the approximate total volume to be collected is for the assessments in Section 1.3.1 or 1.3.2 or 1.3.3 or 1.3.4 SoA, as indicated.
08WX9K

PRODUCT: MK-8591A
170
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 20
Blood Volumes (Genetic Analysis and FBR) in the Base Study
Study Period
Screening
Intervention (Base Study)
Viremia Confirm
Total Lymphocyte/
CD4+ T-cell Confirm
Early Discon of 
Treatment
Total Lymphocyte/
CD4+ T-cell Monitor 
(DOR/ISL only)
EoT Follow-up
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 52
(Group 2 only)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Weel 144
(fasting)
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Blood for Genetic Analysis
9
Whole Blood for FBR
8
8
8
8
8
8
8
Approximate Total Blood 
Volume per Visit (mL)
17
8
8
8
8
8
8
Confirm=Confirmation; Discon=discontinuation; DOR=doravirine; EoT=End of Treatment; FBR=future biomedical research; ISL=islatravir; Monitor=Monitoring.
08WX9K

PRODUCT: MK-8591A
171
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Table 21
Blood Volumes (Efficacy, Safety, and PK) in the Optional Study Extension
Study Period
Optional Study 
Extension
Viremia 
Confirmation
Total Lymphocyte/ 
CD4+ T-cell 
Confirmation
Total Lymphocyte/ 
CD4+ T-cell 
Monitoring 
(DOR/ISL only)
Discontinuation of 
Treatment 
(Optional Study 
Extension)
End of Treatment 
Follow-up 
(Optional Study 
Extension)a
Scheduled Day/Week
Week 168
Week 192
Week 216
Week 240
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)a
Plasma HIV-1 RNA Quantification 
(PCR)
6
6
6
6
6
6
(6)
TBNK Panel/CD4+ T-cell Count
6
6
6
6
6
6
6
(6)
Blood (Plasma) for HIV-1 Drug 
Resistance Testing
12
12
12
12
12
12
(12)
Hematology
2
2
2
2
2
2
2
(2)
Chemistry
(6)
Hepatitis B Serology HBV DNA
10
10
HBsAg and HBV DNA (Group 2 
participants with positive anti-HBc)
(10)
(10)
(10)
(10)
Blood (Plasma) for Investigational ISL 
PK
4
4
4
(4)
Blood (Plasma) for DOR and ISL PK
4
Blood (Plasma) for DOR and ISL PK 
(pregnant participants on DOR/ISL)
(4)
(4)
(4)
Total Blood Volume per Visit (mL)
26
36
26
36
22
12
12
26
40
anti-HBc=hepatitis B core antibody; anti-HBs=hepatitis B surface antibody; DNA=deoxyribonucleic acid; DOR=doravirine; EoT=End of Treatment; HbA1c=hemoglobin A1c; HBsAg=hepatitis B 
surface antigen; HBV=hepatitis B virus; HIV-1=human immunodeficiency virus type 1; ISL=islatravir; mL=milliliter; OLE=open-label extension; PCR=polymerase chain reaction; 
PK=pharmacokinetic(s); RNA=ribonucleic acid; SoA=Schedule of Activities; TBNK=T and B lymphocyte and natural killer cells.
a.
For the EoT Follow-up visit, the approximate total volume to be collected is for the assessments in Section 1.3.5 SoA. Alternatively, see Section 1.3.2 or 1.3.3 or 1.3.4 SoA, as indicated
08WX9K

PRODUCT: MK-8591A
172
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
The assessments in Table 22 are for any participant who is pregnant on or after Week 144 
and whose visit schedule will be extended through the duration of the pregnancy to allow 
assessments through each trimester and postpartum.
Table 22
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) Extends 
Beyond Week 144 (Efficacy, Safety, and PK)
Visit Number
Unscheduled
Scheduled Week
Pregnancy 1c
Pregnancy 2c
Pregnancy 3c
Pregnancy 4c
(Postpartum 
≤8 weeks after 
delivery)
EoT Follow-upc
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA
Quantification
6
6
6
6
Plasma for HIV-1 Viral
Drug Resistance Testing
15
15
15
15
15
TBNK Panel/CD4+ T-
cell Count
6
6
6
6
6
Hepatitis B Serology and 
HBV DNA
(DOR/ISL only)a
<--------------------(10)--------------->
Chemistry
6
6
6
6
6
Hematology
2
2
2
2
2
Blood (Plasma) for DOR 
and ISL PKb
4
12
12
4
4
Approximate Total 
Blood Volume per Visit 
(mL)
39
47
47
39
39
DNA=deoxyribonucleic acid; DOR=doravirine; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HIV-1=human 
immunodeficiency virus type 1; ISL=islatravir; PK=pharmacokinetic(s); RNA=ribonucleic acid; TBNK=T and B Lymphocyte and 
Natural Killer Cell
a
Not included in total blood volume at each visit: Pregnant participants (DOR/ISL only) will have 1 sample collected once after
pregnancy is confirmed or local laboratory results reported for HBsAg, anti-HBs, anti-HBc, and HBV DNA during pregnancy.
b
Collect PK samples during pregnancy per Section 8.11.6.1.1.
c
If pregnancy visit occurs at the timeframe of a scheduled optional study extension visit, collection of lab samples should occur per 
this Table. Collection of laboratory samples should not be duplicated.
08WX9K

PRODUCT: MK-8591A
173
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: 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 intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
08WX9K

PRODUCT: MK-8591A
174
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
08WX9K

PRODUCT: MK-8591A
175
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
-
All potential or confirmed DILI events will be reported as an ECI and SAE with 
OME criteria in the absence of other serious criteria.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
08WX9K

PRODUCT: MK-8591A
176
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE that 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
-
Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
-
Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
-
Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care functions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
-
Grade 5 Death: Deaths related to an AE.
08WX9K

PRODUCT: MK-8591A
177
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
08WX9K

PRODUCT: MK-8591A
178
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
08WX9K

PRODUCT: MK-8591A
179
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
08WX9K

PRODUCT: MK-8591A
180
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
08WX9K

PRODUCT: MK-8591A
181
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
08WX9K

PRODUCT: MK-8591A
182
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Participants of Nonchildbearing Potential (PONCBP)
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, are considered PONCBP:
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth not using 
hormonal contraception or HRT. However, in the absence of 12 months of
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth on HRT and whose menopausal status is in 
doubt must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
10.5.2
Contraceptive Requirements
As some baseline ART regimens may decrease efficacy of hormonal contraception by 
potential drug-drug interactions (eg, CYP3A4 inducers), the investigator must assess the 
need for backup contraception to supplement hormonal contraceptives (preferably 
penile/external condoms) in accordance with the participant’s specific baseline ART regimen 
and local product labeling.  In situations where the POCBP’s baseline ART regimen could 
reduce their concomitant hormonal contraception efficacy, then penile/external condoms 
must be used in addition to hormonal contraception.
08WX9K

PRODUCT: MK-8591A
183
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implantb
IUSc
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraceptionb
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionb
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Penile/external or vaginal/internal condom with or without spermicided
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
c
IUS is a progestin releasing IUD
d
Vaginal/internal condom used for contraceptive purposes
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction)d
08WX9K

PRODUCT: MK-8591A
184
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
08WX9K

PRODUCT: MK-8591A
185
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
08WX9K

PRODUCT: MK-8591A
186
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
08WX9K

PRODUCT: MK-8591A
187
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
08WX9K

PRODUCT: MK-8591A
188
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Request for Japan
The baseline ART taken by participants in Group 2 until Week 48 is not categorized as 
“product(s) used in the clinical trial” in Japan.
10.7.2
Country-specific Request for Canada
The baseline ART taken by participants in Group 2 until Week 48 is considered NIMP in 
Canada, as the ART will be a continuation of prestudy treatment.
In Canada, in addition to the criteria in Section 7.1, a participant must be discontinued from 
study intervention per Section 8.11.3 for the following reason:
•
The participant becomes HBsAg-positive or have confirmed quantifiable HBV DNA 
after randomization, per Section 8.3.6.
10.7.3
Country-specific Request for South Africa
Study Intervention(s) Administered
Participants in South Africa previously receiving BIC/FTC/TAF in study MK-8591A-020 
who enroll in MK-8591A-051 and are randomized to Group 2 will continue to receive 
MSD-supplied BIC/FTC/TAF as their ART regimen. See Section 6.1 (Table 2).
08WX9K

PRODUCT: MK-8591A
189
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.8
Appendix 8: Calculation of Creatinine Clearance and eGFR
10.8.1
Cockcroft-Gault Equations
•
If male:
•
If female:
10.8.2
MDRD Equations
eGFR estimated by MDRD-NKDEP:
eGFR (mL/min/1.73 m2) = 175 × (serum creatinine [mg/dL])-1.154 × (Age [years])-0.203 × 
0.742 (if female) × 1.212 (if Black)
08WX9K

PRODUCT: MK-8591A
190
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.9
Appendix 9: AIDS-defining Opportunistic Infections that Require 
Discontinuation of Study Intervention
Per Section 7.1, a participant must be discontinued from study intervention if they have a 
new AIDS-defining opportunistic infection as listed below, ie, a Category C condition 
according to the CDC 1993 Revised Classification System for HIV Infection and Expanded 
Surveillance Case Definition for AIDS Among Adolescents and Adults [Centers for Disease 
Control (CDC) 1992].
•
Candidiasis of bronchi, trachea, or lungs
•
Candidiasis, esophageal
•
Cervical cancer, invasive
•
Coccidioidomycosis, disseminated or extrapulmonary
•
Cryptococcosis, extrapulmonary
•
Cryptosporidiosis, chronic intestinal (greater than 1 month's duration)
•
Cytomegalovirus disease (other than liver, spleen, or nodes)
•
Cytomegalovirus retinitis (with loss of vision)
•
Encephalopathy, HIV-related
•
Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, 
pneumonitis, or esophagitis
•
Histoplasmosis, disseminated or extrapulmonary
•
Isosporiasis, chronic intestinal (greater than 1 month's duration)
•
Kaposi's sarcoma
•
Lymphoma, Burkitt's (or equivalent term)
•
Lymphoma, immunoblastic (or equivalent term)
•
Lymphoma, primary, of brain
•
Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary
•
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
•
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
•
Pneumocystis carinii pneumonia
•
Pneumonia, recurrent
•
Progressive multifocal leukoencephalopathy
•
Salmonella septicemia, recurrent
•
Toxoplasmosis of brain
•
Wasting syndrome due to HIV
08WX9K

PRODUCT: MK-8591A
191
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.10 Appendix 10: Approved HIV-1 RNA Quantification Assays for Local Viral Load 
Monitoring
For this study, allowed US FDA-approved HIV-1 RNA quantification assays for local viral 
load monitoring are listed in Table 23.
This list represents the US FDA-approved nucleic acid testing assays for HIV-1 RNA 
detection and quantification that have a lower limit of detection of <50 copies/mL. 
Additional details can be found at: www.fda.gov/vaccines-blood-biologics/blood-blood-
products/approved-blood-products and www.fda.gov/vaccines-blood-biologics/hiv-1.
Table 23
Approved HIV-1 RNA Quantification Assays for Local Viral Load Monitoring
Tradename
Infectious 
Agent
Format
Specimen
Use
Manufacturer
APTIMA 
HIV-1 Quant 
Assay
APTIMA 
HIV-1 Quant 
Dx Assay
HIV-1
TMA
Plasma/ 
Serum
Patient Monitoring: 
Quantitation of HIV-1 
RNA in plasma of 
HIV-1 infected 
individuals.
Addition of claim for 
Qualitative detection 
HIV-1 RNA on Panther 
platform
Hologic Inc., 
San Diego, CA
US License 1592
COBAS 
HIV-1
Quantitative 
PCR
Plasma
Patient Monitoring: 
Quantitation of HIV-1 
RNA in plasma of 
HIV-1 infected 
individuals
Roche Molecular 
Systems, Inc., 
Pleasanton, CA
US License 1636
Abbott 
RealTime 
HIV-1
ABBOTT 
Molecular, Inc., 
Des Plaines, IL
(US License NA)
Amplicor 
HIV-1 
Monitor Test
Roche Molecular 
Systems, Inc., 
Pleasanton, CA
US License 1636
COBAS 
AmpliPrep/
COBAS 
TaqMan 
HIV-1 Test
Roche Molecular 
Systems, Inc., 
Pleasanton, CA
US License 1636
FDA=United States Food and Drug Administration; HIV-1=human immunodeficiency virus type 1; NA=not available; 
PCR=polymerase chain reaction; RNA=ribonucleic acid; TMA=transcription-mediated amplification; US=United States.
08WX9K

PRODUCT: MK-8591A
192
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
3TC
lamivudine
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AIDS
acquired immunodeficiency syndrome
albumin/Cr
albumin/creatinine ratio
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
APaT
All-Participants-as-Treated
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the curve
B-2M/Cr
beta-2-microglobulin/creatinine ratio
BIC
bictegravir
BLOQ
below the limit of quantification
BMD
bone mineral density
BMI
body mass index
BP
blood pressure
C24
concentration after 24 hours
CDER
Center for Drug Evaluation and Research
CFR
Code of Federal Regulations
CI
confidence interval
cLDA
constrained longitudinal data analysis
Cmax
maximum plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
08WX9K

PRODUCT: MK-8591A
193
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Abbreviation
Expanded Term
COVID-19
coronavirus disease caused by severe acute respiratory syndrome 
coronavirus 2
Cr
creatinine
CrCl
creatinine clearance
CRF
Case Report Form
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group
Ctrough
lowest concentration reached before the next dose is administered
CYP
cytochrome P450
DAIDS
Division of AIDS
DAO
data as observed
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
doravirine
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
eDMC
external Data Monitoring Committee
EFV
efavirenz
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ePROs
electronic patient-reported outcomes
EQ-5D-5L
EuroQol 5-dimensional descriptive system, 5-level version
EU
European Union
FAS
Full Analysis Set
FAS-E
full analysis set-extension
FBR
future biomedical research
08WX9K

PRODUCT: MK-8591A
194
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Abbreviation
Expanded Term
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDC
fixed-dose combination
FSH
follicle-stimulating hormone 
FSR
first site ready
FTC
emtricitabine
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
HIV-SI/SDM
Human Immunodeficiency Virus Symptom Index (also known as the 
Human Immunodeficiency Virus Symptom Distress Module)
HIVTSQ
Human Immunodeficiency Virus Treatment Satisfaction Questionnaire
HIVTSQs
Human Immunodeficiency Virus Treatment Satisfaction Questionnaire 
status version
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
HTA
Health Technology Assessment
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure
IC50
inhibitory concentration required for 50% inhibition
ICF
Informed Consent Form
08WX9K

PRODUCT: MK-8591A
195
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Abbreviation
Expanded Term
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
InSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
IRB
Institutional Review Board
IRT
interactive response technology
ISL
islatravir
ISL-TP
islatravir-triphosphate
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
lactational amenorrhea method
LDA
longitudinal data analysis
LDL-C
low-density lipoprotein cholesterol
LLOQ
lower limit of quantification
M=F
missing data treated as treatment failure
MAR
missing at random
MCAR
missing completely at random
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MNAR
missing not at random
NIMP
noninvestigational medicinal product
NKDEP
National Kidney Disease Education Program
NNRTI
non-nucleoside reverse transcriptase inhibitor
non-HDL-C
non-high-density lipoprotein cholesterol
NRTI
nucleoside analog reverse transcriptase inhibitor
NRTTI
nucleoside/nucleotide reverse transcriptase translocation inhibitor
08WX9K

PRODUCT: MK-8591A
196
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Abbreviation
Expanded Term
OF
observed failure
OME
Other important medical event
PCR
polymerase chain reaction
PDLC
predefined limit of change
PI
protease inhibitor
PK
pharmacokinetic(s)
PLWH
people living with HIV
POCBP
participant(s) of childbearing potential
PONCBP
participant(s) of nonchildbearing potential
PP
per-protocol
PrEP
pre-exposure prophylaxis
PRO
patient-reported outcome
PT
prothrombin time
PTs
preferred terms
QD
once-daily
QM
once-monthly
QW
once-weekly
RBC
red blood cell
RBP/Cr
retinol-binding protein/creatinine ratio
RNA
ribonucleic acid
RR
respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SMQs
Standardized MedDRA Queries
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
08WX9K

PRODUCT: MK-8591A
197
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
Abbreviation
Expanded Term
SUSAR
suspected unexpected serious adverse reaction
TAF
tenofovir alafenamide
TBNK
T and B Lymphocyte and Natural Killer Cell
TC
total cholesterol
TDF
tenofovir disoproxil fumarate
TG
triglyceride
TN
treatment-naïve 
TP
triphosphate
ULN
upper limit of normal
US
United States
VS
virologically suppressed
WBC
white blood cell
WHO
World Health Organization
08WX9K

PRODUCT: MK-8591A
198
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
11
REFERENCES
[Bailin, S. S., et al 2020]
Bailin SS, Gabriel CL, Wanjalla CN, Koethe JR. 
Obesity and weight gain in persons with HIV. Curr 
HIV/AIDS Rep. In press 2020.
[07ZG3C]
[Burger, D., et al 2005]
Burger D, van der Heiden I, la Porte C, van der Ende 
M, Groeneveld P, Richter C, et al. Interpatient 
variability in the pharmacokinetics of the HIV non-
nucleoside reverse transcriptase inhibitor efavirenz: 
the effect of gender, race, and CYP2B6 
polymorphism. Br J Clin Pharmacol. 2005;61(2):148-
54.
[057GSX]
[Buzon-Martin, L. 2020]
Buzon-Martin L. Weight gain in HIV-infected 
individuals using distinct antiretroviral drugs. AIDS 
Rev. 2020;22:158-67.
[07ZG4Y]
[Cahn, P., et al 2019]
Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, 
Clarke AE, et al. Dolutegravir plus lamivudine versus 
dolutegravir plus tenofovir disoproxil fumarate and 
emtricitabine in antiretroviral-naive adults with HIV-
1 infection (GEMINI-1 and GEMINI-2): week 48 
results from two multicentre, double-blind, 
randomised, non-inferiority, phase 3 trials. Lancet. 
2019 Jan 12;393:143-55.
[054KXQ]
[Carr, A., et al 1998]
Carr A, Samaras K, Burton S, Law M, Freund J, 
Chisholm DJ, et al. A syndrome of peripheral 
lipodystrophy, hyperlipidaemia and insulin resistance 
in patients receiving HIV protease inhibitors. AIDS 
1998;12(7):F51-F58.
[03Q6RY]
[Centers for Disease 
Control (CDC) 1992]
Centers for Disease Control (CDC). 1993 Revised 
classification system for HIV infection and expanded 
surveillance case definition for AIDS among 
adolescents and adults. MMWR 1992;41(RR-17):1-
17.
[03RH6J]
[Charpentier, C., et al 
2014]
Charpentier C, Choquet M, Joly V, Yeni P, Visseaux 
B, Caseris M, et al. Virological outcome at week 48 
of three recommended first-line regimens using 
ultrasensitive viral load and plasma drug assay. J 
Antimicrob Chemother. 2014 Oct;69(10):2819-25.
[04PYMQ]
08WX9K

PRODUCT: MK-8591A
199
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
[Clopper, C. J. and 
Pearson, E. S. 1934]
Clopper CJ, Pearson ES. The use of confidence or 
fiducial limits illustrated in the case of the binomial. 
Biometrika 1934;26(4):404-13.
[00V5VX]
[Department of 
HIV/AIDS 2015]
Department of HIV/AIDS. Transgender people and 
HIV. Geneva (Switzerland): World Health 
Organization (WHO); 2015 Jul. 32 p.
[05BDGP]
[European AIDS Clinical 
Society 2021]
European AIDS Clinical Society. Guidelines: version 
11.0: October 2021. Brussels (Belgium): European 
AIDS Clinical Society (EACS); 2021. 149 p.
[07XP7W]
[Farahani, M., et al 2017]
Farahani M, Mulinder H, Farahani A, Marlink R. 
Prevalence and distribution of non-AIDS causes of 
death among HIV-infected individuals receiving 
antiretroviral therapy: a systematic review and meta-
analysis. Int J STD AIDS. In press 2017.
[0822J6]
[Food and Drug 
Administration (CDER) 
2015]
Food and Drug Administration (CDER). Human 
Immunodeficiency Virus-1 Infection: Developing 
Antiretroviral Drugs for Treatment Guidance for 
Industry [Internet]. Silver Spring, MD: U.S. 
Department of Health and Human Services; 2015. 
Available from: 
https://www.fda.gov/downloads/drugs/guidancecomp
lianceregulatoryinformation/guidances/ucm355128.p
df.
[04MT4V]
[Hill, A., et al 2019]
Hill A, Waters L, Pozniak A. Are new antiretroviral 
treatments increasing the risks of clinical obesity? J 
Virus Erad. 2019;5:41-3.
[058G5N]
[Johnson, M., et al 2019]
Johnson M, Kumar P, Molina JM, Rizzardini G, 
Cahn P, Bickel M, et al. Switching to 
doravirine/lamivudine/tenofovir disoproxil fumarate 
(DOR/3TC/TDF) maintains HIV-1 virologic 
suppression through 48 weeks: results of the DRIVE-
SHIFT trial. J Acquir Immune Defic Syndr. 2019 
Aug 1;81(4):463-72.
[05B4PY]
[Joint United Nations 
Programme on 
HIV/AIDS 2017]
Joint United Nations Programme on HIV/AIDS 
(UNAIDS). Ending AIDS: progress towards the 90-
90-90 targets. Slides presented at: 9th International 
AIDS Society (IAS) Conference on HIV Science; 
2017 Jul 23-26; Paris (France).
[058SY8]
08WX9K

PRODUCT: MK-8591A
200
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
[Kenward, M. G. and 
Roger, J. H. 1997]
Kenward MG, Roger JH. Small sample inference for 
fixed effects from restricted maximum likelihood. 
Biometrics 1997;53:983-97.
[00V5VW]
[Liang, K-Y and Zeger, 
S. L. 2000]
Liang K-Y, Zeger SL. Longitudinal data analysis of 
continuous and discrete responses for pre-post 
designs. Sankyha: The Indian Journal of Statistics 
2000;62(Series B, Part 1):134-48.
[00V5V6]
[Llibre, J. M., et al 2018]
Llibre JM, Hung CC, Brinson C, Castelli F, Girard 
PM, Kahl LP, et al. Efficacy, safety, and tolerability 
of dolutegravir-rilpivirine for the maintenance of 
virological suppression in adults with HIV-1: phase 
3, randomised, non-inferiority SWORD-1 and 
SWORD-2 studies. Lancet. 2018 Mar 3;391:839-49. 
Erratum in: Lancet. 2018 Feb 1.
[0528SS]
[Maurer, W., et al 2011]
Maurer W, Glimm E, Bretz F. Multiple and repeated 
testing of primary, coprimary, and secondary 
hypotheses. Stat Biopharm Res. 2011;3(2):336-52.
[045MYM]
[Michailidis E 2014]
Michailidis E, et al. 4-Ethynyl-2-fluoro-2-
deoxyadenosine (EFdA) Inhibits HIV-1 Reverse 
Transcriptase with Multiple Mechanisms. J Biol 
Chem 2014; 289(35):24533-24548.
[04PXGP]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative analysis of 
two rates. Statist Med 1985;4:213-26.
[00W9P2]
[Molina, J. M., et al 
2018]
Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, 
DeJesus E, et al. Doravirine versus ritonavir-boosted 
darunavir in antiretroviral-naive adults with HIV-1 
(DRIVE-FORWARD): 48-week results of a 
randomised, double-blind, phase 3, non-inferiority 
trial. Lancet HIV. 2018 May;5:e211-20.
[05RFGF]
[National Institute of 
Allergy and Infectious 
Diseases 2017]
National Institute of Allergy and Infectious Diseases. 
Division of AIDS (DAIDS) table for grading the 
severity of adult and pediatric adverse events, 
corrected version 2.1 [Internet]. Bethesda, MD: 
NIAID; 2017. Available from: https://rsc.tech-
res.com/docs/default-source/safety/division-of-aids-
(daids)-table-for-grading-the-severity-of-adult-and-
pediatric-adverse-events-corrected-v-2-
1.pdf?sfvrsn=2.
[04R7PK]
08WX9K

PRODUCT: MK-8591A
201
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
[Orkin, C., et al 2019]
Orkin C, Squires KE, Molina JM, Sax PE, Wong 
WW, Sussmann O, et al. 
Doravirine/lamivudine/tenofovir disoproxil fumarate 
is non-inferior to efavirenz/emtricitabine/tenofovir 
disoproxil fumarate in treatment-naive adults with 
Human Immunodeficiency Virus-1 Infection: week 
48 results of the DRIVE-AHEAD trial. Clin Infect 
Dis. 2019 Feb 15;68(4):535-44.
[0580VV]
[Panel on Antiretroviral 
Guidelines for Adults and 
Adolescents 2022]
Panel on Antiretroviral Guidelines for Adults and 
Adolescents. Guidelines for the use of antiretroviral 
agents in adults and adolescents with HIV: Jan 2022. 
Washington (DC): Department of Health and Human 
Services (HHS). [Last updated: 2022 Jan 20]. 460 p.
[080MHG]
[Panel on Treatment of 
Pregnant Women with 
HIV Infection and Prev 
2018]
Panel on Treatment of Pregnant Women with HIV 
Infection and Prevention of Perinatal Transmission. 
Recommendations for the use of antiretroviral drugs 
in pregnant women with HIV infection and 
interventions to reduce perinatal HIV transmission in 
the United States: Dec 2018. Washington (DC): 
Department of Health and Human Services (HHS). 
[Last updated: 2018 Dec 7]. 365 p.
[05BXZW]
[Poteat, T., et al 2016]
Poteat T, Scheim A, Xavier J, Reisner S, Baral S. 
Global epidemiology of HIV infection and related 
syndemics affecting transgender people. J Acquir 
Immune Defic Syndr. 2016 Aug 15;72(suppl 
3):S210-9.
[05BDHN]
[Ribaudo, H. J., et al 
2013]
Ribaudo HJ, Smith KY, Robbins GK, Flexner C, 
Haubrich R, Chen Y, et al. Racial differences in 
response to antiretroviral therapy for HIV infection: 
an AIDS Clinical Trials Group (ACTG) study 
analysis. Clin Infect Dis. 2013 Dec 1;57(11):1607-17.
[057GSZ]
[Shah, S., et al 2021]
Shah S, Hindley L, Hill A. Are new antiretroviral 
treatments increasing the risk of weight gain? Drugs. 
2021;81:299-315.
[07ZG4L]
[Taylor, E. B. 2021]
Taylor EB. The complex role of adipokines in 
obesity, inflammation, and autoimmunity. Clin Sci. 
2021;135:731-52.
[083NDN]
08WX9K

PRODUCT: MK-8591A
202
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
[U.S. Prescribing 
Information 2017]
U.S. Prescribing Information: SUSTIVA (efavirenz) 
capsules for oral use; SUSTIVA (efavirenz) tablets 
for oral use: Oct 2017.
[04VGFN]
[U.S. Prescribing 
Information 2019]
U.S. Prescribing Information: VIREAD (tenofovir 
disoproxil fumarate) tablets, for oral use; VIREAD 
(tenofovir disoproxil fumarate) powder, for oral use: 
Apr 2019.
[057N3H]
[Vandenhende, M. A., et 
al 2015]
Vandenhende MA, Ingle S, May M, Chene G, 
Zangerle R, Van Sighem A, et al. Impact of low-level 
viremia on clinical and virological outcomes in 
treated HIV-1-infected patients. AIDS. 
2015;29(3):373-83.
[056V0P]
[Vazquez-Carrera, M. 
2016]
Vazquez-Carrera M. Unraveling the effects of 
PPARbeta/delta on insulin resistance and 
cardiovascular disease. Trends Endocrinol Metab. 
2016 May;27(5):319-34.
[058MZ6]
[Wandeler, G., et al 
2016]
Wandeler G, Johnson LF, Egger M. Trends in life 
expectancy of HIV-positive adults on antiretroviral 
therapy across the globe: comparisons with general 
population. Curr Opin HIV AIDS. 2016 
Sep;11(5):492-500.
[080V4Y]
[Weintrob, A. C., et al 
2009]
Weintrob AC, Grandits GA, Agan BK, Ganesan A, 
Landrum ML, Crum-Cianflone NF, et al. Virologic 
response differences between African Americans and 
European Americans initiating highly active 
antiretroviral therapy with equal access to care. J 
Acquir Immune Defic Syndr. 2009 Dec 
15;52(5):574-80.
[0576P6]
[Wong, A., et al 2019]
Wong A, Goldstein D, Mallolas J, DeJesus E, 
Johnson M, Molina JM, et al. Efficacy and safety of 
doravirine/lamivudine/tenofovir disoproxil fumarate 
(DOR/3TC/TDF) in treatment-naive adults with HIV-
1 and transmitted nonnucleoside reverse transcriptase 
inhibitor resistance mutations [letter]. J Acquir 
Immune Defic Syndr. 2019 Dec 1;82(4):e47-9.
[05FKKY]
08WX9K

PRODUCT: MK-8591A
203
PROTOCOL/AMENDMENT NO.: 051-04
MK-8591A-051-04 FINAL PROTOCOL
07-MAR-2025
[Wood, B. R. 2021]
Wood BR, Huhn GD. Excess weight gain with 
integrase inhibitors and tenofovir alafenamide: what 
is the mechanism and does it matter? Open Forum 
Infect Dis. 2021;8(12):ofab542.
[07ZG56]
[World Health 
Organization 2021]
World Health Organization. Consolidated guidelines 
on HIV prevention, testing, treatment, service 
delivery and monitoring: recommendations for a 
public health approach. Geneva (Switzerland): World 
Health Organization (WHO); 2021 Jul. 592 p.
[080MHJ]
08WX9K