'COMBINE-2': Real-world Evidence for Effectiveness of Two Drug Regimen, Antiretroviral Therapy With Integrase Inhibitors Plus a Reverse Transcriptase Inhibitor

Dolutegravir (DTG) is a well-tolerated 2nd generation integrase strand transfer inhibitor (INSTI); rilpivirine (RPV) is a well-tolerated non- nucleoside reverse transcriptase inhibitors (NNRTI) and lamivudine (3TC) is a nucleoside reverse transcriptase inhibitors (NRTIs). This study aims to gather the real-world evidence to evaluate effectiveness of the two-drug regimen (2DR). This is a multi-site observational study in subjects who have started and/or who plan to initiate 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor. The study does not require any changes to the routine standard of care that subjects receive. Approximately 500 eligible subjects will be included from potential investigational sites across Europe and data from them will be collected either retrospectively or prospectively.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Dolutegravir (DTG); Drug: Lamivudine (3TC); Drug: Rilpivirine (RPV)

• Study Type: Observational
• Enrollment (Actual): 774

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08041
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of HIV positive male or female subjects aged 18 years or over and who have started 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor from 2014 onwards as a first-line treatment among naïve subjects, or a switching option for those with HIV RNA suppression on current treatment (stable switches), or a second-line treatment for those with virological failure on prior treatment.

Description

Inclusion Criteria:

• HIV positive male or female subjects aged 18 years or over and who have started 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor from 2014 onwards as a first-line treatment among naïve subjects, or a switching option for those with HIV RNA suppression on current treatment (stable switches), or a second-line treatment for those with virological failure on prior treatment.

Exclusion Criteria:

• No specific exclusion criteria

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Treatment-naïve participants; Participants received a two-drug regimen (2DR) consisting of an integrase inhibitor plus a reverse transcriptase inhibitor, as a first-line treatment for Human Immunodeficiency Virus (HIV) infection.	Drug: Dolutegravir (DTG); DTG is a 2nd generation integrase strand transfer inhibitor. Subjects receiving DTG as a part of 2DR treatment will be included in the study.; Drug: Lamivudine (3TC); 3TC is a nucleoside reverse transcriptase inhibitor. Subjects receiving 3TC as a part of 2DR treatment will be included in the study.; Drug: Rilpivirine (RPV); RPV is a non-nucleoside reverse transcriptase inhibitor. Subjects receiving RPV as part of 2DR treatment will be included in the study.
Stable switch participants; Participants received a two-drug regimen (2DR) consisting of an integrase inhibitor plus a reverse transcriptase inhibitor, as a switching treatment option for HIV infection, whilst virologically suppressed (whilst having HIV RNA suppression) on current treatment.	Drug: Dolutegravir (DTG); DTG is a 2nd generation integrase strand transfer inhibitor. Subjects receiving DTG as a part of 2DR treatment will be included in the study.; Drug: Lamivudine (3TC); 3TC is a nucleoside reverse transcriptase inhibitor. Subjects receiving 3TC as a part of 2DR treatment will be included in the study.; Drug: Rilpivirine (RPV); RPV is a non-nucleoside reverse transcriptase inhibitor. Subjects receiving RPV as part of 2DR treatment will be included in the study.
Prior virological failure participants; Participants received a two-drug regimen (2DR) consisting of an integrase inhibitor plus a reverse transcriptase inhibitor, as a second-line treatment for HIV infection, due to virological failure (VF) on prior treatment.	Drug: Dolutegravir (DTG); DTG is a 2nd generation integrase strand transfer inhibitor. Subjects receiving DTG as a part of 2DR treatment will be included in the study.; Drug: Lamivudine (3TC); 3TC is a nucleoside reverse transcriptase inhibitor. Subjects receiving 3TC as a part of 2DR treatment will be included in the study.; Drug: Rilpivirine (RPV); RPV is a non-nucleoside reverse transcriptase inhibitor. Subjects receiving RPV as part of 2DR treatment will be included in the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Treatment-naïve Participants With Human Immunodeficiency Virus Ribonucleic Acid (HIV-RNA) Levels Less Than (<)50 Copies/Milliliter (c/mL) at 24 Weeks After 2DR (Two-drug Regimen) Initiation		At Week 24
Number of Treatment-naïve Participants With HIV-RNA Levels <50 c/mL at 48 Weeks After 2DR Initiation		At Week 48
Number of Treatment-naïve Participants With HIV-RNA Levels <50 c/mL at 96 Weeks After 2DR Initiation		At Week 96
Number of Treatment-experienced Viremic Participants With HIV-RNA Levels <50 c/mL at Week 24		At Week 24
Number of Treatment-experienced Viremic Participants With HIV-RNA Levels <50 c/mL at Week 48		At Week 48
Number of Treatment-experienced Viremic Participants With HIV-RNA Levels <50 c/mL at Week 96		At Week 96
Number of Treatment-naïve Participants Experiencing Virologic Failure (VF) [Up to 24 Weeks]	VF was defined as virologic rebound (after achieving suppression, 2 consecutive HIV RNA level greater than or equal to [>=] 50 copies/mL or 1 HIV RNA level >=50 copies/mL followed by study treatment discontinuation) or virologic non-response (2 consecutive VL>=200 copies/mL after at least 24 weeks of treatment).	Up to 24 weeks
Number of Treatment-naïve Participants Experiencing VF [Up to 48 Weeks]	VF was defined as virologic rebound (after achieving suppression, 2 consecutive HIV RNA level greater than or equal to [>=] 50 copies/mL or 1 HIV RNA level >=50 copies/mL followed by study treatment discontinuation) or virologic non-response (2 consecutive VL>=200 copies/mL after at least 48 weeks of treatment).	Up to 48 weeks
Number of Treatment-naïve Participants Experiencing VF [Up to 96 Weeks]	VF was defined as virologic rebound (after achieving suppression, 2 consecutive HIV RNA level greater than or equal to [>=] 50 copies/mL or 1 HIV RNA level >=50 copies/mL followed by study treatment discontinuation) or virologic non-response (2 consecutive VL>=200 copies/mL after at least 96 weeks of treatment).	Up to 96 weeks
Number of Stable Switch Participants With VF Within the First 24 Weeks	VF was defined as 2 consecutive HIV RNA >=50 c/mL or 1 HIV RNA >50c/mL followed by study treatment discontinuation or missing value.	Up to Week 24
Number of Stable Switch Participants With VF Within the First 48 Weeks	VF was defined as 2 consecutive HIV RNA >=50 c/mL or 1 HIV RNA >50c/mL followed by study treatment discontinuation or missing value.	Up to Week 48
Number of Stable Switch Participants With VF Within the First 96 Weeks	VF was defined as 2 consecutive HIV RNA >=50 c/mL or 1 HIV RNA >50c/mL followed by study treatment discontinuation or missing value.	Up to Week 96
Number of Treatment-experienced Viremic Participants Experiencing VF [Up to 24 Weeks]	VF was defined as virologic rebound (after achieving suppression, 2 consecutive HIV RNA >= 50 copies/mL or 1 HIV RNA level >=50 copies/mL followed by study treatment discontinuation) or virologic non-response (2 consecutive VL >=200 copies/mL after at least 24 weeks of treatment). Treatment-experienced viremic participants refers to individuals who have previously undergone HIV treatment but had virological failure in prior treatment.	Up to 24 weeks
Number of Treatment-experienced Viremic Participants Experiencing VF [Up to 48 Weeks]	VF was defined as virologic rebound (after achieving suppression, 2 consecutive HIV RNA >= 50 copies/mL or 1 HIV RNA level >=50 copies/mL followed by study treatment discontinuation) or virologic non-response (2 consecutive VL >=200 copies/mL after at least 48 weeks of treatment). Treatment-experienced viremic participants refers to individuals who have previously undergone HIV treatment but had virological failure in prior treatment.	Up to 48 weeks
Number of Treatment-experienced Viremic Participants Experiencing VF [Up to 96 Weeks]	VF was defined as virologic rebound (after achieving suppression, 2 consecutive HIV RNA >= 50 copies/mL or 1 HIV RNA level >=50 copies/mL followed by study treatment discontinuation) or virologic non-response (2 consecutive VL >=200 copies/mL after at least 96 weeks of treatment). Treatment-experienced viremic participants refers to individuals who have previously undergone HIV treatment but had virological failure in prior treatment.	Up to 96 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With HIV RNA Levels >=200 c/mL After 24 Weeks, 48 Weeks and 96 Weeks		At Week 24, Week 48 and Week 96
Number of Participants With Low Level Viremia	Low level viremia was defined as virologic load >=50 and <200 c/mL.	At Week 24, Week 48 and Week 96
Time to Virologic Suppression Among Treatment-naïve Participants and Treatment-experienced Viremic Participants, Who Achieved Suppression	Suppression of VL was evaluated at 24 weeks, 48 weeks and 96 weeks and time to virologic suppression was planned to be evaluated until 96 weeks.	Up to Week 96
Time to Virologic Failure in the Stable Switch Population	VF was defined as virologic rebound (after achieving suppression, 2 consecutive HIV RNA level greater than or equal to [>=] 50 copies/mL or 1 HIV RNA level >=50 copies/mL followed by study treatment discontinuation) or virologic non-response (2 consecutive VL>=200 copies/mL after at least 48 weeks of treatment).	Up to Week 96
Number of Participants With Emergent Resistance Mutations Following Virologic Failure (VF) Events		Up to Week 96
Number of Participants Who Discontinue Their Baseline 2DR and Who Stable Switch to a Different Regimen While Virologically Suppressed (HIV RNA <50 Copies/mL) at Switch	A stable switch was defined as a switching option for participants with HIV RNA suppression on current treatment with viral load <50 c/mL at time of switch.	Up to Week 96
Number of Participants Who Discontinue Their Baseline 2DR and Who Switch Following Virologic Failure	Virologic rebound or virologic non-response in participants, was considered as virologic failure.	Up to Week 96
Number of Participants Who Discontinue Their Baseline 2DR Who Are Switching for Safety or Other Reasons	Safety reasons include tolerability, toxicity and other reasons.	Up to Week 96
Number of Participants With AEs and SAEs	An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward event resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Determination of an event as AE or SAE was at the discretion of the treating clinician and taken from the medical record.	Up to Week 96
Cluster of Differentiation (CD)4+ and CD8+ T Cell Counts		At baseline (Week 0), Week 24, Week 48 and Week 96
CD4/CD8 Ratio		At baseline (Week 0), Week 24, Week 48 and Week 96

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Investigators: Study Director: GSK Clinical Trials, ViiV Healthcare

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2019
• Primary Completion (Actual): April 14, 2023
• Study Completion (Actual): December 5, 2023

Study Registration Dates

• First Submitted: July 19, 2018
• First Submitted That Met QC Criteria: July 12, 2019
• First Posted (Actual): July 15, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 17, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: HIV; Lamivudine; Dolutegravir; 2DR; COMBINE-2
• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; HIV Infections; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Rilpivirine; Dolutegravir; Lamivudine
• Other Study ID Numbers: 207859

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No