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

Study Overview
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Brief Summary
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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.

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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Dolutegravir (DTG)
* Drug: Lamivudine (3TC)
* Drug: Rilpivirine (RPV)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Subjects receiving 2DR treatment<br>Data will be collected from HIV positive male or female adult subjects who have started 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor from 2014. | Drug: Dolutegravir (DTG)<br>* DTG is a 2nd generation integrase strand transfer inhibitor. Subjects receiving DTG as a part of 2DR treatment will be included in the study.<br>Drug: Lamivudine (3TC)<br>* 3TC is a nucleoside reverse transcriptase inhibitor. Subjects receiving 3TC as a part of 2DR treatment will be included in the study.<br>Drug: Rilpivirine (RPV)<br>* RPV is a non-nucleoside reverse transcriptase inhibitor. Subjects receiving RPV as part of 2DR treatment will be included in the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 copies/milliliter (c/mL) at Week 24 | Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 24 will be assessed. | Week 24 | 
| Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 48 | Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 48 will be assessed. | Week 48 | 
| Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 96 | Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 96 will be assessed. | Week 96 | 
| Number of subjects who lose virologic control within the first 24 weeks after switching to a 2-DR | Virologic control is defined as 2 consecutive HIV RNA levels >50 c/mL or HIV RNA >50c/mL followed by study treatment discontinuation or missing value. Number of subjects who lose virologic control will be assessed using a Kaplan-Meier Method. | Week 24 | 
| Number of subjects who lose virologic control within the first 48 weeks after switching to a 2-DR | Virologic control is defined as 2 consecutive HIV RNA levels >50 c/mL or HIV RNA >50c/mL followed by study treatment discontinuation or missing value. Number of subjects who lose virologic control will be assessed using a Kaplan-Meier Method. | Week 48 | 
| Number of subjects who lose virologic control within the first 96 weeks after switching to a 2-DR | Virologic control is defined as 2 consecutive HIV RNA levels >50 c/mL or HIV RNA >50c/mL followed by study treatment discontinuation or missing value. Number of subjects who lose virologic control will be assessed using a Kaplan-Meier Method. | Week 96 | 
| Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 24 | Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 24 will be assessed. | Week 24 | 
| Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 48 | Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 48 will be assessed. | Week 48 | 
| Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 96 | Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 96 will be assessed. | Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with HIV RNA >200 c/mL after 24 weeks | Subjects will be assessed for HIV RNA >200 c/mL after Week 24. | Week 24 | 
| Number of subjects with HIV RNA >200 c/mL after 48 weeks | Subjects will be assessed for HIV RNA >200 c/mL after Week 48. | Week 48 | 
| Number of subjects with HIV RNA >200 c/mL after 96 weeks | Subjects will be assessed for HIV RNA >200 c/mL after Week 96. | Week 96 | 
| Number of subjects with low level viremia | Low level viremia is defined as virologic load >50 and <200 c/mL. Number of subjects with low level viremia will be assessed at indicated time points. | Up to Week 96 | 
| Time to virologic suppression | Virologic suppression is defined as viral load < 50 c/mL at the end of 6months/12months/18 months or as pre-specified. | Up to Week 96 | 
| Time to virologic failure | Time to virologic failure in the stable switch Population will be assessed. Subjects with virologic rebound or virologic non-response will be considered as failure. | Up to Week 96 | 
| Number of subjects with resistance profile in case of virologic failure | Subjects with virologic rebound or virologic non-response will be considered as failure. Results of all HIV resistance tests performed before and during antiretroviral treatment will be evaluated to analyze resistance profile in case of virologic failure. | Up to Week 96 | 
| Number of subjects with stable switch while virologically suppressed | A switching option for those with HIV RNA suppression on current treatment will be called as 'Stable switch'. Number of subjects with stable switch while virologically suppressed will be analyzed. | Up to Week 96 | 
| Number of subjects with Switch after Failure | Subjects with virologic rebound or virologic non-response will be considered as failure. Number of subjects with Switch after Failure will be analyzed. | Up to Week 96 | 
| Number of subjects switching for safety reasons | Number of subjects switching for safety reasons including tolerability, toxicity and other reasons will be evaluated. | Up to Week 96 | 
| Number of subjects with adverse events (AEs) and serious AEs (SAEs) | An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, 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 will be categorized as SAE. | Up to Week 96 | 
| cluster of differentiation (CD)4+ and CD8+ T cell counts | All available CD4 and CD8 results since first starting 2DR treatment will be collected to analyze CD4+ and CD8+ T cell counts. | Up to Week 96 | 
| CD4/CD8 ratio at each time point | All available CD4 and CD8 results since first starting 2DR treatment will be collected to analyze CD4/CD8 ratio at each time point | Up to Week 96 | 
| Number of factors associated with plasma HIV-RNA > 50 c/mL | If number of failure allows, analysis to assess factors associated with success at week 96 in naïve and treatment experienced populations and with virologic failure in population switching with HIV RNA suppression will be analyzed. | Up to Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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2DR, HIV, Lamivudine, COMBINE-2, Dolutegravir