2DR Versus 3DR in a Prospective Randomized Controlled Switch Trial

Study Overview
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Brief Summary
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The aim of this study is to monitor virological and immunological markers in participants who are switching from a classic triple drug regimen (3DR) to dual therapy (2DR). We aim to monitor whether this has an influence on different parameters such as severity of HIV disease (evaluated by viral load and viral reservoir size), presence of non-AIDS related health complications, impact the phenotype and function of the immune system. By conducting this study we want to assess whether switching from 3DR to 2DR implies an increased risk for 'subclinical' failure. We especially want to make sure that this switch does not increase the HIV reservoir, does not increase inflammation or immune exhaustion in patients living with HIV and that it can be considered as a safe long term alternative for the classic 3DR. The primary objective is to demonstrate non inferiority at W48 of the 2DR DTG/3TC (Dovato) regimen compared to BIC/TAF/FTC (Biktarvy) in terms of the amount of intact replication competent HIV sequences with a non-inferiority margin of 12% quantified by the fraction intact HIV viral sequences quantified by an intact proviral DNA assay, present in blood CD4 cells.

Official Title
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Virological and Immunological Assessment in HIV Positive Participants on 2DR Versus 3DR in a Prospective Randomized Controlled Switch Trial

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: Dual versus triple therapy in treatment of HIV-1 infection.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age = or >18 years. Ability and willingness to provide written informed consent. Ability to attend the complete schedule of assessments and patient visits. Ability and willingness to have blood samples collected and stored indefinitely and used for various research purposes. HIV RNA < 50 copies/mL for at least 3 months on a 2nd generation INSTI based regimen. Females of childbearing potential should be on effective contraception Exclusion Criteria: Current presence of opportunistic infection (AIDS defining events as defined in category C of the CDC clinical classification). Evidence of active HBV infection (Hepatitis B surface antigen positive or HBV viral load positive in the past and no evidence of subsequent seroconversion (seroconversion= HBV antigen or viral load negative and positive HBV surface antibody). Evidence of active HCV infection: HCV antibody positive result within 60 days prior to study entry with positive HCV viral load or, if the HCV antibody result is negative, a positive HCV RNA result within 60 days prior to study entry. Pregnancy or breastfeeding. Patients unable to understand the study protocol or any other condition that in the investigator's opinion may compromise compliance with the study protocol Decompensated liver cirrhosis (Child-Pugh B/C) Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (apart from hyperbilirubinemia or jaundice due to Gilbert's syndrome or asymptomatic gallstones) Psychiatric and psychological disorders, which in the opinion of the investigator, will interfere with the trial conduct or safety of the participant. Previous participation in a trial evaluating an immune modulating agent. Active drug or alcohol use/addiction such that, in the opinion of the site investigator, would interfere with adherence to study requirements. Treatment failure on an integrase inhibitor containing regimen and reported baseline resistance Creatinine Clearance <50 Tuberculosis treatment Documented M184V Previous virological failure >200 copies/mL on NRTI Subjects with history or presence of allergy to any of the study drugs or their components ALT >5 times the ULN, OR ALT >3xULN and bilirubin >1.5xULN (with >35% direct bilirubin)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dovato<br>We aim to include 134 adult HIV-infected patients with HIV RNA < 50 copies/mL for at least 3 months on any stable 2nd generation integrase based triple therapy antiretroviral regimen. Patients will be randomized 1:2 to switch to or stay on the triple regimen BIC/TAF/FTC (Biktarvy) (N=45) or to switch to the dual regimen DTG/3TC (Dovato) (N=89). | Drug: Dual versus triple therapy in treatment of HIV-1 infection.<br>* cfr arm decsription<br>|
| Active Comparator: Biktarvy<br>We aim to include 134 adult HIV-infected patients with HIV RNA < 50 copies/mL for at least 3 months on any stable 2nd generation integrase based triple therapy antiretroviral regimen. Patients will be randomized 1:2 to switch to or stay on the triple regimen BIC/TAF/FTC (Biktarvy) (N=45) or to switch to the dual regimen DTG/3TC (Dovato) (N=89). | Drug: Dual versus triple therapy in treatment of HIV-1 infection.<br>* cfr arm decsription<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in amount of intact replication-competent HIV-1 sequences in CD4 cells between 2 regimens | The primary objective is to demonstrate non inferiority at W48 of the 2DR DTG/3TC (Dovato) regimen compared to BIC/TAF/FTC (Biktarvy) in HIV-1 infected individuals in terms of the amount of intact replication-competent HIV-1 sequences with a non-inferiority margin of 12% quantified by the fraction intact HIV viral sequences quantified by the intact proviral DNA assay (IPDA), present in blood CD4 cells. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full length sequencing of the virus | Full length sequencing of the virus at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of interleukin-6 (IL-6) | Quantification of IL-6 at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of high-sensitivity C-reactive protein (hs-CRP) | Quantification of hs-CRP at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of D-Dimers | Quantification of D-Dimers at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of Human Leukocyte Antigen - DR isotype (HLA-DR) | Quantification of HLA-DR at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of cluster of differentiation 38 (CD38) | Quantification of CD38 on both cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) immune cells at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of soluble cluster of differentiation 27 (sCD27) | Quantification of sCD27 at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of soluble cluster of differentiation 40 (sCD40) | Quantification of sCD40 at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of programmed cell death protein 1 (PD-1) | Quantification of the T cell exhaustion marker PD-1 at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of cluster of differentiation 28 (CD28) | Quantification of the T cell exhaustion marker CD28 at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of cluster of differentiation 57 (CD57) | Quantification of the T cell exhaustion marker CD57 at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of soluble cluster of differentiation 14 (sCD14) | Quantification of markers of microbial translocation sCD14 at baseline, W48, W144 and W240 | 240 weeks | 
| Quantification of CD4/CD8 ratio | Quantification of CD4/CD8 ratio at baseline, W48, W144 and W240 | 240 weeks | 
| Incidence of metabolic syndrome | Metabolic health will be assessed through incidence of metabolic syndrome at baseline, W48, W144 and W240 | 240 weeks | 
| Weight/body mass index (BMI) change | Metabolic health will be assessed through weight/BMI change at baseline, W48, W144 and W240 | 240 weeks | 
| Waist circumference | Metabolic health will be assessed through waist circumference at baseline, W48, W144 and W240 | 240 weeks | 
| Insuline resistance | Metabolic health will be assessed through insuline resistance at baseline, W48, W144 and W240 | 240 weeks | 
| Dual-energy x-ray absorptiometry (DXA) | Bone mineral density will be assessed through DXA at baseline, W48, W144 and W240 | 240 weeks | 
| FibroScans | Fat distribution will be assessed through FibroScans at baseline, W48, W144 and W240 | 240 weeks | 
| Switch questionnaire | The impact of switching will be assessed through a patient switch questionnaire at baseline, W48, W144 and W240 | 240 weeks | 
| Duplex carotis | In all participants or in a subgroup identified as high and very high cardiovascular risk group will be proposed a duplex carotis at W240 to assess the intima media tickness as a surrogate marker for generalised atherosclerosis and risk of cardio-vascular disease. | 240 weeks | 
| Quantification of lipoproteine A | Quantification of lipoproteine A at W168 | 168 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, dual therapy, triple therapy, virological control, immune activation, metabolic complications