National Multicenter Trial Evaluating Two Treatments in Patients With Primary Human Immunodeficiency Virus (HIV-1) Infection

Study Overview
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Brief Summary
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The purpose of this study is to compare the impact of two combination of two tablets once daily: dolutegravir associated with emtricitabine / tenofovir versus darunavir / cobicistat associated with emtricitabine / tenofovir on DNA HIV measured in PBMC at 48 weeks in patients with primary HIV-1 infection.

Detailed Description
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Phase III, randomized (1: 1), comparative, superiority, open-label, parallel assignment, national multicenter trial evaluating two treatments in patients with primary HIV-1 infection. Comparison of the two combinations regarding: Viral reservoir at W48 Early inhibition of viral replication, Plasmatic and cellular cumulative viremia at W48, Immune reconstitution with CD4, CD8 levels and CD4 / CD8 ratio, Activation parameters decrease, Adherence to treatments, Treatments tolerance, Adverse events, Quality of life (by self-administered questionnaires). Study of the pharmacokinetics / dynamics relationship of the decay of plasma, cellular and spermatic compartments' viral loads. 50 participants per group will be enrolled in 40 sites in France. Co- inclusion in ANRS CO 06 PRIMO cohort will be offered

Official Title
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Phase III Multicenter Randomized Trial Evaluating in Patients at the Time of the Primary HIV-1 Infection, the Impact on the Viral Reservoir of a Combination Including Tenofovir/Emtricitabine and Dolutegravir or Tenofovir/Emtricitabine and Darunavir/Cobicistat

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Dolutegravir
* Drug: Darunavir-cobicistat
* Drug: Emtricitabine-Tenofovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at screening visit. Patients with primary HIV-1 infection: Any results achieved in the previous 10 days of inclusion visit will be taken into account. If the Enzyme Linked ImmunoSorbent Assay (ELISA) test result does not dissociate the signals antibodies and p24 antigen or in case of rapid test result : Negative ELISA / rapid test and positive HIV-1 RNA confirmed by a second positive HIV-1 RNA. Positive ELISA / rapid test and WB-HIV1 [0-5] band (s) or IB-HIV-1 [0-3] band(s) confirmed by a positive HIV-1 RNA. If the ELISA test result dissociated p24 antigen and antibodies signals: ELISA Ac - / p24 - and positive HIV-1 RNA confirmed by a second positive HIV-1 RNA. ELISA Ac - / p24 + confirmed by a positive HIV-1 RNA. ELISA Ac + / p24 + or - and WB-HIV1 [0-5] band (s) or IB-HIV-1 [0-3] band(s) confirmed by a positive HIV-1 RNA. Written informed consent signed by the person and the investigator no later than the day of the screening visit and before any exam performed in the trial (article L1122-1-1 Public Health Code). Affiliate or beneficiary of a social security system (Article L1121-11 of the Public Health Code) (the State Medical Aid or AME is not a social security system). Patients followed in selected centers, accepting additional constraints and having signed a consent, will participate to virological, immunological and pharmacological sub-studies. Patient agreeing to participate in the trial for 1 year according to the defined terms. Exclusion Criteria: Any antiretroviral treatment (for Pre-Exposure Prohylaxis or Post-exposure prophylaxis) during the 4 weeks preceding inclusion. Associated pathology with urgent care needed. Prothrombin Ratio < 50%. Creatinine clearance < 70 mL / min (Cockroft). aspartate transaminase (AST), alanine transaminase (ALT), or bilirubin (total and conjugated) ≥ 10 times the upper limit of normal. Patient with isolated HIV-2 viral strain. Women of childbearing potential without effective contraception method (see appendix A6). Pregnant or breastfeeding women. Person under legal guardianship or deprived of liberty by a judicial or administrative decision. Patient participating in another research evaluating other treatments with an exclusion period ongoing at the screening visit. Planned absence which could prevent optimal trial participation (vacation abroad, moving, imminent job change ...). Co-administration of prohibited treatments (see § 9.5). History or presence of allergy to the study drugs or their components; Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification. Any symptoms or laboratory values suggesting a systemic disorder (renal, hepatic, cardiovascular, pulmonary) or other medical conditions that could interfere with the interpretation of trial results or compromise the health of patients.

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 |
| --- | --- |
| Experimental: Dolutegravir + Emtricitabine/Tenofovir<br>Patients will take Dolutegravir 50 mg (= Tivicay, 1 tablet per day) with Emtricitabine 200 mg / Ténofovir 245 mg (=Truvada, 1 tablet per day) for 48 weeks | Drug: Dolutegravir<br>* Oral use, 50mg/day<br>* Other names: Tivicay;Drug: Emtricitabine-Tenofovir<br>* Oral use, Emtricititabine : 200mg/day Ténofovir : 245mg<br>* Other names: Truvada;|
| Active Comparator: Darunavir/Cobicistat + Emtricitabine/Ténofovir<br>Patients will take Darunavir 800 mg / Cobicistat 150 mg (=Rezolsta, 1 tablet per day) + Emtricitabine 200 mg / Ténofovir 245 mg (=Truvada, 1 tablet per day) for 48 weeks | Drug: Darunavir-cobicistat<br>* Oral use, 800-150mg/day<br>* Other names: Rezolsta;Drug: Emtricitabine-Tenofovir<br>* Oral use, Emtricititabine : 200mg/day Ténofovir : 245mg<br>* Other names: Truvada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV-DNA levels in the peripheral blood mononuclear cell (PBMC) at week 48 |  | week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative cellular viremia up to week 48 |  | week 48 | 
| Cumulative plasmatic viremia (HIV-1 RNA) at week 48 |  | week 48 | 
| Cumulative plasmatic viremia using the values obtained by ultrasensitive quantification for all HIV-1-RNA values < 50 copies / mL. |  | week 48 | 
| Levels of HIV-1 RNA in plasma at week 2, week 4, week 8, week 12, week 24, week 36, week 48 and changes between week 0 and week 48 |  | week 2, week 4, week 8, week 12, week 24, week 36, week 48 | 
| Percentage of patients with HIV-1 RNA <50 copies / mL at week 2, week 4, week 8, week 12, week 24, week 36, week 48 |  | week 2, week 4, week 8, week 12, week 24, week 36, week 48 | 
| Proportion of patients with HIV-1-RNA plasma below the ultrasensitive technique quantification threshold at week 2, week 4, week 8, week 12, week 24, week 36 and week 48 |  | week 2, week 4, week 8, week 12, week 24, week 36 and week 48 | 
| Total DNA-HIV levels measured in PBMC at week 2, week 4, week 8, week 12, week 24, week 36 and week 48 |  | week 2, week 4, week 8, week 12, week 24, week 36 and week 48 | 
| Total DNA-HIV levels measured in PBMC: changes between week 0 and week 48. |  | between week 0 and week 48 | 
| CD4 and CD8 counts and percentage at week 2, week 4, week 8, week 12, week 24, week 36, week 48. |  | week 2, week 4, week 8, week 12, week 24, week 36, week 48 | 
| CD4 and CD8 counts and percentage changes between week 0 and week 48. |  | between week 0 and week 48. | 
| CD4/CD8 ratio at week 2, week 4, week 8, week 12, week 24, week 36, week 48. |  | week 2, week 4, week 8, week 12, week 24, week 36, week 48 | 
| CD4/CD8 ratio changes between week 0 and week 48. |  | between week 0 and week 48. | 
| Pharmacokinetic: mean concentrations between week 0 and week 48 will be linked to plasma RNA-VIH and DNA-VIH decrease. |  | between week 0 and week 48 | 
| Pharmacokinetic: cumulative AUC between week 0 and week 48 will be linked to plasma RNA-VIH and DNA-VIH decrease. |  | between week 0 and week 48 | 
| Trial treatments tolerance using self-administered questionnaires of symptoms experienced. |  | week 0, week 4, week 8, week 12, week 24, week 36 and week 48 | 
| Reported quality of life using self-administered questionnaire (PROQOL-HIV questionnaire). |  | between week 0 and week 48 | 
| Number, nature and time of occurrence of stage 3 or 4 clinical and biological adverse events (using ANRS scale to grade severity of adverse events in adults). |  | between week 0 and week 48 | 
| HIV infection progression defined by occurrence of B or C stage clinical events or death between week 0 and week 48 |  | between week 0 and week 48 | 
| Evolution of Metabolic disorders assessed by measurement of cholesterol, triglycerides, blood glucose and lipase |  | between week 0 and week 48 | 
| Evolution of Renal function assessed by urea and serum creatinine. |  | between week 0 and week 48 | 
| Adherence to treatments using self-administered questionnaires |  | week 4, week 8, week 12, week 24, week 36 and week 48 | 
| Adherence to treatments using pills' counts by local pharmacist |  | week 4, week 8, week 12, week 24 and week 36 | 
| Adherence to treatments using MEMS (Medical Event Monitoring System) data collected during the first 3 months |  | between week 0 and week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary infection