Optimized Phase III Trial of Immuno-stimulation with Maraviroc, a CCR5 antagonist, combined with Anti Retroviral Therapy (cART) in advanced, Late diagnosed HIV-1 infected patients with an AIDS-defining event and/or CD4 counts below 200 cells/mm3.

INTERVENTION: Trade Name: CELSENTRI 300 Product Name: CELSENTRI 300 Pharmaceutical Form: Coated tablet Pharmaceutical form of the placebo: Coated tablet Route of administration of the placebo: Oral use Trade Name: CELSENTRI 150 Product Name: CELSENTRI 150 Pharmaceutical Form: Coated tablet Pharmaceutical form of the placebo: Coated tablet Route of administration of the placebo: Oral use CONDITION: Confirmed HIV‐1 infection; Adult patients (age >18 years); CD4+ T lymphocytes < 200/mm3 and/or previous AIDS‐defining‐illness at W‐2 or W‐4; Patient naïve from any antiretroviral; In women, use of a contraceptive method, and lack of actual pregnancy; Patients with a coverage from social health; After informed consent. Therapeutic area: Diseases [C] ‐ Virus Diseases [C02] SECONDARY OUTCOME: Secondary end point(s): Secondary end points are:; o Clinical Events:; ? New ADE (opportunistic events consistent with the 1993 CDC expanded surveillance definition plus additional events associated with immunosuppression in the patient population targeted for enrolment),; ? Non B or C; ? Serious non‐AIDS events,; ? Grade 4 events (APPENDIX XIII); ? All causes of mortality (related or not to AIDS).; o Immunological end points (APPENDIX X):; ? Absolute number of T CD4+ lymphocytes; ? Percentage of patients with > 200 CD4+ T lymphocytes at W4, W8, W12, W24, W36, W48, W60, W72,; ? Phenotypic analysis of CD4+ T lymphocytes, CD8+ T lymphocytes (naïve, central memory cells, and cytotoxic cells) and evolution of markers of immune activation (expression of HLA‐DR and CD38 on CD4 and CD8 T cells) at W0, W8, W24, W60 (substudy),; ? Seric markers of immune activation (inflammation): Hs‐CRP, fibrinogen, IL‐6, IL‐1‐beta, IFN‐alpha, d‐dimers, SAA and sCD14 at W0, W8, W24, W60 (substudy),; ? Density of CCR5 and CXCR4 expression at W0, W8, W24 (substudy),; ? Expression of homing receptors on CD4 T lymphocytes (% of cells CD4+a4b7+CCR9+) at W0, W8, W24 (substudy),; ? Evaluation of HIV‐1 and recall‐antigen specific immune responses by Intra‐Cellular Staining (ICS) at W0, W24 (substudy).; o Virological end points (APPENDIX IX):; ? Percentage of patients with a plasma HIV‐1 RNA < 400 copies/mL and <50 copies/mL at W0, W4, W8, W12, W24, W36, W48, W60, W72,; ? Plasma HIV‐1 RNA at W‐4, W0, W4, W8, W12, W24, W36, W48, W60, W72,; ? Tropism testing performed by Tropisme Test Toulouse at baseline (W0) on plasma HIV‐1 RNA and in patients with detectable plasma HIV‐1 RNA during the study (on the first sample with HIV‐1 RNA > 1000 copies/ml after week 24),; ? Resistance testing performed in patients with detectable plasma HIV‐1 RNA during the study (on the second sample with HIV��1 RNA > 400 copies/ml after week 24),; Virological study (for all patients enrolled in France):; ? HIV‐1 DNA in PBMC (peripheral blood mononuclear cells) at W0, W24, W72 (whole blood samples),; ? Tropism testing by genotypic analysis of the V3 loop to investigate (1) the correlation with virology response at W0 on plasma HIV RNA, and (2) the tropism evolution in patients with undetectable viral load at W0, W24, W72 on HIV‐1 DNA.; Seminal compartment sub‐study (for 20 patients in each group):; ? HIV viral load will be determined at W0, W24,; ? HIV tropism will be determined at W0, W24.; ; o Pharmacokinetic (PK) end points (APPENDIX VIII); ? PK analysis:; ? Determinations of MVC trough plasma concentration of MVC (Cmin; 12 ? 2 hours after the last drug intake) at W4 and W24 in all patients randomized in Group 2* using UPLC‐MS/MS,; • Distributions of MVC Cmin by dosing regimen and according to the associated PI Ritonavir‐boosted or EFV,; • Between and within patients variability of MVC Cmin,; ? Substudy in 25 patients in each group to calculate the:; • Steady‐state plasma area under curve (AUC) of MVC at W4 based on the determination of 0h, 1h, 3h, 6h, 8h, 12h post dose concentrations of MVC,; • Average of MVC concentration at W4 (Cave = AUC/12h),; • Free fraction AUC (unbound to plasma protein) of MVC at W4,; ? Determination of MVC Cmin for study discontinuations (before the end point) (adverse events, virological failure, etc.),; ? Determination of MVC seminal at W24 in a subgroup of 20 patients from Group 2,; ? Pharmacokinetic‐Pharmacodynamic (PK‐PD) relationship:; ? Relationship between MVC Cmin at W4 and W24 and virological response at W8, W12, W36, W48, W60 and W72 in all patients randomized in Group 2*,; ? Percentage of patients with a MVC Cmin = 50 ng/mL by dosing group in all patients randomized in Group 2,; ? Relationship between MVC Cave (free and total) at W4 and virological response at W24, W36, W48, W60 and W72 in a subgroup of 25 patients,; ? Relationship between MVC Cmin (free and total) at W4 and virological response at W24, W36, W48, W60 and W72 in a subgroup of 25 patients,; ? Analysis of MVC Cmin in patients demonstrating changes of their tropism results according to the genotype or/and the Tropisme Test Toulouse,; ? Relationship between MVC Cmin at W24 in seminal plasma and virological response in seminal and blood plasma at W0 and W24 in a subgroup of patients.; ? Drug‐drug interactions by determination of associated PI Ritonavir‐boosted or EFV plasma concentrations in all patients randomized in Group 2 using UPLC‐MS/MS,; ? Safety of the strategy,; ? Cost‐effectiveness study. Timepoint(s) of evaluation of this end point: W4 and virological response at W24, W36, W48, W60 and W72 INCLUSION CRITERIA: Confirmed HIV‐1 infection; Adult patients (age > 18 years); CD4+ T lymphocytes < 200/mm3 and/or previous AIDS‐defining‐illness at W‐2 or W‐4; Patient naïve from any antiretroviral; In women, use of a contraceptive method, and lack of actual pregnancy; Patients with a coverage from social health; After informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 408 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range PRIMARY OUTCOME: Main Objective: To demonstrate the clinical benefit of the adjunction of Maraviroc to a combination of antiretroviral therapy in naïve and late diagnosed HIV‐1 infected patients. ; The clinical benefit is the reduction of the occurrence of a composite outcome consisting of new AIDS‐defining event (ADE), Non B or C events, serious non‐AIDS events, IRIS and death.; Primary end point(s): The primary composite end point is defined in the appendix XI and XII and includes the following events: ; o New ADE (opportunistic events consistent with the 1993 CDC expanded surveillance definition plus additional events associated with immunosuppression in the patient population targeted for enrolment) (APPENDIX XI).; o Non B or C:; ? Aspergillosis, invasive,; ? Bartonellosis, includes bacillary angiomatosis and peliosis hepatis,; ? Chagas disease (American trypanosomiasis) of the central nervous system (CNS),; ? Leishmaniasis, visceral (kala‐azar),; ? Lymphoma, Hodgkin's,; ? Lymphoma, non‐Hodgkin's, other cell type,; ? Microsporidiosis, chronic intestinal (> 1 month's duration),; ? Nocardiosis,; ? Penicillium marneffei, extrapulmonary,; ? Pneumocystis jiroveci, extrapulmonary,; ? Rhodococcus equi disease,; ? Severe infections: defined by sepsis with bacteremia requiring overnight hospitalisation, or pneumonia requiring overnight hospitalisation.; o Serious non‐AIDS events (APPENDIX XII):; ? Cardiovascular disease (CVD): myocardial infarction, stroke, coronary revascularization,; ? Chronic end stage renal disease (ESRD),; ? Liver failure,; ? Non‐AIDS‐defining cancers except basal and squamous cell skin cancers,; ? IRIS,; o All causes of mortality (related or not to AIDS).; Secondary Objective: ‐ To compare Maraviroc to Placebo arm for each component of the primary composite end point and other major outcomes; ; ‐ Impact of CCR5 tropism on primary and major secondary end points; ; ‐ Immunologic evaluation;; ‐ Virological evaluation;; ‐ Pharmacology substudy;; ‐ Safety of the strategy;; ‐ Cost‐effectiveness study.; Timepoint(s) of evaluation of this end point: W4 and virological response at W24, W36, W48, W60 and W72