Maraviroc (CCR5) Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine if Maraviroc administration can decrease IRIS incidence in HIV infected patients initiating ARV therapy.

Detailed Description
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This is a randomized, double blind, placebo-controlled, multicenter study testing the utility of a CCR5 antagonist (Maraviroc) as an adjuvant to a standard HAART regimen to decrease the incidence of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-infected patients naïve to antiretroviral treatment. The study duration will be 60 weeks, 276 subjects (138 per arm) will be recruited. The population included will be HIV-infected patients starting antiretroviral (ARV) therapy at the participating centers in Mexico and South Africa with a CD4 T cell count <100 cells/ul. Subjects will be randomized to receive either Maraviroc (study drug) or placebo in addition to background ARV therapy. The background antiretroviral regimen for all subjects will be: Efavirenz 600mg QD + Tenofovir 300 mg / Emtricitabine 200 mg QD; subjects will be randomized to one of the following arms: Arm A: background ARV + maraviroc 600mg po BID; Arm B: background ARV + placebo po BID. Patients will be followed for 48 weeks. The primary endpoint will be the occurrence of a defined IRIS event by week 24 of follow up. The success of the ARV therapy will also be evaluated by virologic and immunologic response at 24 and 48 weeks. Three immunology sub-studies are planned: 1) Sub-study A will be conformed by a subgroup of 40 subjects (20 from Mexico and 20 from South Africa), additional blood sampling will be performed to evaluate expression of immune activation markers; movement of central memory T cells into cell cycle and frequencies of expandable pathogen-reactive CD4+ and CD8+ T cells in circulation; 2) Sub-study B will be conformed by another subgroup of 60 subjects (all from South Africa), additional blood sampling will be performed to evaluate monocyte and CD4 T cell gene expression as related to activation-induced apoptosis and cytokine secretion.; 3) Sub-study C will evaluate the incidence of thromboembolic disease in the study patients along with baseline evaluation of possible bio-markers of pro-coagulant state.

Official Title
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CCR5 Antagonism to Decrease the Incidence of the Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients

Conditions
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Immune Reconstitution Inflammatory Syndrome, HIV, HIV Infections

Intervention / Treatment
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* Drug: maraviroc
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, as documented by any licensed rapid test kit and confirmed by Western blot or ELISA test kit at any time prior to study enrollment. Plasma HIV-1 RNA is acceptable as an alternative confirmatory test. Men and women age > 18 years. Have not received any antiretroviral treatment before entering the study. Patients who received Single dose nevirapine or any duration of AZT for PMTC will not be considered ARV naïve. CD4+ cell count of </=100 cells/mm3 obtained within 90 days prior to study entry. HIV RNA level > 1,000 copies/mL obtained within 90 days prior to study entry. Patients with an opportunistic or HIV-related infection may be included according to the clinical judgment of the main investigator in each center when the patient is ready and able to start ARV therapy. Laboratory values obtained within 30 days prior to study entry: Absolute neutrophil count (ANC) > 500/mm3. Hemoglobin > 8.0 g/dL. Platelet count > 50,000/mm3. AST (SGOT), ALT (SGPT), and alkaline phosphatase minor of 5 times ULN. Total bilirubin minor of 2.5 times ULN. Creatinine clearance minor of 50* mL/min as estimated by the Cockcroft-Gault equation or Creatinine Clearance > 50ml/min as calculated by a formal creatinine clearance measurement All women of reproductive potential (have not reached menopause or undergone hysterectomy, oophorectomy, or tubal ligation) must have a negative serum or urine b-HCG pregnancy test performed within 7 days before study entry. Female subjects who are not of reproductive potential (have reached menopause or undergone hysterectomy, oophorectomy, or tubal ligation) or whose male partner has undergone successful vasectomy with resultant azoospermia or has azoospermia for any other reason, are eligible without requiring the use of contraception. Documentation of menopause, sterilization (hysterectomy, oophorectomy, tubal ligation, or vasectomy) and azoospermia by patient-reported history is acceptable. All subjects must agree not to participate in a conception process (i.e., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female study volunteer/male partner must agree to use a form of contraception as specified in the note below while receiving protocol-specified medication(s) and for one month after stopping the medication(s). Ability and willingness of subject or legal guardian/representative to give written informed consent. Exclusion Criteria: Pregnancy and breast-feeding. Active neoplasia or previous history of neoplasia. (Except localized non visceral Kaposi´s Sarcoma; localized squamous or basal cell carcinoma of the skin, or intraepithelial cervical neoplasia grade III or less). Use of the following drugs within 180 days prior to study entry: systemic cancer chemotherapy, systemic investigational agents, and immunomodulators (growth factors, immune globulin, interleukins, interferons). Use of systemic corticosteroids in the last 2 weeks prior to randomization. Decompensated liver disease (defined as stage C of Child-Pugh classification) at the beginning of the study. An altered mental status that in the opinion of the investigator, will compromise the adherence to the protocol. Allergy/sensitivity to study drug(s) or their formulations that cannot be substituted by another agent as described in section 5.1 Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements. Serious illness that renders a subject unable to take the antiretroviral study regimen. Serious medical illness that in the opinion of the investigator compromises the adherence and/or follow up of the protocol.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maraviroc<br>Maraviroc 600mg po BID Background antiretroviral regimen (Efavirenz 600mg QD + Tenofovir 300 mg /Emtricitabine 200 mg QD) plus Maraviroc 600 mg BID | Drug: maraviroc<br>* Maraviroc 600mg po BID every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops. Efavirenz 600 mg qd every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops. Tenofovir/Emtricitabine 300/200 mg qd from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.<br>* Other names: Truvada;|
| Placebo Comparator: Placebo<br>Placebo po BID Background antiretroviral regimen (Efavirenz 600mg QD + Tenofovir 300 mg /Emtricitabine 200 mg QD plus Placebo po BID | Drug: Placebo<br>* Placebo tablets po BID every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops. Efavirenz 600 mg qd every day from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops. Tenofovir/Emtricitabine 300/200 mg qd from the entry visit until week 48 or until IRIS event or unacceptable toxicity develops.<br>* Other names: Truvada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to occurrence of an IRIS event |  | The initial 24 week period of observation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to occurrence of a severe IRIS event |  | The initial 24 week period of observation | 
| Occurrence of either an IRIS event or death |  | By 24 and 48 weeks | 
| Proportion of subjects who develops an IRIS case |  | By week 24 | 
| Proportion of subjects who develop a severe IRIS case |  | Week 24 | 
| Proportion of subjects who develop a confirmed, non dermatologic IRIS case |  | Week 24 | 
| Proportion of subjects who develop an unmasking or paradoxical IRIS event |  | Week 24 | 
| Frequency of cardiovascular, cerebrovascular, non AIDS related neoplasia, cirrhosis, renal failure and death in both treatment arms |  | During the study (from entry to week 60) | 
| Frequency of AIDS defining events and AIDS related events in both arms of treatment |  | From basline to study end | 
| General survival |  | At week 24 and 48 | 
| Survival without IRIS |  | At weeks 24 and 48 | 
| Proportion of patients with VL<50 copies/mL |  | At weeks 8, 24 and 48 | 
| Changes form baseline in CD4+ cells count |  | From baseline to weeks 12, 24 and 48 | 
| Safety and tolerability of the treatment regimens |  | Along the study | 
| Incidence of HIV drug resistance |  | Baseline to week 60 | 
| Prevalence of CCR5 tropism |  | Baseline | 
| Prevalence of CCR5 HIV tropism |  | At virological failure occurrence | 
| Baseline predictors of IRIS |  | Baseline | 
| Genetic polymorphisms associated with the occurrence of IRIS |  | Baseline | 
| To evaluate the rol of biomarkers (CRP) in predicting or identifying IRIS and the effect of Maraviroc on this marker |  | Baseline to IRIS event | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune reconstitution inflammatory syndrome, CCR5 antagonist, Maraviroc, HIV, treatment naive