Raltegravir + Lopinavir/Ritonavir Versus Efavirenz + Tenofovir + Emtricitabine in Treatment Naive Patients

Study Overview
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Brief Summary
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CCTG 589 is a randomized, open-label, pilot study comparing the efficacy, safety and tolerability of RAL plus LPV/r to EFV plus TDF/FTC in HIV-infected, treatment-naïve subjects. Subjects will be ineligible if they have any evidence of drug resistant virus in the past or at the time of screening (if never previously tested). Those who are found to be eligible will be randomized 1:1 to initiate either LPV/r (400/100 mg) plus RAL (400mg), both given twice-daily, or fixed dose combination of EFV (600 mg), TDF (300 mg) and FTC (200 mg) given as once-daily Atripla® for 48 weeks. Hypotheses The novel nucleoside-sparing combination of LPV/r + RAL will have a faster phase 1 viral decay rate compared to standard-of-care therapy with EFV/TDF/FTC in antiretroviral-naïve patients. Faster phase 1 viral decay dynamics will be associated with improved longer-term (week 48) viral suppression. Faster phase 1 viral decay dynamics will be associated with accelerated early (Day 0-14) clearance of cell-associated HIV DNA. Faster phase 1 viral decay dynamics will be associated with greater early (baseline to week 12) CD4+ T-cell recovery. The LPV/r + RAL arm will have greater decreases in early (baseline to week 4) CD4/CD8 T-cell immune activation and apoptosis which will be associated with greater late (week 12 to week 48) CD4+ T-cell recovery. Subjects treated with LPV/r + RAL arm will have smaller changes in total cholesterol and triglycerides from baseline than those receiving EFV/TDF/FTC.

Detailed Description
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The purpose of this study is to determine how well a new anti-HIV drug combination (RAL plus LPV/r) taken twice a day decreases the amount of HIV found in participants' blood (viral load) compared to taking the once-a-day combination pill Atripla®. This study will also try to determine if the new combination has fewer side effects and is tolerated better than Atripla®. Another reason this study is being done is to see if this new drug combination helps participants' body's CD4 cells recover differently and will also look at how well participants' bodies absorbs these drugs and how safe these drugs are when given together.

Official Title
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Nucleoside-Sparing Combination Therapy With Lopinavir/Ritonavir (LPV/r) + Raltegravir (RAL) vs. Efavirenz (EFV) + Tenofovir Disoproxil Fumarate + Emtricitabine (TDF/FTC) in Antiretroviral-Naïve Patients

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Kaletra + Isentress
* Drug: Atripla


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV-1 infection. Treatment naïve (defined as having never received any HIV antiretroviral agents in past). CD4+ T-cell count greater than or equal to 50 cells/mm3 HIV viral load greater than or equal to 5,000 copies/mL Laboratory values obtained by screening laboratories within 30 days of entry: Absolute neutrophil count (ANC) greater than 750/mm3. Hemoglobin greater than 8.0 g/dL. Platelet count greater than 50,000/mm3. Calculated creatinine clearance (CrCl) > 60 mL/min as estimated by the Cockcroft-Gault equation: For men, (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72) = CrCl (mL/min) For women, multiply the result by 0.85 = CrCl (mL/min) AST (SGOT), ALT (SGPT), and alkaline phosphatase less than 5 x ULN. Total bilirubin less than 2.5 x ULN. Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period. Men and women age greater than or equal to 18 years. Ability to obtain prescription for HIV antiretroviral medications and to have required prescriptions filled prior to entry. Ability and willingness of subject to give written informed consent Exclusion Criteria: Pregnancy or breast-feeding Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 30 days prior to study entry (day 0). Acute therapy for serious infection or other serious medical illnesses (in the judgment of the site investigator) requiring systemic treatment and/or hospitalization within 14 days prior to study entry (day 0). Evidence of HIV seroconversion within 6 months prior to study entry. Evidence of any major HIV drug resistance-associated mutation on any genotype performed prior to study entry or at the time of screening. History of chronic hepatitis C (defined as HCV antibody positive and HCV RNA detectable). History of chronic active hepatitis B (defined as surface antigen positive and/or HBV DNA detectable). Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements. Use of any immunomodulator, HIV vaccine, or investigational therapy within 30 days of study entry. Use of human growth hormone within 30 days prior to study entry. Initiation of testosterone or anabolic steroids within 30 days prior to study entry. (Exception: Chronic replacement dosages in patient's with diagnosed hypogonadism is allowed).

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: 1 - Kaletra + Isentress taken twice daily<br>Kaletra (lopinavir/ritonavir 400/100 mg) + Isentress (Raltegravir 400 mg) twice-daily | Drug: Kaletra + Isentress<br>* kaletra 2 tabs twice a day + Raltegravir 1 tab twice a day<br>* Other names: Lopinavir/ritonavir (LPV/r) + Raltegravir (RAL);|
| Active Comparator: 2 - Atripla taken once daily<br>Sustiva (EFV 600 mg), Viread (TDF 300 mg) and Emtriva (FTC 200 mg) taken as Atripla® once-daily | Drug: Atripla<br>* Atripla 1 tab once a day<br>* Other names: Efavirenz (EFV) + Tenofovir Disoproxil Fumarate + Emtricitabine (TDF/FTC);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Compare the Phase 1 Viral Decay Rates Between LPV/r + RAL vs. EFV/TDF/FTC Treatment Combinations. | Repeated HIV RNA measured at different time points (baseline, days 2, 7, 10, 14) will be treated as the outcome variable in a linear mixed-effects model. The primary fixed effects will include time, treatment group, treatment group-by-time interaction; random effects will include both intercept and slope allowing each subject to have individual baseline viral load and viral decay (rate of decrease in viral load following initiation of antiretroviral therapy). The treatment group-by- time interaction term in the model will indicate the difference in viral decay rates between the two treatment groups. Baseline covariate adjustment will be included if necessary. | Baseline, days 2, 7, 10, 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral Suppression Efficacy at 48 Weeks | To determine the antiviral efficacy of LPV/r + RAL compared to EFV/TDF/FTC after 48 weeks of treatment by achieving undetectable viral load | 48 weeks | 
| Compare Early Activated CD4+ T-cell Recovery Rates From Baseline to Week 4. | To compare early (baseline to Week 4) activated CD4+ T-cell recovery rates between treatment regimens. | Baseline to Week 4 | 
| Compare Late Activated CD4+ T-cell Recovery Rates Between Treatment Regimens From Baseline to Week 48 | To compare late (baseline to Week 48) activated CD4+ T-cell recovery rates between treatment regimens. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV treatment, Treatment-naive, Adult