Clinical trial NCT00775606: Immune Reconstitution of Lopinavir/Ritonavir-Based vs Efavirenz-based HAART in Advanced HIV Disease
Official title: A Phase 4 Study of the Effect on Immune Reconstitution of a Lopinavir/Ritonavir-Based Versus an Efavirenz-based HAART (Highly Active Antiretroviral Therapy) Regimen in Antiretroviral-Naïve Subjects With Advanced HIV Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Acquired Immune Deficiency Syndrome
Keywords: AIDS, HIV
Lead sponsor: Rush University Medical Center
Sponsor class: OTHER
Collaborators: name: University of Chicago
name: University of Illinois at Chicago
name: Ruth M. Rothstein CORE Center
name: Abbott
name: Gilead Sciences
First posted: 2008-10-20
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The ideal anti-HIV medications for patients with advanced HIV disease is unknown. There is evidence that anti-HIV regimens that contain protease inhibitors can enhance immune function better than regimens that do not contain protease inhibitors. This is a study that will determine the difference in immune enhancement capabilities between an anti-HIV regimen that contains the protease inhibitor - lopinavir-ritonavir, and a regimen that contains efavirenz. Both medications are recommended as first line treatments for HIV-infected patients. This study will recruit HIV-positive patients that need to start anti-HIV treatment because their CD4+ T-cells are below 200. The usual threshold for starting treatment is a CD4+ T-cell less than 350. Subjects will be randomized to treatment with either an anti-HIV regimen that contains lopinavir-ritonavir or a regimen that contains efavirenz. The study will determine the difference in immune reconstitution over 24 weeks of treatment with study medications. Among the immune parameters that will be measured is the ability of each subject to respond to vaccination with the tetanus-diphtheria vaccine and the 23-valent pneumococcal vaccine. Both vaccines are also recommended for HIV-positive patients but HIV-positive patients tend to have a lower response rate to these vaccines.

Detailed description: DESIGN: ICE-001 is a phase IV, randomized, two-arm unblinded study, comparing the effect on immune reconstitution of open-label ritonavir (RTV)-enhanced lopinavir (LPV) to efavirenz (EFV), in combination with daily emtricitabine (FTC)/tenofovir (TDF) as initial therapy for HIV-1 infection in HIV-infected treatment naïve subjects with CD4+ T-cells less than 200 cells/ml.

DURATION: Subjects will participate in ICE-001 for approximately 48 weeks after starting study treatment.

SAMPLE SIZE: ICE-001 will enroll 60 subjects (30 per treatment arm).

POPULATION: HIV-1-infected, antiretroviral (ARV) drug-naïve (≤7 days of ARV treatment at anytime prior to study entry) men and women between18 to 60 years of age with plasma HIV-1 RNA levels \>1000 copies/mL and CD4+ T-cell counts \< 200 cells/ml obtained within 90 days prior to study entry.

STRATIFICATION: Subjects will be stratified at screening based on plasma HIV-1 RNA levels \<100,000 and ≥100,000 copies/mL.

REGIMEN: At entry subjects will be randomized to one of the following:

* ARM A: LPV 400 mg/RTV 100 mg BID + FTC 200 mg/TDF 300 mg QD
* ARM B: EFV 600 mg QD/FTC 200 mg/TDF 300 mg fixed dose combination QD

The objective is to determine the differences in the degree of immune reconstitution in HIV-infected patients with a CD4+ T-cell count \< 200 cells/ml who initiated treatment with LPV/RTV + FTC/TDF compared to EFV/FTC/TDF.

Study visits will occur at screening, pre-entry, entry and weeks 1, 4, 8, 12, 24 and 48 after study entry. Study medications will be provided at entry after randomization. At most study visits, clinical assessments, including histories, physical exams and determination of drug adherence, will occur. Blood for hematologic and metabolic safety assessments and for the assessment of immune parameters will be obtained. Immune parameters that will be measured include levels of T-cell apoptosis, maturation and activation. Frequencies of various T-cell subsets and other lymphocyte populations will also be done. Response to vaccination with tetanus-diphtheria vaccine and 23-valent pneumococcal polysaccharide vaccine (both given at week 8) will be measured.

Eligibility criteria: Inclusion Criteria:

1. HIV-1 infection
2. The absence of exclusionary resistance mutations on a genotypic resistance assay
3. Antiretroviral (ARV) drug-naïve
4. Screening HIV-1 RNA \>1000 copies/mL
5. Screening CD4+ T-cell count \< 200 cells/ml
6. Laboratory values obtained within 30 days prior to study entry.

   * Absolute neutrophil count (ANC) \>500/mm3
   * Hemoglobin \>8.0 g/dL
   * Platelet count \>40,000/mm3
   * AST (SGOT), ALT (SGPT), and alkaline phosphatase \<5 x ULN
   * Total bilirubin \<2.5 x ULN
   * Calculated creatinine clearance ≥60 mL/min (by Cockcroft-Gault equation)
7. For women of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to initiating study medications.
8. Contraception requirements
9. Men and women age \>18 years and \< 60 years.
10. Ability and willingness of subject or legal guardian/representative to give written informed consent.

Exclusion Criteria:

1. Currently breast-feeding.
2. Use of immunomodulators, vaccines, growth hormone, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
3. Known allergy/sensitivity to study drugs, pneumococcal polysaccharide vaccine, tetanus-diphtheria vaccine
4. Receipt of pneumococcal polysaccharide vaccine or tetanus-diphtheria vaccine in the past 5 years.
5. Active drug or alcohol use or dependence
6. Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 14 days prior to study entry.
7. Requirement for any current medications that are prohibited with any study treatment.
8. Evidence of any major resistance-associated mutation on any genotype or evidence of significant resistance on any phenotype performed at any time prior to study entry
9. Current or anticipated imprisonment or involuntary incarceration in a medical facility for psychiatric or physical (e.g., infectious disease) illness
10. History of, or current bipolar disorder, major depression, schizophrenia or other psychotic disorders

Primary outcomes:
measure: CD4+ (Cluster of Differentiation 4) T-cell Apoptosis
timeFrame: 24 weeks from treatment initiation (baseline and week 24)
Secondary outcomes:
measure: CD4+ T-cell Change
timeFrame: 24 weeks after treatment initiation (baseline and week 24)
measure: Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency
timeFrame: baseline measurements
measure: Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency
timeFrame: week 24 measurements
measure: Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies
timeFrame: baseline measurements
measure: Activated and Regulatory CD4+ and CD8+ T-cell Frequencies
timeFrame: week 24 measurements
measure: Response to Immunization With Pneumococcus Polysaccharide and Tetanus-diphtheria Vaccines
timeFrame: 4 weeks after treatment initiation
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois Medical Center
state: Illinois
city: Chicago
country: United States
facility: Howard Brown Health Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Hospital
state: Illinois
Study officials:
affiliation: Rush University Medical Center
name: Allan R. Tenorio, M.D.
role: STUDY_CHAIR
References:
citation: Pitrak DL, Novak RM, Estes R, Tschampa J, Abaya CD, Martinson J, Bradley K, Tenorio AR, Landay AL. Short communication: Apoptosis pathways in HIV-1-infected patients before and after highly active antiretroviral therapy: relevance to immune recovery. AIDS Res Hum Retroviruses. 2015 Feb;31(2):208-16. doi: 10.1089/aid.2014.0038. Epub 2014 Nov 11.