Immune Reconstitution of Lopinavir/Ritonavir-Based vs Efavirenz-based HAART in Advanced HIV Disease

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

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.

Study Overview

• Status: Terminated
• Conditions: Acquired Immune Deficiency Syndrome
• Intervention / Treatment: Drug: Lopinavir 400 mg/ritonavir 100 mg; Drug: Efavirenz

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospital
    • Chicago, Illinois, United States, 60612
      • University Of Illinois Medical Center
    • Chicago, Illinois, United States, 60613
      • Howard Brown Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ARM B/Efavirenz; Subjects randomized to Arm B initiated Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD	Drug: Efavirenz; Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg fixed dose combination QD; Other Names: Atripla
Active Comparator: ARM A/Lopinavir/ritonavir; Subjects randomized to Arm A initiated Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD	Drug: Lopinavir 400 mg/ritonavir 100 mg; Lopinavir 400 mg/ritonavir 100 mg fixed dose combination BID + emtricitabine 200 mg/tenofovir 300 mg fixed dose combination QD; Other Names: Truvada; Kaletra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD4+ (Cluster of Differentiation 4) T-cell Apoptosis	Change in the percentage of naive CD4 T-cells undergoing apoptosis as measured by propidium iodide staining. This is a lab test that measures the percentage of naive CD4 T-cells that are undergoing cell death. The change in this measure is obtained by determining the difference between the percentage of naive CD4 T-cells undergoing apoptosis at week 24 of treatment and the percentage undergoing apoptosis at baseline.	24 weeks from treatment initiation (baseline and week 24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD4+ T-cell Change	This measures the change in CD4+ T-cells from baseline to week 24 of treatment.	24 weeks after treatment initiation (baseline and week 24)
Response to Immunization With Pneumococcus Polysaccharide and Tetanus-diphtheria Vaccines	Response to immunization with pneumococcus polysaccharide and tetanus-diphtheria vaccines was not done due to small sample size	4 weeks after treatment initiation
Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency	Naive, central memory, effector memory, and T reg CD4+ T-cell frequency at baseline	baseline measurements
Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency	Naive, central memory and effector memory, and T reg CD4+ T-cell frequency at week 24	week 24 measurements
Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies	Activation and proliferation of CD4+ and CD8+ T cells were measured at baseline	baseline measurements
Activated and Regulatory CD4+ and CD8+ T-cell Frequencies	Activation of CD4+ and CD8+ T cells were measured at week 24	week 24 measurements

Collaborators and Investigators

• Sponsor: Rush University Medical Center
• Collaborators: Gilead Sciences; University of Chicago; University of Illinois at Chicago; Abbott; Ruth M. Rothstein CORE Center
• Investigators: Study Chair: Allan R. Tenorio, M.D., Rush University Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: October 17, 2008
• First Submitted That Met QC Criteria: October 17, 2008
• First Posted (Estimated): October 20, 2008

Study Record Updates

• Last Update Posted (Actual): May 26, 2023
• Last Update Submitted That Met QC Criteria: May 2, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: AIDS, HIV
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Slow Virus Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Ritonavir; Lopinavir; Efavirenz
• Other Study ID Numbers: ICE-001