Acquired Immune Deficiency Syndrome
Conditions
Keywords
AIDS, HIV
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.
Interventions
DRUGLopinavir 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
DRUGEfavirenz
Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg fixed dose combination QD
Sponsors
University of Chicago
University of Illinois at Chicago
Ruth M. Rothstein CORE Center
Abbott
Gilead Sciences
Rush University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CD4+ (Cluster of Differentiation 4) T-cell Apoptosis | 24 weeks from treatment initiation (baseline and week 24) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response to Immunization With Pneumococcus Polysaccharide and Tetanus-diphtheria Vaccines | 4 weeks after treatment initiation | Response to immunization with pneumococcus polysaccharide and tetanus-diphtheria vaccines was not done due to small sample size |
| CD4+ T-cell Change | 24 weeks after treatment initiation (baseline and week 24) | This measures the change in CD4+ T-cells from baseline to week 24 of treatment. |
| Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | baseline measurements | Naive, central memory, effector memory, and T reg CD4+ T-cell frequency at baseline |
| Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | baseline measurements | Activation and proliferation of CD4+ and CD8+ T cells were measured at baseline |
| Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | week 24 measurements | Activation of CD4+ and CD8+ T cells were measured at week 24 |
Countries
United States
Participant flow
Pre-assignment details
Two subjects withdrew participation prior to starting study
Participants by arm
| Arm | Count |
|---|---|
| ARM A Subjects randomized to Arm a will initiate Lopinavir 400 mg/ritonavir 100 mg BID + emtricitabine 200 mg/tenofovir 300 mg QD | 8 |
| ARM B Subjects randomized to Arm B will initiate Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 300 mg QD | 5 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study sponsor terminated funding | 3 | 0 |
Baseline characteristics
| Characteristic | ARM B | ARM A | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 8 Participants | 13 Participants |
| Age, Continuous | 30.6 years STANDARD_DEVIATION 7.1 | 34.5 years STANDARD_DEVIATION 9.4 | 33 years STANDARD_DEVIATION 8.5 |
| Region of Enrollment United States | 5 participants | 8 participants | 13 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 0 / 5 |
| serious Total, serious adverse events | 0 / 8 | 0 / 5 |
Outcome results
Primary
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.
Time frame: 24 weeks from treatment initiation (baseline and week 24)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ARM A/Lopinavir-ritonavir | CD4+ (Cluster of Differentiation 4) T-cell Apoptosis | -12.33 per cent | Standard Deviation 12.34 |
| ARM B/Efavirenz | CD4+ (Cluster of Differentiation 4) T-cell Apoptosis | -8.01 per cent | Standard Deviation 7.97 |
Secondary
Activated and Regulatory CD4+ and CD8+ T-cell Frequencies
Activation of CD4+ and CD8+ T cells were measured at week 24
Time frame: week 24 measurements
Population: 10 subjects contributed to the week 24 data (6 randomized to lopinavir/ritonavir and 4 randomized to efavirenz).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| ARM A/Lopinavir-ritonavir | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Activation of CD4+ T cells at week 24 | 8.70 percentage of cells |
| ARM A/Lopinavir-ritonavir | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Activation of CD8+ T cells at week 24 | 20.92 percentage of cells |
| ARM A/Lopinavir-ritonavir | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Proliferation of CD4+ T cells at week 24 | 0.47 percentage of cells |
| ARM A/Lopinavir-ritonavir | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Proliferation of CD8+ T cells at week 24 | 0.81 percentage of cells |
| ARM B/Efavirenz | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Proliferation of CD8+ T cells at week 24 | 0.48 percentage of cells |
| ARM B/Efavirenz | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Activation of CD4+ T cells at week 24 | 7.39 percentage of cells |
| ARM B/Efavirenz | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Proliferation of CD4+ T cells at week 24 | 0.52 percentage of cells |
| ARM B/Efavirenz | Activated and Regulatory CD4+ and CD8+ T-cell Frequencies | Activation of CD8+ T cells at week 24 | 17.17 percentage of cells |
Secondary
Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies
Activation and proliferation of CD4+ and CD8+ T cells were measured at baseline
Time frame: baseline measurements
Population: 11 subjects contributed to the baseline data (6 randomized to lopinavir/ritonavir and 5 randomized to efavirenz).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| ARM A/Lopinavir-ritonavir | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Activation of CD4+ T cells at baseline | 12.85 percentage of cells |
| ARM A/Lopinavir-ritonavir | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Activation of CD8+ T cells at baseline | 34.61 percentage of cells |
| ARM A/Lopinavir-ritonavir | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Proliferation of CD4+ T cells at baseline | 1.21 percentage of cells |
| ARM A/Lopinavir-ritonavir | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Proliferation of CD8+ T cells at baseline | 1.39 percentage of cells |
| ARM B/Efavirenz | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Proliferation of CD8+ T cells at baseline | 1.25 percentage of cells |
| ARM B/Efavirenz | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Activation of CD4+ T cells at baseline | 12.35 percentage of cells |
| ARM B/Efavirenz | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Proliferation of CD4+ T cells at baseline | 1.25 percentage of cells |
| ARM B/Efavirenz | Activation and Proliferation of CD4+ and CD8+ T-cell Frequencies | Activation of CD8+ T cells at baseline | 33.57 percentage of cells |
Secondary
CD4+ T-cell Change
This measures the change in CD4+ T-cells from baseline to week 24 of treatment.
Time frame: 24 weeks after treatment initiation (baseline and week 24)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ARM A/Lopinavir-ritonavir | CD4+ T-cell Change | 176.83 cells/mm3 | Standard Deviation 101.39 |
| ARM B/Efavirenz | CD4+ T-cell Change | 102.6 cells/mm3 | Standard Deviation 150.45 |
Secondary
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
Time frame: baseline measurements
Population: 11 subjects contributed to the baseline data (6 randomized to lopinavir/ritonavir and 5 randomized to efavirenz).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of naive CD4+ T cells at baseline | 32.67 percentage of cells |
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of central memory CD4+ T cells at baseline | 11.54 percentage of cells |
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of effector memory CD4+ T cells at baseline | 36.44 percentage of cells |
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of CD4+ Treg cells at baseline | 7.35 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of CD4+ Treg cells at baseline | 6.96 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of naive CD4+ T cells at baseline | 24.70 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of effector memory CD4+ T cells at baseline | 47.32 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of central memory CD4+ T cells at baseline | 9.02 percentage of cells |
Secondary
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
Time frame: week 24 measurements
Population: 10 subjects contributed to the week 24 data (6 randomized to lopinavir/ritonavir and 4 randomized to efavirenz).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of naive CD4+ T cells at week 24 | 29.08 percentage of cells |
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of central memory CD4+ T cells at week 24 | 10.89 percentage of cells |
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of effector memory CD4+ T cells at week 24 | 34.98 percentage of cells |
| ARM A/Lopinavir-ritonavir | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of CD4+ Treg cells at week 24 | 5.58 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of CD4+ Treg cells at week 24 | 5.51 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of naive CD4+ T cells at week 24 | 25.73 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of effector memory CD4+ T cells at week 24 | 44.82 percentage of cells |
| ARM B/Efavirenz | Naive, Central Memory, Effector Memory, and T Reg CD4+ T-cell Frequency | Mean percentage of central memory CD4+ T cells at week 24 | 8.28 percentage of cells |
Secondary
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
Time frame: 4 weeks after treatment initiation
Population: Response to PPSV23 and Td vaccines was not performed due to the small sample size.