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

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.

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