Trial of TDF/FTC + Raltegravir Versus TDF/FTC + Efavirenz in HIV-1-Infected Women (ICE-002)

Open Label, Randomized Trial of TDF/FTC+Raltegravir Vs. TDF/FTC+Efavirenz in HIV-1-Infected Women: Differential Effects on Viral Suppression/Reservoir, & Immune Parameters in Different Compartments, Including Gut & Genital Tract

Raltegravir not only has a unique mechanism of action, but may also have other unique effects on suppression of viral replication, viral reservoir, and immune reconstitution in blood and other important compartments. This may in part be due to the pharmacokinetics of Raltegravir in blood and gut tissue. Efavirenz will be the comparator antiretroviral drug in this study, with both drugs being used as part of a three-drug regimen with tenofovir and emtricitabine.

The primary objectives are to determine differences in the effects of 2 anti-retroviral regimens, Raltegravir + Truvada versus Atripla, with respect to:

1. Viral load in plasma, genital tract (vaginal secretions), and gut (by in situ hybridization).
2. Latent viral reservoir (pro-viral DNA) in the peripheral blood and genital tract.
3. Immune effects (CD4/CD8 immunophenotypes) in gut and PBMCs and plasma cytokine profiles.

The secondary objective is to determine the pharmacokinetics of Raltegravir in blood and gut tissue; relative tissue/compartment penetration compared to Efavirenz.

Study Overview

• Status: Withdrawn
• Conditions: HIV-1 Infections
• Intervention / Treatment: Drug: TDF/FTC Once-Daily + Raltegravir 400 mg Orally Twice-Daily; Drug: TDF/FTC + Efavirenz (Atripla) Once-Daily

Detailed Description

This is a phase III, prospective, randomized (1:1), multicenter, open label study comparing the effects of two HAART regimens:

• Arm A: Raltegravir 400 mg PO BID + TDF/FTC (Truvada, 300/200 mg) One PO Daily
• Arm B: Efavirenz + TDF/FTC (Atripla) Once PO Daily

The following local sites: Mt. Sinai, Rush University Medical Center, Stroger Hospital, University of Chicago and University of Illinois will work together to enroll 10 eligible women meeting all eligibility criteria (5 per study arm) over a one year time period. These 10 women will be randomized 1:1 to receive either TDF/FTC + Raltegravir or TDF/FTC + Efavirenz (Atripla). There will be 2 baseline evaluations prior to initiation of study therapy. Subjects will be followed for 48 weeks after initiation of study treatment.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60608
      • Mt. Sinai Hospital
    • Chicago, Illinois, United States, 60622
      • The Ruth M. Rothstein CORE Center (of Cook County)

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Eligible subjects will be antiretroviral naïve (< 7 days of HAART at any time prior to entry) with plasma HIV-1 RNA > 50,000 copies/mL (obtained within 90 days prior to study entry by any laboratory that has a CLIA certification or its equivalent) and moderate immune suppression within 90 days prior to study entry.
2. HIV-1 infected, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test. Alternatively, if a licensed ELISA is not available, two HIV-1 RNA values >2000 copies/mL at least 24 hours apart performed by any laboratory that has CLIA certification or its equivalent may be used to document infection.
3. Female sex, Age > 18 and < 60 years, Pre-menopausal.
4. Screening CD4+ T-cell count between 200-350 cells/mm3 obtained within 90 days prior to study entry by any laboratory that has a CLIA certification or its equivalent.
5. The absence of exclusionary resistance mutations on a genotypic resistance assay (absence of exclusionary NRTI or NNRTI resistance mutations by genotype testing)
6. Antiretroviral (ARV) drug-naïve (defined as 7 days of ARV treatment at any time prior to entry).

7. Laboratory values obtained within 45 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 ULN
   • Total bilirubin 2.5 x ULN

   • Calculated creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault equation:

     • For women, multiply the result by 0.85 = CrCl (mL/min)

8. Negative serum or urine pregnancy test within 48 hours prior to initiating study medications unless otherwise specified by product labeling.

   • Female candidates of reproductive potential is defined as women who have had regular menses over the preceding 24 months
9. Contraception requirements for women who have not undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral tubal ligation).

10. Female candidates of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to the following:

    • If the regimen does not include EFV, they must agree to use at least one reliable method of contraception while receiving the protocol-specified drugs and for 6 weeks after stopping the medications.
    • If the regimen includes EFV, they must agree to use two reliable methods of contraception: a barrier method of contraception (e.g., condoms, diaphragm, or cervical cap with or without spermicide) together with another reliable form of contraceptive (e.g., a second barrier method, an IUD, or a hormone-based contraceptive) while receiving EFV and for 6 weeks after stopping EFV.

Exclusion Criteria:

1. Menopausal (may affect quantity of genital tract secretions) or any serious illness that requires treatment and/or hospitalization until the patient completes therapy
2. Any active infection, including co-infection with hepatitis B or C
3. Any neoplasm
4. Immunosuppressive therapy
5. Requirement for any medications that are prohibited by any of the study treatments
6. Significant liver or renal dysfunction

7. Baseline resistance to any of the study drugs by genotypic testing

   • NRTI: M41L, K65 R, D76N, T69D, K70R, L74V/I, y115F, Q151M, M184V, L210W, T215any, K219Q/E
   • NNRTI:L100I, K103N, V106A/M, V108I, Y181C/I, Y188C/L/H, G190anyA/S
8. Alcohol or substance abuse problems or psychiatric conditions that impair the ability of the subject to comply with the study protocol

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; TDF/FTC Once-Daily + Raltegravir 400 mg Orally Twice-Daily	Drug: TDF/FTC Once-Daily + Raltegravir 400 mg Orally Twice-Daily; TDF/FTC Once-Daily + Raltegravir 400 mg Orally Twice-Daily; Other Names: TDF/FTC Once-Daily + Raltegravir (Isentress) 400 mg Orally Twice-Daily
Active Comparator: 2; TDF/FTC + Efavirenz (Atripla) Once-Daily	Drug: TDF/FTC + Efavirenz (Atripla) Once-Daily; TDF/FTC + Efavirenz (Atripla) Once-Daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Viral load in plasma, genital tract (vaginal secretions), and gut (by in situ hybridization)	48 weeks
Latent viral reservoir (pro-viral DNA) in the peripheral blood and genital tract	48 weeks
Immune effects (CD4/CD8 immunophenotypes) in gut and PBMCs and plasma cytokine profiles	48 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Determine the pharmacokinetics of Raltegravir in blood and gut tissue; relative tissue/compartment penetration compared to Efavirenz	48 weeks

Collaborators and Investigators

• Sponsor: Rush University Medical Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Alan L. Landay, Ph.D., Rush University Medical Center

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Anticipated): June 1, 2013
• Study Completion (Anticipated): December 1, 2013

Study Registration Dates

• First Submitted: May 7, 2009
• First Submitted That Met QC Criteria: September 24, 2009
• First Posted (Estimate): September 25, 2009

Study Record Updates

• Last Update Posted (Estimate): May 6, 2015
• Last Update Submitted That Met QC Criteria: May 4, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: HIV; Women; Raltegravir; Viral Suppression; Viral Reservoir; Immune Parameters; Gut; Genital Tract
• Additional Relevant MeSH Terms: 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; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Raltegravir Potassium; Efavirenz; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: 08102303-IRB01; Merck IISP #33421