Switching From Efavirenz to Atazanavir/ Ritonavir in HIV-infected Subjects With Good Virologic Suppression

A Randomized Study to Evaluate the Effect of Switching From Efavirenz to Atazanavir/ Ritonavir on Lipoatrophy and Mitochondrial Dysfunction in HIV-infected Subjects With Good Virologic Suppression

The purposes of this study are to evaluate if switching an antiretroviral medication from efavirenz (EFV) to atazanavir/ ritonavir (ARV/r) will, in a 96-week period, change:

1. the amount of fat in HIV patients with lipoatrophy,
2. metabolic lab values such as your lipid (fat) profile, glucose (blood sugar), and insulin (a hormone that regulates glucose) in HIV patients with lipoatrophy.

Study Overview

• Status: Terminated
• Conditions: HIV Infection; Mitochondrial Dysfunction
• Intervention / Treatment: Drug: Efavirenz; Drug: Atazanavir/ritonavir

Detailed Description

Our study will evaluate the effects on peripheral fat of switching from EFV to ATV/r over 96 weeks in HIV+ patients with clinical lipoatrophy. From a virologic standpoint, EFV and ATV/r are medications which are recommended equally as preferred components of antiretroviral regimens in the December 2009 version of the Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents.[20] The study subjects should be receiving a stable EFV-containing antiretroviral (ART) regimen for at least 48 weeks prior to study entry. Blood will be saved for further investigations if needed. Safety parameters will be regularly assessed throughout the study. In addition, a subcutaneous fat biopsy will be obtained to measure fat mtDNA, mtRNA, and fat apoptosis. These measurements would provide significant insight into the clinical changes which have been recently described.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. HIV infection
2. Age > or = 18 years old.
3. Signed informed consent.
4. Clinical lipoatrophy of at least moderate severity and in at least two different areas of the following: face, arms, legs, or buttocks (as self reported by the patient and confirmed by the physician).
5. Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized.

6. All subjects must not participate in a conception process (e.g. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female subject/ male partner must use condoms (male or female) in addition to one of the following forms of contraception while on study: either a spermicidal agent, diaphragm, cervical cap, IUD, or hormonal-based contraception.

   Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control.

7. Receiving EFV-containing antiretroviral regimen for at least the last 48 weeks prior to study entry. Backbone NRTI regimens can include tenofovir, abacavir, emtricitabine, and/ or lamivudine. Backbone NRTI regimens cannot include zidovudine, stavudine, or didanosine. Breaks in therapy for a maximum of 5 consecutive days will be allowed during these 48 weeks, including the period immediately preceding study entry.
8. Patient willing and able to stop aspirin/ NSAIDS for 7 days before study entry and the scheduled skin biopsy procedures.
9. HIV-1 RNA < 400 copies/mL for at least 90 days prior to study entry.

10. Laboratory values obtained within 60 days prior to study entry:

    1. Absolute neutrophil count (ANC) ≥ 500 / mm3
    2. Hemoglobin ≥ 9.0 g/dL
    3. Platelet count ≥ 75,000/ mm3
    4. Creatinine clearance > 50 mL / min
    5. PT/PTT < 1.2 ULN

Exclusion Criteria:

1. Receipt of AZT, d4T, ddI, or ddC at study entry or within 24 weeks of entry
2. Life expectancy < 12 months
3. Women who are pregnant or breastfeeding
4. WOCBP unwilling to use contraception WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period
5. Women with a positive pregnancy test.
6. Sexually active fertile men not using effective birth control if their partners are WOCBP.

7. Other Exclusion Criteria

   1. Prisoners or subjects who are involuntarily incarcerated.
   2. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
8. Clinically important illness within 14 days prior to study entry
9. Inability to communicate effectively with the study personnel.
10. Bleeding diathesis
11. Supplementation with recombinant growth hormone, growth hormone releasing factor, anabolic steroids, estrogen or testosterone, unless it is for replacement purposes.
12. Have no plans to alter any vitamin supplementation that subjects are receiving at study entry. This includes all vitamin supplementation, coenzyme Q, N acetyl cysteine, L-acetyl carnitine, and uridine.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Efavirenz 600 mg; Serving as the Control Arm - patients will maintain EFV-containing antiretroviral regimen	Drug: Efavirenz; Maintain dosage - 600 mg orally QHS for 96 weeks; Other Names: Sustiva®: 50 mg, 200 mg
Experimental: Arm B - Atazanavir/Ritonavir; Atazanavir 300 mg orally with Ritonavir 100 mg orally once daily for 96 wks	Drug: Atazanavir/ritonavir; 300 mg orally once daily with Ritonavir 100mg orally once daily for 96 weeks; Other Names: Reyataz®: 100 mg, 150 mg, 200 mg, 300 mg; Norvir®: 100 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in DEXA-measured Limb Fat Between the EFV and ATV/r Arms	To examine the effect of switching from EFV- to ATV/r on limb fat in HIV-1 infected patients with established lipoatrophy, the primary objective of this trial will be to compare changes over 48 weeks in DEXA-measured limb fat between the EFV arm and ATV/r.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare Changes for DEXA-measured Limb Fat Between EFV and ATV/r Arms	To examine the effect of switching from EFV- to ATV/r on limb fat in HIV-1 infected patients with established lipoatrophy, a secondary objective of this trial will be to compare changes over 96 weeks in DEXA-measured limb fat between the EFV arm and ARV/r.	96 weeks
Compare Changes in CD4, HIV-1 RNA Levels and Adverse Events in Two Arms	To examine the effect of switching from EFV to ATV/r on safety in HIV-1 infected patients, a secondary objective of this trial will be to compare changes over 96 weeks in CD4 cell count, HIV-1 RNA levels, and adverse events between the EFV arm and the ATV/r arm	96 weeks
Compare Changes in Fat mtDNA, mtRNA and Fat Apoptosis Between the Two Arms	To examine the effect of switching from EFV to ATV/r on fat mtDNA, mtRNA, and fat apoptosis in HIV-1 infected patients, a secondary objective of this trial will be to compare changes over 96 weeks in fat mtDNA, mt RNA levels and fat apoptosis between the EFV arm and ARV/r arm.	96 weeks
Comparing Fasting Lipid Levels Between the Two Arms	To examine the effect of switching from EFV to ATV/r on lipids in HIV-1 infected patients, a secondary objective of this trial will be to compare changes over 96 weeks in fasting lipid levels between the EFV arm and ATV/r arm.	96 weeks
Comparing Glucose Metabolism (Fasting Insulin, QUIKI and HOMA-IR) Between the Two Arms	To examine the effect of switching from EFV to ATV/r on glucose metabolism in HIV-1 infected patients, a secondary objective of this trial will be to compare changes over 96 weeks in fasting insulin, QUIKI and HOMA-IR between the EFV arm and the ATV/r arm	96 weeks
Compare Changes in Levels of Hs-CRP Between the Two Arms	To examine the effect of switching from EFV to ATV/r on highly sensitive C-reactive protein (hs-CRP) in HIV-1 infected patients, a secondary objective of this trial will be to compare changes over 96 weeks in hs (highly sensitive) - CRP levels between the EFV arm and the ATV/r arm.	96 weeks
Correlate the Changes in DEXA-measured Fat Limb With Fat mtDNA, mtRNA and Fat Apoptosis	A secondary objective of this trial will be to correlate the changes in DEXA-measured limb fat with those of fat mtDNA, mtRNA levels and fat apoptosis	96 weeks

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: Bristol-Myers Squibb; National Institute of Allergy and Infectious Diseases (NIAID); Case Western Reserve University
• Investigators: Principal Investigator: Marisa Tungsiripat, MD, The Cleveland Clinic

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: September 2, 2010
• First Submitted That Met QC Criteria: September 2, 2010
• First Posted (Estimate): September 3, 2010

Study Record Updates

• Last Update Posted (Actual): August 11, 2017
• Last Update Submitted That Met QC Criteria: August 10, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: HIV; mitochondrial dysfunction; Lipoatrophy
• 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; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; 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; Atazanavir Sulfate; Efavirenz
• Other Study ID Numbers: 10-418; 5K23AI070078 (U.S. NIH Grant/Contract); BMS100MT (Other Grant/Funding Number: Bristol Myers Squibb)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO