Effects of Treatment Changes on Fat Wasting in the Arms and Legs of HIV Patients

A Restrictively Randomized, Open-Label, Controlled, Pilot Study of the Effect of a Thymidine Analogue Substitution or Change to a Nucleoside-Sparing Regimen on Peripheral Fat Wasting

The goals of this study are to find out if fat wasting and weight loss in the arms and legs of HIV patients taking highly active antiretroviral therapy (HAART) are caused by nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and if wasting can be reversed if the NRTI is stopped and replaced with other anti-HIV drugs.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Lipodystrophy; Wasting Disease
• Intervention / Treatment: Drug: Nevirapine; Drug: Abacavir sulfate; Drug: Lopinavir/Ritonavir; Drug: Atazanavir/Ritonavir

Detailed Description

Recent studies suggest body shape changes, fat redistribution, and fat lipoatrophy may be related to the NRTI component of patients' HAART and not to the protease inhibitor (PI) component. The hypothesis of this study is that thymidine analogues such as stavudine (d4T) and zidovudine (ZDV) cause lipoatrophy more so than non-thymidine analogues and that removal of thymidine analogues from HAART in patients with defined lipoatrophy will reverse this process.

In Step 1, patients will undergo axial mid-thigh and abdomen computer tomography (CT) scans. If the CT scans are readable, patients are restrictively and randomly assigned to 1 of 2 treatment arms in Step 2. Patients in Arm A-1 will replace the thymidine analogue component (stavudine [d4T] or zidovudine [ZDV]) of their HAART with abacavir (ABC). Patients in Arm B-1 will discontinue their current HAART and will receive a PI and a nonnucleoside reverse transcriptase inhibitor (NNRTI), either lopinavir/ritonavir (LPV/r) and nevirapine (NVP) or atazanavir, ritonavir, and NVP. Patients currently on efavirenz (EFV) not provided by the study may choose to continue with EFV instead of switching to NVP. Comparisons will be made to the baseline values of subcutaneous fat measured by mid-thigh and abdominal CT. Patients in Arms A-1 and B-1 remain on study for a total of 48 weeks and do not advance to Step 3.

Two additional groups (Arms A-2 and B-2) made no changes to HAART for 28 weeks to evaluate the natural history of change in lipoatrophy over time; accrual into these groups and into Step 3 has been discontinued. At Week 28, patients in Arms A-2 and B-2 were registered to Step 3 and switched from HAART to a designated new treatment. Arm A-2 patients will replace d4T or ZDV with ABC for 48 weeks. Arm B-2 patients replace their HAART with LPV/r plus NVP for 48 weeks. If patients in Arms A-2 and B-2 have not completed the 28-week delay and have not switched regimens, they will enter Step 4 and be reregistered into Arms A-1 and B-1, respectively, remaining on their treatment assignment for 48 weeks. If patients in Arms A-2 and B-2 have already switched regimens, then they will continue on their new regimens until Week 76.

• Study Type: Interventional
• Enrollment: 150
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA CARE Center CRS
    • Torrance, California, United States, 90502-2052
      • Harbor-UCLA Med. Ctr. CRS
  • Colorado
    • Aurora, Colorado, United States, 80262
      • University of Colorado Hospital CRS
  • Hawaii
    • Honolulu, Hawaii, United States, 96816
      • Univ. of Hawaii at Manoa, Leahi Hosp.
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Med. Ctr. ACTG CRS
    • Chicago, Illinois, United States
      • Cook County Hosp. CORE Ctr.
  • Indiana
    • Indianapolis, Indiana, United States
      • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
    • Indianapolis, Indiana, United States
      • Methodist Hosp. of Indiana
    • Indianapolis, Indiana, United States
      • Indiana Univ. School of Medicine, Wishard Memorial
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med. Ctr., ACTG CRS
    • Fall River, Massachusetts, United States
      • SSTAR, Family Healthcare Ctr.
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455-0392
      • University of Minnesota, ACTU
  • Missouri
    • Saint Louis, Missouri, United States, 63108
      • St. Louis ConnectCare, Infectious Diseases Clinic
    • St. Louis, Missouri, United States, 63108
      • Washington U CRS
  • New York
    • New York, New York, United States, 10003
      • Beth Israel Med. Ctr., ACTU
    • New York, New York, United States, 10016
      • NY Univ. HIV/AIDS CRS
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0405
      • Univ. of Cincinnati CRS
    • Cleveland, Ohio, United States, 44109-1998
      • MetroHealth CRS
    • Columbus, Ohio, United States, 432101228
      • The Ohio State University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp. of the Univ. of Pennsylvania CRS
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hosp. ACTG CRS
    • Providence, Rhode Island, United States
      • Rhode Island Hosp.
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt Therapeutics CRS
  • Texas
    • Galveston, Texas, United States, 775550435
      • Univ. of Texas Medical Branch, ACTU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Note: accrual into Arms A-2 and B-2 of this study has been discontinued.

Inclusion Criteria for Step 1

• HIV infected
• Experiencing a loss of fat since starting anti-HIV therapy, especially in the arms and legs
• Receiving anti-HIV therapy of 3 or more drugs, including either stavudine or zidovudine, for 24 weeks or more prior to study screening
• Viral load less than 500 copies/ml at study screening and within 60 days prior to study entry
• CD4 count of 100 or more cells/mm3 obtained within 60 days prior to study entry
• Approved methods of contraception
• Written informed consent

Exclusion Criteria for Step 1

• Currently receiving abacavir sulfate or have received abacavir sulfate in the past AND any or all of the following: unable to tolerate lopinavir/ritonavir (LPV/r) or nevirapine (NVP); failed anti-HIV treatment containing LPV/r, any other 2 PIs, or any other NNRTI; taking lamivudine (3TC) or tenofovir disoproxil fumarate (TDF) for hepatitis B virus infection and need to remain on a 3TC- or TDF-containing regimen; or have a low chance of response to LPV/r plus NVP
• Cancer treatment 6 months prior to study entry
• Initiated oral drugs to lower blood sugar level 24 weeks prior to study entry. Patients who have taken oral drugs to lower their blood sugar levels for 24 weeks or more prior to study entry are eligible.
• Began therapy with male sex hormones 24 weeks prior to study entry. Patients who have had continuous, stable therapy with male sex hormones for 24 weeks or more prior to study entry are eligible.
• Certain medications within 14 days prior to study entry
• Serious illness within 14 days prior to study entry
• Hepatitis within 60 days prior to study entry
• Thyroid problems
• Drug or alcohol use which, in the opinion of the investigator, would interfere with the study
• Currently using experimental agents except when approved by the study
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Robert L Murphy, MD, Northwestern University Medical Center; Study Chair: Pablo Tebas, MD, University of Pennsylvania, Adult Clinical Trials Unit

Publications and helpful links

General Publications

• Calza L, Manfredi R, Chiodo F. Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother. 2004 Jan;53(1):10-4. doi: 10.1093/jac/dkh013. Epub 2003 Nov 25.
• Calza L, Manfredi R, Chiodo F. Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management. Int J Antimicrob Agents. 2003 Aug;22(2):89-99. doi: 10.1016/s0924-8579(03)00115-8.
• Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000 Feb 18;14(3):F25-32. doi: 10.1097/00002030-200002180-00001.
• McComsey G. Update on mitochondrial toxicity of antiretrovirals and its link to lipodystrophy. AIDS Rev. 2002 Jul-Sep;4(3):140-7.
• Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000 Jul 7;14(10):1309-16. doi: 10.1097/00002030-200007070-00002.
• Tebas P, Zhang J, Hafner R, Tashima K, Shevitz A, Yarasheski K, Berzins B, Owens S, Forand J, Evans S, Murphy R. Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110. J Antimicrob Chemother. 2009 May;63(5):998-1005. doi: 10.1093/jac/dkp071. Epub 2009 Mar 19.

Study record dates

Study Major Dates

• Study Start: March 1, 2002
• Study Completion (Actual): March 1, 2005

Study Registration Dates

• First Submitted: December 20, 2001
• First Submitted That Met QC Criteria: December 20, 2001
• First Posted (Estimate): December 21, 2001

Study Record Updates

• Last Update Posted (Estimate): July 29, 2013
• Last Update Submitted That Met QC Criteria: July 26, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Nevirapine; Reverse Transcriptase Inhibitors; Anti-HIV Agents; HIV-1; RNA, Viral; Viral Load; Treatment Experienced; HIV Protease Inhibitors; Ritonavir; Abacavir; HIV Wasting Syndrome; ABT 378
• Additional Relevant MeSH Terms: Metabolic Diseases; Skin Diseases; Nutrition Disorders; Body Weight; Body Weight Changes; Lipid Metabolism Disorders; Emaciation; Weight Loss; Skin Diseases, Metabolic; Wasting Syndrome; Cachexia; Lipodystrophy; 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; Nevirapine; Ritonavir; Lopinavir; Atazanavir Sulfate; Abacavir
• Other Study ID Numbers: A5110; AACTG A5110; ACTG A5110