Clinical trial NCT00028314: Effects of Treatment Changes on Fat Wasting in the Arms and Legs of HIV Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Lipodystrophy
Wasting Disease
Keywords: HIV-1
Abacavir
Nevirapine
Ritonavir
RNA, Viral
HIV Protease Inhibitors
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Viral Load
HIV Wasting Syndrome
ABT 378
Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-12-21
Enrollment: 150
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp. CORE Ctr.
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Wishard Memorial
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp. of Indiana
state: Indiana
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Fall River
country: United States
facility: SSTAR, Family Healthcare Ctr.
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis ConnectCare, Infectious Diseases Clinic
state: Missouri
city: St. Louis
country: United States
facility: Washington U CRS
state: Missouri
city: New York
country: United States
facility: Beth Israel Med. Ctr., ACTU
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS
state: Rhode Island
city: Providence
country: United States
facility: Rhode Island Hosp.
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Galveston
country: United States
facility: Univ. of Texas Medical Branch, ACTU
state: Texas
Study officials:
affiliation: Northwestern University Medical Center
name: Robert L Murphy, MD
role: STUDY_CHAIR
affiliation: University of Pennsylvania, Adult Clinical Trials Unit
name: Pablo Tebas, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: McComsey G. Update on mitochondrial toxicity of antiretrovirals and its link to lipodystrophy. AIDS Rev. 2002 Jul-Sep;4(3):140-7.
citation: 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.
citation: 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.