Clinical trial NCT00050895: Comparing the Safety, Effectiveness, and Tolerability of Three Anti-HIV Drug Regimens for Treatment-Naive Patients
Official title: A Phase III, Randomized, Open-Label Comparison of Lopinavir/Ritonavir Plus Efavirenz Versus Lopinavir/Ritonavir Plus 2 NRTIs Versus Efavirenz Plus 2 NRTIs as Initial Therapy for HIV-1 Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Reverse Transcriptase Inhibitors
HIV Protease Inhibitors
Drug Therapy, Combination
Delayed Action Preparations
Treatment Naive
HIV-1
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2003-01-01
Enrollment: 775
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: With new strategies and drugs available, many different regimens exist for the treatment of HIV. The purpose of this study is to compare three different anti-HIV drug regimens as first-time treatments for HIV infection.

Detailed description: Numerous treatment options are available to HIV infected patients who are antiretroviral (ARV) therapy naive, but an optimal regimen has not yet been established. This study will compare a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, a ritonavir (RTV)-enhanced protease inhibitor (PI)-based regimen, and a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the initial treatment of HIV infection.

Patients will be randomly assigned to one of three study arms. In Arm A, patients will receive lopinavir/ritonavir (LPV/r) twice daily and efavirenz (EFV) once daily before bed. Arm B patients will receive LPV/r twice daily, lamivudine (3TC) once daily, plus either stavudine extended release (d4T XR) once daily, zidovudine (ZDV) twice daily, or tenofovir disoproxil fumarate (TDF) once daily. Patients in Arm C will receive EFV once daily before bed and 3TC plus either d4T XR once daily before bed, ZDV twice daily, or TDF once daily before bed.

Study visits will occur every 4 weeks until Week 24, then every 8 weeks thereafter for a maximum of 96 weeks. Blood will be drawn at every visit and a urine sample will be collected every 8 weeks. Body measurements will be taken at Weeks 24, 48, 72, and 96. Whole body dual-energy x-ray absorptiometry (DEXA) scans will be done at Weeks 48 and 96. Patients must fast before study visits at Weeks 12, 24, 48, 72, and 96. Women in the study will have gynecological assessments every 24 weeks.

Eligibility criteria: Inclusion Criteria for Step 1:

* HIV infected
* HIV viral load of 2000 copies/ml or greater within 60 days prior to study entry
* Willing to use acceptable means of contraception
* d4T XR, TDF, or ZDV chosen as part of an initial regimen prior to randomization to a study arm
* Coenrolled in ACTG A5152s

Exclusion Criteria for Step 1:

* On ARV therapy for 7 days or more any time prior to study entry
* NNRTIs or 3TC at any time prior to study entry
* Current peripheral neuropathy of Grade 2 or higher
* Pregnancy or breastfeeding
* Immunomodulators, vaccines, or investigational therapies within 30 days of study entry. Patients taking a stable or tapering dose of prednisone at less than 10 mg are not excluded.
* Human growth hormone within 30 days prior to study entry
* Initiation of testosterone or anabolic steroids within 30 days prior to study entry
* Certain other medications within 30 days of study entry
* Hypersensitivity to components of the study drug formulations
* Drug or alcohol use or dependence that would interfere with adherence to study requirements
* Acute therapy for serious medical illnesses requiring systemic treatment and/or hospitalization within 14 days prior to study entry
* Recent infection with drug-resistant HIV

Primary outcomes:
measure: Time from study entry to virologic failure
measure: time from study entry to regimen completion
Secondary outcomes:
measure: 20 % or more loss in peripheral fat
measure: increase in lactic acid levels at least 2-4old above the upper limit of normal (ULN)
measure: 20 % or more increase in truncal fat accumulation
measure: fasting cholesterol level equal to or greater than 240 mg/dl
measure: Grade 3 or greater elevation in fasting triglyceride levels
measure: change from baseline in insulin resistance
timeFrame: at Weeks 24, 48 and 96
measure: change from baseline of whole-body bone density and whole-body bone mineral content
timeFrame: at Weeks 48 and 96
measure: time to confirmed virologic failure while on Steps I (initial randomized regimen) or II (within class substitutes for initial regimen toxicity) OR treatment-limiting toxicity on Steps I or II
measure: number of antiretroviral classes with resistance mutations at virologic failure
measure: number of missed medication doses
timeFrame: 4 days prior
measure: change from baseline in self-reported symptoms OR occurrence of reporting an increase in symptoms
timeFrame: at Weeks 4, 48, 72 and 96
measure: change from baseline in body image OR occurrence of reporting body image distress
timeFrame: at Weeks 24, 48, 72 and 96
measure: time until treatment-limiting toxicity OR occurrence of Grades 3 or 4 toxicity
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: USC CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Sacramento
country: United States
facility: Univ. of California Davis Med. Ctr., ACTU
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Med. Ctr.
state: California
city: San Mateo
country: United States
facility: San Mateo County AIDS Program
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: Washington
country: United States
facility: Georgetown University CRS (GU CRS)
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Ctr. CRS
state: Georgia
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: Methodist Hosp. of Indiana
state: Indiana
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: Iowa City
country: United States
facility: Univ. of Iowa Healthcare, Div. of Infectious Diseases
state: Iowa
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. 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: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Omaha
country: United States
facility: Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
state: Nebraska
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
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: New York
country: United States
facility: Cornell CRS
state: New York
city: New York
country: United States
facility: Columbia Univ., HIV Prevention and Treatment Medical Ctr.
state: New York
city: New York
country: United States
facility: HIV Prevention & Treatment CRS
state: New York
city: New York
country: United States
facility: Weill Med. College of Cornell Univ., The Cornell CTU
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Rochester
country: United States
facility: AIDS Care CRS
state: New York
city: Rochester
country: United States
facility: McCree McCuller Wellness Ctr. at the Connection, Infectious Disease Unit
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Raleigh
country: United States
facility: Wake County Health and Human Services CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation, Div. of Medicine, Infectious Diseases
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Philadelphia
country: United States
facility: Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pitt CRS
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hosp.
state: Rhode Island
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Durban
country: South Africa
facility: Durban Adult HIV CRS
state: KwaZulu-Natal
Study officials:
affiliation: University of Pittsburgh
name: Sharon Riddler, MD
role: STUDY_CHAIR
affiliation: University of California, San Diego, Division of Infectious Diseases
name: Richard Haubrich, MD
role: STUDY_CHAIR
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citation: Leonard MA, Cindi Z, Bradford Y, Bourgi K, Koethe J, Turner M, Norwood J, Woodward B, Erdem H, Basham R, Baker P, Rebeiro PF, Sterling TR, Hulgan T, Daar ES, Gulick R, Riddler SA, Sinxadi P, Ritchie MD, Haas DW. Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor-Containing Regimens. Clin Infect Dis. 2021 Oct 5;73(7):e2153-e2163. doi: 10.1093/cid/ciaa1219.
citation: Mollan KR, Smurzynski M, Eron JJ, Daar ES, Campbell TB, Sax PE, Gulick RM, Na L, O'Keefe L, Robertson KR, Tierney C. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014 Jul 1;161(1):1-10. doi: 10.7326/M14-0293.
citation: Bronke C, Almeida CM, McKinnon E, Roberts SG, Keane NM, Chopra A, Carlson JM, Heckerman D, Mallal S, John M. HIV escape mutations occur preferentially at HLA-binding sites of CD8 T-cell epitopes. AIDS. 2013 Mar 27;27(6):899-905. doi: 10.1097/QAD.0b013e32835e1616.
citation: Hulgan T, Haubrich R, Riddler SA, Tebas P, Ritchie MD, McComsey GA, Haas DW, Canter JA. European mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy in AIDS Clinical Trials Group Study A5142. AIDS. 2011 Jan 2;25(1):37-47. doi: 10.1097/QAD.0b013e32833f9d02.
citation: Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, Garren KW, George T, Rooney JF, Brizz B, Lalloo UG, Murphy RL, Swindells S, Havlir D, Mellors JW; AIDS Clinical Trials Group Study A5142 Team. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008 May 15;358(20):2095-106. doi: 10.1056/NEJMoa074609.