Comparison of Three Different Initial Treatments Without Protease Inhibitors for HIV Infection

HIV Infections Clinical Trial

Official title:

Phase III, Randomized, Double-Blind Comparison of Three Protease Inhibitor-Sparing Regimens for the Initial Treatment of HIV Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00013520
• Other study ID #: A5095
• Secondary ID: 10212ACTG A5095A
• Status: Completed
• Phase: Phase 3
• First received: March 16, 2001
• Last updated: May 17, 2012
• Est. completion date: June 2005

Study information

• Verified date: May 2012
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the effectiveness, safety, and tolerability of 3 anti-HIV combination treatments that do not use protease inhibitors (PIs).

The current rule for starting treatment of HIV infection is to combine members from different classes of anti-HIV drugs, such as 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either a PI or a nonnucleoside reverse transcriptase inhibitor (NNRTI). However, these combinations can be complicated and difficult to take, can cause a number of side effects, and may become ineffective. Combinations that are simpler, better tolerated, and more effective are needed. Because PIs can cause long-term side effects and because HIV can become resistant to many of them at the same time, anti-HIV combination treatments that do not use PIs are being tested.

Description:

Current treatment guidelines recommend combination regimens of 2 nucleoside analogues with either a PI or an NNRTI for the initial treatment of HIV infection. However, the efficacy of current regimens is limited by their complexity, pharmacokinetic characteristics, short- and long-term side effects, and drug-resistance profiles at the time of virologic failure. Consequently, the identification of new initial regimens that are simpler, better tolerated, preserve treatment options in the event of failure, and improve antiretroviral potency is needed. In addition, recent concern over the long-term toxicities of PIs and the extensive cross-resistance among the available PIs have led to the testing of PI-sparing regimens.

Participants will be in this study for a minimum of 120 weeks and a maximum of approximately 4 years. In Step 1, patients are randomly selected to receive 1 of 3 blinded treatment regimens: abacavir (ABC)/lamivudine (3TC)/zidovudine (ZDV)/efavirenz (EFV), ABC/3TC/ZDV, or 3TC/ZDV/EFV. Patients with confirmed virologic failure on Step 1 and two successive plasma HIV RNA levels of 10,000 copies/ml or greater must register to Step 2. Patients with confirmed virologic failure on Step 1 and whose plasma HIV RNA is under 10,000 copies/ml may remain on Step 1 or register to Step 2. [AS PER AMENDMENT 04/11/03: Discontinuation of Arm B was recommended. Consequently, Arms A and C were unblinded to EFV but not to ABC. A number of options are available for patients originally randomized to Arm B.]

Step 2 is open label. Regimens include 2 or 3 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with EFV, atazanavir (ATZ), ritonavir-boosted ATZ, or tenofovir disoproxil fumarate (TDF). Patients on Arm B treatment who have an HIV RNA level less than 200 copies/ml within the past 8 weeks are eligible for randomization to open-label intensification of Arm B on Step 3.

Step 3 regimens include ABC/3TC/ZDV plus either EFV or TDF. Patients with evidence of treatment-limiting toxicity to Step 3 study drugs have the option of substituting d4T for ZDV, ddI for ABC or TDF, and/or NVP for EFV. Patients with confirmed virologic failure on Step 3 and whose plasma HIV RNA is less than 10,000 copies/ml may either remain on Step 3 or register to Step 4. Patients with two successive plasma HIV RNA levels of 10,000 copies/ml or greater on Step 3 must register to Step 4.

Step 4 is open label. Regimens include two or three NRTIs plus EFV, ATV, ritonavir-boosted ATV, or TDF. Clinical assessments and laboratory evaluations are done at entry, at Weeks 2, 4, 6, 8, 12, 16, 20, 24, and then every 8 weeks thereafter for the duration of the study. Evaluations are also required when a protocol-allowed drug substitution is made.

In addition, 3 substudies are being conducted: a neurology substudy for efavirenz, a pharmacology substudy for atazanavir, and a viral dynamics substudy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1125
• Est. completion date: June 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

Inclusion Criteria

Patients may be eligible for this study if they:

• Are HIV-positive.

• Have a viral load of at least 400 copies/ml within 90 days prior to study entry.

• Are at least 16 years old.

• Weigh at least 40 kg.

• Have a negative pregnancy test within 48 hours before starting study drugs, if female and able to have children.

• Agree to use 2 effective methods of birth control while taking, and for 3 months after stopping, the study medications.

• Provide written consent of a parent or guardian, if under 18 years of age.

Exclusion Criteria

Patients will not be eligible for this study if they:

• Have taken anti-HIV drugs in the past.

• Are allergic to any of the study drugs or ingredients.

• Are pregnant or breast-feeding.

• Have taken any of the following drugs within 14 days prior to study entry:

amiodarone, astemizole, bepridil, cisapride, ergot or ergot derivatives, systemic itraconazole, systemic ketoconazole, midazolam, propoxyphene, quinidine, rifampin, terfenadine, thalidomide, triazolam, or St. John's wort.

• Have taken drugs that influence the immune system, HIV or other vaccines, or investigational drugs within 30 days prior to study entry. Prednisone at a dose of 10 mg or less daily is allowed.

• Have taken drugs or been hospitalized for serious infections or medical illnesses within 14 days prior to study entry.

• Have growths or tumors that require drug therapy.

• Have Pneumocystis carinii pneumonia that is not clinically stable and whose treatment is not completed at least 7 days prior to study entry.

• Have infections or medical illnesses that are not under control or that have not received complete treatment before study entry.

• Have any condition that, in the opinion of the investigator, would prevent them from properly participating in the study.

• Abuse drugs or alcohol.

• This study has been updated to exclude patients who are receiving systemic itraconazole and rifabutin.

Study Design

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Infection

Intervention

Drug:
• Abacavir sulfate, Lamivudine and Zidovudine

• Atazanavir

• Lamivudine/Zidovudine

• Abacavir sulfate

• Efavirenz

• Nevirapine

• Lamivudine

• Stavudine

• Zidovudine

• Didanosine

Locations

Country	Name	City	State
Puerto Rico	Puerto Rico-AIDS CRS	San Juan
United States	The Ponce de Leon Ctr. CRS	Atlanta	Georgia
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland
United States	Alabama Therapeutics CRS	Birmingham	Alabama
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Bmc Actg Crs	Boston	Massachusetts
United States	Brigham and Women's Hosp. ACTG CRS	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS	Boston	Massachusetts
United States	SUNY - Buffalo, Erie County Medical Ctr.	Buffalo	New York
United States	Unc Aids Crs	Chapel Hill	North Carolina
United States	Cook County Hosp. CORE Ctr.	Chicago	Illinois
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS	Chicago	Illinois
United States	Univ. of Cincinnati CRS	Cincinnati	Ohio
United States	Case CRS	Cleveland	Ohio
United States	MetroHealth CRS	Cleveland	Ohio
United States	The Ohio State Univ. AIDS CRS	Columbus	Ohio
United States	Duke Univ. Med. Ctr. Adult CRS	Durham	North Carolina
United States	SSTAR, Family Healthcare Ctr.	Fall River	Massachusetts
United States	Regional Center for Infectious Disease, Wendover Medical Center CRS	Greensboro	North Carolina
United States	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii
United States	Indiana Univ. School of Medicine, Infectious Disease Research Clinic	Indianapolis	Indiana
United States	Indiana Univ. School of Medicine, Wishard Memorial	Indianapolis	Indiana
United States	Methodist Hosp. of Indiana	Indianapolis	Indiana
United States	Univ. of Iowa Healthcare, Div. of Infectious Diseases	Iowa City	Iowa
United States	UCLA CARE Center CRS	Los Angeles	California
United States	USC CRS	Los Angeles	California
United States	Univ. of Miami AIDS CRS	Miami	Florida
United States	University of Minnesota, ACTU	Minneapolis	Minnesota
United States	Vanderbilt Therapeutics CRS	Nashville	Tennessee
United States	Beth Israel Med. Ctr., ACTU	New York	New York
United States	Columbia Univ., HIV Prevention and Treatment Medical Ctr.	New York	New York
United States	Cornell CRS	New York	New York
United States	HIV Prevention & Treatment CRS	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	Weill Med. College of Cornell Univ., The Cornell CTU	New York	New York
United States	Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.	Omaha	Nebraska
United States	Stanford CRS	Palo Alto	California
United States	Hosp. of the Univ. of Pennsylvania CRS	Philadelphia	Pennsylvania
United States	Philadelphia Veterans Admin. Med. Ctr. A6205 CRS	Philadelphia	Pennsylvania
United States	Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.	Philadelphia	Pennsylvania
United States	Pitt CRS	Pittsburgh	Pennsylvania
United States	Rhode Island Hosp.	Providence	Rhode Island
United States	The Miriam Hosp. ACTG CRS	Providence	Rhode Island
United States	AIDS Care CRS	Rochester	New York
United States	McCree McCuller Wellness Ctr. at the Connection, Infectious Disease Unit	Rochester	New York
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	UC Davis Medical Center	Sacramento	California
United States	Univ. of California Davis Med. Ctr., ACTU	Sacramento	California
United States	Ucsd, Avrc Crs	San Diego	California
United States	Ucsf Aids Crs	San Francisco	California
United States	Santa Clara Valley Med. Ctr.	San Jose	California
United States	San Mateo County AIDS Program	San Mateo	California
United States	Willow Clinic A0507 CRS	San Mateo	California
United States	University of Washington AIDS CRS	Seattle	Washington
United States	St. Louis ConnectCare, Infectious Diseases Clinic	St. Louis	Missouri
United States	Washington U CRS	St. Louis	Missouri
United States	Harbor-UCLA Med. Ctr. CRS	Torrance	California
United States	Georgetown University CRS (GU CRS)	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (9)

Clifford DB, Evans S, Yang Y, Acosta EP, Goodkin K, Tashima K, Simpson D, Dorfman D, Ribaudo H, Gulick RM. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med. 2005 Nov 15;143(10):714-21. — View Citation

Feinberg J. Meeting notes from the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Trizivir vs. efavirenz: results from ACTG 5095. AIDS Clin Care. 2003 Sep;15(9):78-9. — View Citation

Gulick RM, Ribaudo HJ, Shikuma CM, Lalama C, Schackman BR, Meyer WA 3rd, Acosta EP, Schouten J, Squires KE, Pilcher CD, Murphy RL, Koletar SL, Carlson M, Reichman RC, Bastow B, Klingman KL, Kuritzkes DR; AIDS Clinical Trials Group (ACTG) A5095 Study Team. — View Citation

Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA 3rd, Acosta EP, Schackman BR, Pilcher CD, Murphy RL, Maher WE, Witt MD, Reichman RC, Snyder S, Klingman KL, Kuritzkes DR; AIDS Clinical Trials Group Study A5095 Team. Triple-nucleoside — View Citation

H Ribaudo, D Clifford, R Gulick, C Shikuma, K Klingman, S Snyder, and E Acosta. Relationships between Efavirenz Pharmacokinetics, Side Effects, Drug Discontinuation, Virologic Response, and Race: Results from ACTG A5095/A5097s. CROI 2004. Abstract 132.

Kuritzkes DR, Ribaudo HJ, Squires KE, Koletar SL, Santana J, Riddler SA, Reichman R, Shikuma C, Meyer WA 3rd, Klingman KL, Gulick RM; ACTG A5166s Protocol Team. Plasma HIV-1 RNA dynamics in antiretroviral-naive subjects receiving either triple-nucleoside — View Citation

Paredes R, Lalama CM, Ribaudo HJ, Schackman BR, Shikuma C, Giguel F, Meyer WA 3rd, Johnson VA, Fiscus SA, D'Aquila RT, Gulick RM, Kuritzkes DR; AIDS Clinical Trials Group (ACTG) A5095 Study Team. Pre-existing minority drug-resistant HIV-1 variants, adhere — View Citation

Ribaudo HJ, Kuritzkes DR, Schackman BR, Acosta EP, Shikuma CM, Gulick RM. Design issues in initial HIV-treatment trials: focus on ACTG A5095. Antivir Ther. 2006;11(6):751-60. — View Citation

Schackman BR, Ribaudo HJ, Krambrink A, Hughes V, Kuritzkes DR, Gulick RM. Racial differences in virologic failure associated with adherence and quality of life on efavirenz-containing regimens for initial HIV therapy: results of ACTG A5095. J Acquir Immun — View Citation

External Links

•   Click here for more information about abacavir sulfate
•   Click here for more information about abacavir sulfate, lamivudine, and zidovudine
•   Click here for more information about atazanavir
•   Click here for more information about didanosine
•   Click here for more information about efavirenz
•   Click here for more information about lamivudine
•   Click here for more information about lamivudine, zidovudine
•   Click here for more information about nevirapine
•   Click here for more information about stavudine
•   Click here for more information about zidovudine
•   Click here for more information on recommended HIV regimens
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