Efavirenz or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir Disoproxil Fumarate or Abacavir/Lamivudine in HIV Infected Treatment-Naive Adults

HIV Infections Clinical Trial

Official title:

A Phase IIIB, Randomized Trial of Open-Label Efavirenz or Atazanavir With Ritonavir in Combination With Double-Blind Comparison of Emtricitabine/Tenofovir or Abacavir/Lamivudine in Antiretroviral-Naive Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00118898
• Other study ID #: ACTG A5202
• Secondary ID: 1U01AI068636ACTG
• Status: Completed
• Phase: Phase 3
• Start date: September 2005
• Est. completion date: November 2009

Study information

• Verified date: September 2018
• Source: AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Currently, the preferred anti-HIV regimens used in the United States consist of two nucleoside reverse transcriptase inhibitors (NRTIs) and the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV). However, with new anti-HIV drugs being approved, alternative regimens need to be tested to determine if new drug combinations have increased effectiveness in treating HIV. The purpose of this study is to test the safety, tolerability, and effectiveness of four different regimens in HIV-infected adults who have never taken anti-HIV drugs.

Description:

Antiretroviral (ARV) treatment regimens consisting of EFV and two NRTIs are the most commonly prescribed regimens for the initial therapy of HIV-infected people in the United States. Such regimens are popular because the drugs are easy to administer, have overall excellent efficacy, and are well tolerated. However, because of concerns about long-term drug toxicity, the development of drug resistance, and potential complications in pregnant women, it is imperative that other drug combinations be investigated as possible alternative initial regimens. Drugs recently approved by the Food and Drug Administration (FDA) for HIV treatment include the protease inhibitor (PI) atazanavir (ATV) and the two NRTI coformulations emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and abacavir/lamivudine (ABC/3TC). Data are limited on the efficacy of these new drugs when part of anti-HIV drug regimens. This study will evaluate and compare the safety, tolerability, and efficacy of four different treatment regimens in HIV-infected treatment-naive adults.

The treatment portion of this study will last 96 weeks after the last participant is enrolled. Participants will be randomly assigned to one of four arms:

• Arm 1 participants will receive EFV, FTC/TDF, and placebo for ABC/3TC.

• Arm 2 participants will receive EFV, ABC/3TC, and placebo for FTC/TDF.

• Arm 3 participants will receive ritonavir (RTV)-boosted ATV, FTC/TDF, and placebo for ABC/3TC.

• Arm 4 participants will receive RTV-boosted ATV, ABC/3TC and placebo for FTC/TDF.

NOTE: Lopinavir/ritonavir may be used in substitution of other drugs for certain participants.

Study visits will occur at study entry; Weeks 1, 2, 4, 8, 16, and 24; and every 12 weeks thereafter. A physical exam, blood collection, and urine collection will occur at most visits. Two pharmacokinetic blood samples will be collected from participants between Weeks 4 and 24. Participants will undergo adherence training at study entry and will be asked to complete adherence questionnaires at selected study visits. Some participants will be asked to participate in ACTG A5224s, a metabolic substudy of ACTG A5202.

The Data Safety Monitoring Board (DSMB) for A5202 met in January 2008 to review the study. After reviewing the study information, the DSMB noted that certain study regimens were significantly less effective than others. Specifically, ABC/3TC-containing regimens were not as effective in controlling the virus as TDF/FTC-containing regimens for participants entering the study with high viral loads. The DSMB also commented that participants assigned to ABC/3TC had a shorter time until they experienced side effects than participants assigned to TDF/FTC. The DSMB had no safety concerns for the other drug comparisons.

Based on DSMB review, in Feb 2008 participants who started the study with high viral loads were told whether they were taking ABC/3TC or TDF/FTC and offered the option to continue or change their NRTI study drug component, after discussion with their doctor. For participants who started the study with lower screening viral loads, study treatment continued without change.

For 74 participant the reason for first treatment modification was "unblinded and switched" as a consequence of the DSMB results (33 on EFV, ABC/3TC, and placebo FTC/TDF arm; 1 on RTV-boosted ATV, FTC/TDF, and placebo ABC/3TC arm; and 40 on RTV-boosted ATV, ABC/3TC, and placebo FTC/TDF arm).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1864
• Est. completion date: November 2009
• Est. primary completion date: November 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

• HIV-infected. A resistance assay must be obtained if the participant has evidence of recent infection. More information on this criterion can be found in the protocol.

• Antiretroviral naive, defined as 7 days or less of ARV treatment at any time prior to study entry. Participants who have received ARVs as part of postexposure prophylaxis or who have received an investigational drug that was not an NRTI, NNRTI, or PI are eligible for this study.

• HIV viral load greater than 1,000 copies/ml within 90 days prior to study entry

• Certain laboratory values obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol

• Willing to use acceptable forms of contraception

• Parent or guardian able and willing to provide written informed consent, if applicable

• Hepatitis B surface antigen (HBsAg) negative at study entry

Exclusion Criteria:

• Immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Individuals receiving either stable physiologic glucocorticoid doses, corticosteroids for acute therapy for pneumocystis pneumonia, or a short course (2 weeks or less) of pharmacologic glucocorticoid therapy will not be excluded.

• Known allergy/sensitivity to study drugs or their formulations

• Active alcohol or drug use that, in the opinion of the investigator, would interfere with adherence to study requirements

• Serious illness requiring systemic treatment or hospitalization. Patients who have completed therapy or are clinically stable on therapy for at least 7 days prior to study entry are not excluded.

• Known clinically relevant cardiac conduction system disease

• Requirement for any current medications that are prohibited with any study treatment.

• Evidence of any major drug resistance-associated mutation on any genotype or evidence of significant resistance on any phenotype performed at any time prior to study entry.

• Current imprisonment or involuntary incarceration for psychiatric or physical (e.g., infectious disease) illness

• Breastfeeding. Women who become pregnant during the study will be unblinded and required to permanently discontinue their study regimens.

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Abacavir/Lamivudine
600 mg abacavir/300 mg lamivudine tablet taken orally daily
• Atazanavir
300 mg tablet taken orally daily
• Efavirenz
600 mg tablet taken orally daily
• Emtricitabine/Tenofovir disoproxil fumarate
200 mg emtricitabine/300 mg tenofovir disoproxil fumarate tablet taken orally daily
• Ritonavir
100 mg tablet taken orally daily
• Abacavir/Lamivudine placebo
Placebo tablet taken orally daily
• Emtricitabine/Tenofovir disoproxil fumarate placebo
Placebo tablet taken orally daily

Locations

Country	Name	City	State
Puerto Rico	Puerto Rico-AIDS CRS (5401)	San Juan
United States	Emory University	Atlanta	Georgia
United States	The Ponce de Leon Center CRS (5802)	Atlanta	Georgia
United States	University of Colorado Hospital CRS (6101)	Aurora	Colorado
United States	IHV Baltimore Treatment CRS (4651)	Baltimore	Maryland
United States	Johns Hopkins Adult AIDS CRS (201)	Baltimore	Maryland
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS (103)	Boston	Massachusetts
United States	Bmc Actg Crs (104)	Boston	Massachusetts
United States	Brigham and Women's Hosp. ACTG CRS (107)	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS (101)	Boston	Massachusetts
United States	SUNY - Buffalo (Rochester) (1102)	Buffalo	New York
United States	Unc Aids Crs (3201)	Chapel Hill	North Carolina
United States	Wake County Department of Health (30076)	Chapel Hill	North Carolina
United States	Cook County Hospital Core Center (2705)	Chicago	Illinois
United States	Northwestern University CRS (2701)	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS (2702)	Chicago	Illinois
United States	University of Cincinnati CRS (2401)	Cincinnati	Ohio
United States	Case CRS (2501)	Cleveland	Ohio
United States	Metro Health CRS (2503)	Cleveland	Ohio
United States	The Ohio State Univ. AIDS CRS (2301)	Columbus	Ohio
United States	Peabody Health Center CRS (31443)	Dallas	Texas
United States	Duke University Medical Center Adult CRS (1601)	Durham	North Carolina
United States	University of Texas, Galveston (6301)	Galveston	Texas
United States	Moses H. Cone Memorial Hospital CRS (3203)	Greensboro	North Carolina
United States	Indiana University Hospital (2601)	Indianapolis	Indiana
United States	Wishard Hospital (2603)	Indianapolis	Indiana
United States	Univ of Iowa Hosp and Clinic (1504)	Iowa City	Iowa
United States	UCLA CARE Center CRS (601)	Los Angeles	California
United States	Usc Crs (1201)	Los Angeles	California
United States	University of Miami AIDS CRS (901)	Miami	Florida
United States	Vanderbilt Therapeutics CRS (3652)	Nashville	Tennessee
United States	Cornell CRS (7804)	New York	New York
United States	Harlem ACTG CRS (31483)	New York	New York
United States	HIV Prevention & Treatment CRS (30329)	New York	New York
United States	NY Univ. HIV/AIDS CRS (401)	New York	New York
United States	Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)	New York	New York
United States	Presbyterian Medical Center - Univ. of PA (6206)	Norristown	Pennsylvania
United States	Stanford CRS (501)	Palo Alto	California
United States	Hosp. of the Univ. of Pennsylvania CRS (6201)	Philadelphia	Pennsylvania
United States	Pitt CRS (1001)	Pittsburgh	Pennsylvania
United States	The Miriam Hosp. ACTG CRS (2951)	Providence	Rhode Island
United States	AIDS Community Health Ctr. ACTG CRS (1108)	Rochester	New York
United States	University of Rochester ACTG CRS (1101)	Rochester	New York
United States	Washington U CRS (2101)	Saint Louis	Missouri
United States	Ucsd, Avrc Crs (701)	San Diego	California
United States	Ucsf Aids Crs (801)	San Francisco	California
United States	University of Washington AIDS CRS (1401)	Seattle	Washington
United States	University of Washington General Clinical Research (1403)	Seattle	Washington
United States	San Mateo County AIDS Program (505)	Stanford	California
United States	Willow Clinic (507)	Stanford	California
United States	Harbor-UCLA Med. Ctr. CRS (603)	Torrance	California
United States	Georgetown University CRS (GU CRS) (1008)	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
AIDS Clinical Trials Group	National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (4)

Anderson PL. Pharmacologic perspectives for once-daily antiretroviral therapy. Ann Pharmacother. 2004 Nov;38(11):1924-34. Epub 2004 Oct 12. Review. — View Citation

Kress KD. HIV update: emerging clinical evidence and a review of recommendations for the use of highly active antiretroviral therapy. Am J Health Syst Pharm. 2004 Oct 1;61 Suppl 3:S3-14; quiz S15-6. Review. Erratum in: Am J Health Syst Pharm. 2004 Nov 15;61(22):2350. — View Citation

Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dubé MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS; AIDS Clinical Trials Group 384 Team. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003 Dec 11;349(24):2293-303. — View Citation

Shafer RW, Smeaton LM, Robbins GK, De Gruttola V, Snyder SW, D'Aquila RT, Johnson VA, Morse GD, Nokta MA, Martinez AI, Gripshover BM, Kaul P, Haubrich R, Swingle M, McCarty SD, Vella S, Hirsch MS, Merigan TC; AIDS Clinical Trials Group 384 Team. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003 Dec 11;349(24):2304-15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Amount of Study Follow-up	Participants were to be followed for 96 weeks after the last enrollment. Accrual was expected to take 96 weeks, thus the planned follow-up time was 96 to 192 weeks, dependent on when in the study the participant enrolled. This outcome summarizes that total amount of actual follow-up in weeks from randomization to last contact.	Follow-up time was variable, median follow-up was 138 weeks
Other	Number of Participants With Virologic Failure	Blood samples for determining virologic failure were obtained at 16 and 24 weeks, and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks and before 24 weeks or >=200 copies/mL at or after 24 weeks.	Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Other	Cumulative Probability of Not Experiencing Virologic Failure	Kaplan-Meier estimate of the cumulative survival probability at week 48 and 96. Blood samples for determining virologic failure were obtained at 16 and 24 weeks, and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks and before 24 weeks or >=200 copies/mL at or after 24 weeks.	At week 48 and 96
Other	Number of Participants With a Grade 3/4 Safety Event	Grade 3/4 safety event is defined as a grade 3 or 4 sign, symptom, or laboratory abnormality that is at least one grade higher than at baseline, total bilirubin and creatine kinase (CPK) were excluded. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables. As-treated analysis censored at 1st modification of initially assigned regimen, participants who never started treatment were excluded.	Over all study follow-up while on initially assigned treatment, median follow-up was 120 weeks
Other	Cumulative Probability of Not Experiencing a Grade 3/4 Safety Event	Kaplan-Meier estimate of the cumulative survival probability at week 48 and 96. Grade 3/4 safety event is defined as a grade 3 or 4 sign, symptom, or laboratory abnormality that is at least one grade higher than at baseline, total bilirubin and creatine kinase (CPK) were excluded. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables. As-treated analysis censored at 1st modification of initially assigned regimen, participants who never started treatment were excluded.	At week 48 and 96
Other	Number of Participants With Treatment Modification	Treatment modification is defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution.	Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Other	Cumulative Probability of Not Experiencing Treatment Modification	Kaplan-Meier estimate of the cumulative survival probability at week 48 and 96. Treatment modification is defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution.	At week 48 and 96
Other	Number of Participants With Regimen Failure	Blood samples for determining virologic failure were obtained at 16 and 24 weeks, and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks and before 24 weeks or >=200 copies/mL at or after 24 weeks. Treatment modification was defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution.	Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Other	Cumulative Probability of Not Experiencing Regimen Failure	Kaplan-Meier estimate of the cumulative survival probability at week 48 and 96. Blood samples for determining virologic failure were obtained at 16 and 24 weeks, and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks and before 24 weeks or >=200 copies/mL at or after 24 weeks. Treatment modification was defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution.	At week 48 and 96
Primary	Time From Randomization to Virologic Failure	Blood samples for determining virologic failure were obtained at visit weeks 16 and 24 , and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks after randomization and before 24 weeks, or >=200 copies/mL at or after 24 weeks. The 5th percentile for time to virologic failure is the time (in weeks) at which 5% of the participants have experienced virologic failure.	Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Primary	Time From Treatment Dispensation to a Grade 3/4 Safety Event	Grade 3/4 safety event is defined as a grade 3 or 4 sign, symptom, or laboratory abnormality that is at least one grade higher than at baseline, total bilirubin and creatine kinase (CPK) were excluded. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.	All follow-up while on initially assigned regimen; the median (25th, 75th percentile) follow-up while on initial regimen was 120 (54, 156) weeks and the range was 0 to 205 weeks.
Primary	Time From Treatment Dispensation to Treatment Modification	Treatment modification is defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution.	Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Secondary	Time From Treatment Dispensation to Regimen Failure (First Occurrence of Virologic Failure or Treatment Modification)	Blood samples for determining virologic failure were obtained at 16 and 24 weeks, and every 12 weeks thereafter. Virologic failure was defined as a confirmed plasma HIV-1 RNA level >= 1000 copies/mL at or after 16 weeks and before 24 weeks or >=200 copies/mL at or after 24 weeks. Treatment modification was defined as the 1st modification of the regimen, including a permanent discontinuation, switch, or substitution.	Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Secondary	The Number of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL		At Weeks 48 and 96
Secondary	Number of Participants With HIV-1 RNA Levels Less Than 200 Copies/mL		At Weeks 48 and 96
Secondary	Change in CD4 Count (Cells/mm3) From Baseline	Change was calculated as the CD4 count at Week 48 (or at Week 96) minus the baseline CD4 count (mean of pre-entry and entry values).	At Weeks 48 and 96
Secondary	Number of Participants With Virologic Failure and Emergence of Major Resistance	Emergence of resistant virus was assessed by genotypic testing performed at Stanford University for all participants who met criteria for virologic failure and retrospectively on baseline samples from these participants. Major mutations were defined by International AIDS Society-United States of America (2008), as well as T69D, L74I, G190C/E/Q/T/V for reverse transcriptase and L24I, F53L, I54V/A/T/S, G73C/S/T/A, N88D for protease.	Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Secondary	Number of Participants Experiencing Certain Targeted Clinical Events, Including Death, AIDS-defining Illness, and HIV-1 Related Events.	AIDS-defining illnesses were defined per CDC category C definition. HIV-1 related events were defined per CDC category B definition. Events underwent study chair review for classification. See link below for more details.; http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm	Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Secondary	Change in Fasting Total Cholesterol Level From Baseline	Only fasting results are included. The protocol did not require that samples be collected fasting.	At Weeks 48 and 96
Secondary	Change in Fasting High-density Lipoprotein (HDL) Cholesterol Level From Baseline	Only fasting results are included. The protocol did not require that samples be collected fasting.	At Weeks 48 and 96
Secondary	Change in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Level From Baseline	Only fasting results are included. The protocol did not require that samples be collected fasting.	At Weeks 48 and 96
Secondary	Change in Fasting Triglyceride Level From Baseline	Only fasting results are included. The protocol did not require that samples be collected fasting.	At Weeks 48 and 96