Clinical trial NCT00811954: Comparative Study of Three NNRTI-Sparing HAART Regimens
Official title: The ARDENT Study: Atazanavir, Raltegravir, or Darunavir With Emtricitabine/Tenofovir for Naive Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infection
Keywords: Treatment naive
Treatment inexperienced
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Bristol-Myers Squibb
name: Gilead Sciences
name: Merck Sharp & Dohme LLC
name: Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA
First posted: 2008-12-19
Enrollment: 1814
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The U.S. Department of Health and Human Services (HHS) guidelines recommend that HIV infected patients who have never received anti-HIV therapy be treated with a triple drug regimen. The most commonly prescribed and successful regimen contains the medication efavirenz (EFV). However, this regimen may not be an option for everyone, hence alternative regimens are needed.

This study was designed to look at how well different combinations of anti-HIV drugs work to decrease the amount of HIV in the blood (viral load) of and allow immune system recovery in people who have never received anti-HIV therapy. This study also examined drug tolerability and safety for the various drug combinations.

Detailed description: Of the five anti-HIV drug classes, four were recommended as first-line regimens for patients who have never received anti-HIV treatment before (treatment naive): nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), Integrase Inhibitors (INIs) and protease inhibitors (PIs). The U.S. Department of Health and Human Services (HHS) guidelines recommend that treatment-naive HIV infected patients be treated with a triple drug regimen that includes 2 NRTIs + 1 NNRTI, 2 NRTIs + INI, or 2 NRTIs + 1 PI as their initial treatment regimen.

According to data, an efavirenz (EFV)-containing regimen (2 NRTIs + 1 NNRTI, with EFVas the NNRTI) requires fewer pills for the patient, has mild and few side effects, and is more effective in reducing viral load than other regimens, making it the preferred choice for most patients. However, for some patients, an EFV-containing regimen is not feasible due to side effects, acquired NNRTI-resistant HIV virus, or other undesirable effects. For these patients, it is necessary to find alternative regimens with comparable safety and efficacy. This study examined how well different combinations of anti-HIV drugs work, including safety and drug tolerability for various combinations.

This was a phase III, prospective, randomized study. Participants was randomly assigned to one of three different groups (treatment arms)-A, B, or C -each representing a different drug combination regimen, none of which contained an NNRTI.

Arm A: Atazanavir (ATV) + Ritonavir (RTV) + Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)

Arm B: Raltegravir (RAL) + FTC/TDF

Arm C: Darunavir (DRV) + RTV + FTC/TDF

The duration of this study was between 96 and 192 weeks, depending on when the participant enrolled. There were a total of 1,809 participants, approximately 600 per treatment arm. Screening and pre-entry evaluations must occur prior to the participant starting any study medication, treatments, or interventions. Participants were randomly assigned to their treatment groups at the entry visit and must begin treatment within 72 hours of randomization. Participants was told which group they were in and what medications they were administered. The study drugs were distributed at entry. All drugs were provided by the study with the exception of RTV, which would have to be obtained through the participant's primary care physician (Group A or C). If a participant was unable to tolerate any of the study medications during the course of the study then their doctor could switch them to another regimen.

During the study, participants was asked to return to the clinic at Weeks 4, 8, 16, 24, 36, and 48 and then every 16 weeks until the end of the study. They were also contacted by telephone during Week 2 to check on their status. Visits were last about 1 hour. At most visits, participants had a physical exam and answered questions about any medications they were taken. Additionally, participants completed questionnaires addressing their smoking and alcohol habits, had blood drawn, and were asked to give urine samples. At some visits, participants had to come to the clinic without having eaten for 8 hours. If the participant was female and able to become pregnant, a pregnancy test might be given at any visit if pregnancy was suspected.

Some participants of A5257 were asked to participate in an optional metabolic substudy A5260s. This substudy took place at only some study sites and continued last up to 144 weeks, including time on A5257. The primary focus of this substudy was to examine carotid artery intima-media thickness (CIMT) as it relates to both RTV- and RAL-containing regimens. Randomization, stratification, treatment assignments, and study visits were as per A5257.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infected
* No evidence of any exclusionary mutations defined as any major NRTI or PI resistance-associated mutation on any genotype or evidence of significant NRTI or PI resistance on any phenotype performed at any time prior to study entry. NNRTI-associated resistance mutations are not excluded. More information on this criterion can be found in the study protocol.
* No prior anti-HIV therapy. More information on this criterion can be found in the study protocol.
* Viral load is 1000 copies/mL or higher, as measured within 90 days prior to study entry
* Certain laboratory values obtained within 60 days prior to study entry
* Ability to obtain RTV by prescription
* Completed cardiovascular risk assessment. More information on this criterion can be found in the study protocol.
* Must agree to use acceptable forms of contraception while receiving study drugs and for 6 weeks after stopping the medications. More information on this criterion is available in the protocol.
* Negative pregnancy test within 72 hours before initiating antiretroviral medication
* Participating in research at any AIDS Clinical Trial Group (ACTG) clinical research site or select International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group sites
* Ability and willingness of subject or legal guardian/representative to give written informed consent

Exclusion Criteria:

* Use of immunomodulators, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Those using stable physiologic glucocorticoid doses, a short course of pharmacologic glucocorticoid, corticosteroids for acute therapy treating an opportunistic infection, inhaled or topical corticosteroids, or granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) will not be excluded.
* Known allergy or sensitivity to study drugs or their ingredients. A history of sulfa allergy is not excluded.
* Any condition that, in the opinion of the investigator, would compromise the participant's ability to participate in the study
* Serious illness requiring systemic treatment and/or hospitalization until participant either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 7 days prior to study entry
* Requirement for any current medications that are prohibited with any study drugs
* Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness
* Any prior use of entecavir for treatment of hepatitis B for greater than 8 weeks while the participant was known to be HIV infected
* Presence of decompensated cirrhosis
* Pregnant or breastfeeding

Primary outcomes:
measure: Cumulative Probability of First Virologic Failure by Week 96
timeFrame: From study entry to week 96
measure: Cumulative Incidence of Discontinuation of the RAL or PI Component of Randomized Treatment for Toxicity by Week 96
timeFrame: From study entry to week 96
Secondary outcomes:
measure: Cumulative Incidence of First Adverse Event by Week 96
timeFrame: From study entry to week 96
measure: Cumulative Probability of Time to Loss of Virologic Response (TLOVR) by Week 96
timeFrame: From study entry to week 96
measure: Presence of Mutations Associated With NRTI Resistance
timeFrame: At the virologic failure at any time throughout the study (up to 213 weeks)
measure: Presence of Mutations Associated With ATV/RTV or DRV/RTV Resistance
timeFrame: At the virologic failure at any time throughout the study (up to 213 weeks)
measure: Presence of Mutations Associated With INI Resistance
timeFrame: At the virologic failure at any time throughout the study (up to 213 weeks)
measure: CD4+ T-cell Count
timeFrame: At Weeks 24, 48, 96, and 144
measure: CD4+ T-cell Count Changes From Baseline
timeFrame: Study entry to weeks 24, 48, 96, and 144
measure: Incidence of Death or AIDS Defining Events (CDC Category C)
timeFrame: Study entry to off-study at any time throughout the study (up to 213 weeks), participant follow-up time was variable
measure: Incidence of Targeted Serious Non-AIDS Defining Events (Renal Failure, Liver Disease, Serious Metabolic Disorder, and CVD)
timeFrame: Study entry to off-study at any time throughout the study (up to 213 weeks), participant follow-up time was variable
measure: Change in Fasting Total Cholesterol Level From Baseline
timeFrame: Study entry to weeks 48, 96, and 144
measure: Change in Fasting HDL Cholesterol Level From Baseline
timeFrame: Study entry to weeks 48, 96, and 144
measure: Change in Fasting Triglycerides Level From Baseline
timeFrame: Study entry to weeks 48, 96, and 144
measure: Change in Fasting Plasma Glucose Level From Baseline
timeFrame: Study entry to weeks 48, 96, and 144
measure: Change in Framingham 10-year Risk of MI or Coronary Death From Baseline
timeFrame: Study entry to weeks 48, 96, and 144
measure: Change in Waist Circumference From Baseline
timeFrame: Study entry to weeks 48, 96, and 144
measure: Change in Waist:Height Ratio From Baseline
timeFrame: Study entry to weeks 48, 96, and 144
measure: Self-reported Adherence
timeFrame: At Weeks 4, 24, 48, 96, and 144
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Long Beach
country: United States
facility: Miller Children's Hospital
state: California
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: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids 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: Denver
country: United States
facility: Denver Public Health CRS
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS)
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Ft. Lauderdale
country: United States
facility: South Florida Childrens Diagnostic & Treatment Cen (5055)
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Jacksonville (5051)
state: Florida
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS
state: Georgia
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: New Orleans
country: United States
facility: Tulane University New Orleans NICHD CRS (5095)
state: Louisiana
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 CRS
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. 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: Detroit
country: United States
facility: Wayne State Univ. CRS
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hosp. CRS
state: Michigan
city: St. Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Camden
country: United States
facility: Cooper Univ. Hosp. CRS
state: New Jersey
city: Newark
country: United States
facility: New Jersey Medical School- Adult Clinical Research Ctr. CRS
state: New Jersey
city: Bronx
country: United States
facility: Bronx-Lebanon Hosp. Ctr. CRS
state: New York
city: New York
country: United States
facility: Cornell CRS
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: Metropolitan Hospital
state: New York
city: New York
country: United States
facility: HIV Prevention & Treatment CRS
state: New York
city: Rochester
country: United States
facility: AIDS Care CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook NICHD CRS (5040)
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: Greensboro
country: United States
facility: Regional Center for Infectious Disease, Wendover Medical Center CRS (3203)
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: Metro Health CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Portland
country: United States
facility: The Research & Education Group- Portland CRS (31474)
state: Oregon
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: The Miriam Hosp. ACTG CRS
state: Rhode Island
city: Memphis
country: United States
facility: St. Jude/UTHSC CRS
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Dallas
country: United States
facility: Trinity Health and Wellness Center
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth Univ. Medical Ctr. CRS
state: Virginia
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Rio Piedras
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS
Study officials:
affiliation: Emory HIV/AIDS CTU
name: Jeffrey L. Lennox, MD
role: STUDY_CHAIR
affiliation: UCLA AIDS Prevention & Treatment CTU
name: Judith Silverstein Currier, MD, MSc
role: STUDY_CHAIR
affiliation: UCLA AIDS Prevention & Treatment CTU
name: Raphael Landovitz, MD, MSc
role: STUDY_CHAIR
affiliation: Emory HIV/AIDS CTU
name: Igho Ofotokun, MD
role: STUDY_CHAIR
References:
citation: Bartlett JA, Chen SS, Quinn JB. Comparative efficacy of nucleoside/nucleotide reverse transcriptase inhibitors in combination with efavirenz: results of a systematic overview. HIV Clin Trials. 2007 Jul-Aug;8(4):221-6. doi: 10.1310/hct0804-221.
citation: Duvivier C, Ghosn J, Assoumou L, Soulie C, Peytavin G, Calvez V, Genin MA, Molina JM, Bouchaud O, Katlama C, Costagliola D; ANRS 121 study group. Initial therapy with nucleoside reverse transcriptase inhibitor-containing regimens is more effective than with regimens that spare them with no difference in short-term fat distribution: Hippocampe-ANRS 121 Trial. J Antimicrob Chemother. 2008 Oct;62(4):797-808. doi: 10.1093/jac/dkn278. Epub 2008 Jul 18.
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citation: Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55. doi: 10.1016/S0140-6736(08)61081-8.
citation: Hughey CM, Vuong BW, Ribaudo HB, Mitchell CCK, Korcarz CE, Hodis HN, Currier JS, Stein JH. Grayscale Ultrasound Texture Features of Carotid and Brachial Arteries in People With HIV Infection Before and After Antiretroviral Therapy. J Am Heart Assoc. 2022 Mar;11(5):e024142. doi: 10.1161/JAHA.121.024142. Epub 2022 Feb 18.
citation: Li B, Veturi Y, Verma A, Bradford Y, Daar ES, Gulick RM, Riddler SA, Robbins GK, Lennox JL, Haas DW, Ritchie MD. Tissue specificity-aware TWAS (TSA-TWAS) framework identifies novel associations with metabolic, immunologic, and virologic traits in HIV-positive adults. PLoS Genet. 2021 Apr 26;17(4):e1009464. doi: 10.1371/journal.pgen.1009464. eCollection 2021 Apr.
citation: Bares SH, Smeaton LM, Scott SE, Smith BA, Godfrey C, McComsey GA. The Association Between Weight Gain, Sex, and Immune Activation Following the Initiation of Antiretroviral Therapy. J Infect Dis. 2021 Nov 22;224(10):1765-1774. doi: 10.1093/infdis/jiab210.
citation: McComsey GA, Moser C, Currier J, Ribaudo HJ, Paczuski P, Dube MP, Kelesidis T, Rothenberg J, Stein JH, Brown TT. Body Composition Changes After Initiation of Raltegravir or Protease Inhibitors: ACTG A5260s. Clin Infect Dis. 2016 Apr 1;62(7):853-62. doi: 10.1093/cid/ciw017. Epub 2016 Jan 20.
citation: Kelesidis T, Tran TT, Stein JH, Brown TT, Moser C, Ribaudo HJ, Dube MP, Murphy R, Yang OO, Currier JS, McComsey GA. Changes in Inflammation and Immune Activation With Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy: ACTG 5260s. Clin Infect Dis. 2015 Aug 15;61(4):651-60. doi: 10.1093/cid/civ327. Epub 2015 Apr 22.
citation: Ofotokun I, Na LH, Landovitz RJ, Ribaudo HJ, McComsey GA, Godfrey C, Aweeka F, Cohn SE, Sagar M, Kuritzkes DR, Brown TT, Patterson KB, Para MF, Leavitt RY, Villasis-Keever A, Baugh BP, Lennox JL, Currier JS; AIDS Clinical Trials Group (ACTG) A5257 Team. Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis. 2015 Jun 15;60(12):1842-51. doi: 10.1093/cid/civ193. Epub 2015 Mar 12.
citation: Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, Kuritzkes DR, Sagar M, Brown TT, Cohn SE, McComsey GA, Aweeka F, Fichtenbaum CJ, Presti RM, Koletar SL, Haas DW, Patterson KB, Benson CA, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS; ACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014 Oct 7;161(7):461-71. doi: 10.7326/M14-1084.