Clinical trial NCT00537394: Optimizing Treatment for Treatment-Experienced, HIV-Infected People
Official title: The Optimized Treatment That Includes or Omits NRTIs Trial: A Randomized Strategy Study for HIV-1-Infected Treatment-Experienced Subjects Using the cPSS to Select an Effective Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
First posted: 2007-10-01
Enrollment: 517
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of anti-HIV therapy is to prevent HIV from replicating. Long-term control of HIV requires at least two anti-HIV drugs that are active against the virus. Drug resistance is a problem for many treatment-experienced, HIV-infected people. The purpose of this study was to determine the benefit of adding a nucleoside reverse transcriptase inhibitor (NRTI) to a new anti-HIV drug regimen for the suppression of HIV.

Detailed description: Two or more fully active antiretrovirals (ARVs) are recommended for successful suppression of HIV. In people infected with resistant HIV virus, finding two drugs that are fully active against HIV can be a challenge. However, the new generation of anti-HIV drugs has been designed to suppress drug-resistant HIV. These drugs include the FDA-approved protease inhibitors (PIs) darunavir and tipranavir, the investigational non-nucleoside transcriptase inhibitor (nNRTI) etravirine, the FDA-approved fusion inhibitor enfuvirtide, the recently FDA-approved CCR5 inhibitor maraviroc, and the investigational integrase inhibitor raltegravir. Also, it is not yet known whether multiple, partially-active drugs have the same rate of success in suppressing HIV. The purpose of this study was to use HIV resistance testing to predict the potency of a suggested ARV regimen using second generation ARVs and determine if the benefits of adding NRTIs to this new drug regimen outweigh the risks of drug toxicity and pill burden. All participants had treatment experience or resistance to NRTIs, nNRTIs, and PIs, and received novel agents.

An active screening period (after enrollment but before randomization or treatment dispensation), occurred for up to 75 days for all participants, and study participation lasted an additional 96 weeks for those who qualified for either randomization or assignment (i.e. not randomized), to the study intervention. During active screening, all participants remained on their current drug regimen. During screening, phenotypic and genotypic HIV resistance tests were performed on participants' blood samples, as well as a coreceptor tropism assay. Using this information and medication history, the study team determined the best new regimen options for each participant. Each clinician, along with the study participant, then chose a new regimen based on the recommendations of the study team and the participant's preference.

Evaluation for study outcomes began when participants started their new regimen as assigned by either randomization or determined assignment. Stratification between Arms A (Add NRTIs) and B (Omit NRTIs) or Arm C (Non-randomized to Add NRTIs) was based on predicted activity of the new regimen. Those assigned to a regimen with higher predicted activity were randomly assigned to Arm A (Add NRTIs) or B (Omit NRTIs); those assigned a regimen predicted to have lower activity were not randomized, but were assigned to Arm C (Add NRTIs).

Participants in Arms A and C were instructed to take their newly assigned study regimen plus at least 2 NRTIs (personalized from expert recommendation and choice by local provider and participant) for 96 weeks. Participants in Arm B were instructed to take their newly assigned study regimen with no NRTIs for 96 weeks. Participants in all arms who met the primary efficacy outcome of regimen failure remained in the study in order to be followed for important secondary outcomes.

All participants were scheduled to have 13 clinical visits, which included blood collection. At some visits, urine collection and quality of life and adherence questionnaires occurred. A neurocognitive assessment was performed for all participants at time of starting the new study regimen. Participants may also have consented to have cerebrospinal fluid collected via lumbar puncture following study treatment assignment and/or at Week 24. Those participants who consented to cerebrospinal fluid collection also had neurocognitive assessments at the times of collections. Participants were responsible for obtaining certain ARVs not provided by the study, including the ARVs they during the active screening period.

The primary and secondary study objectives and comparisons relate to the randomized arms, and therefore, results are not provided for the non-randomized arm (C). The purpose of the non-randomized arm (C) was to include persons higher baseline resistance (and thus, lower activity scores) in order to address an exploratory objective related to the predictive power of these activity scores (and thus a larger range of scores by inclusion of arm C), on certain, virologic outcomes.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection
* Triple-class drug experience or resistance. More information on this criterion can be found in the protocol.
* Currently on a failing PI-containing regimen that includes 2 other ARVs with no regimen change for 8 weeks prior to study screening
* HIV viral load of 1000 copies/ml or more
* Hepatitis B surface antigen negative within 90 days of study entry
* Able to obtain NRTIs and ritonavir and have required ARVs at time of starting study intervention
* Willing to use acceptable forms of contraception
* Parent or legal guardian willing to provide consent, if applicable
* CD4 count result from a specimen drawn within 120 days prior to study entry
* If any previous HIV-1 viral co-receptor tropism result is available, then most recent specimen date and the tropism result of that specimen AND specimen date and tropism result of any test with either X4 or D/M result, if different from the first specimen, must be available

Inclusion Criteria continued:

* Receipt of successful phenotype/genotype resistance results within 105 days prior to study treatment intervention assignment
* Study team identification of a study regimen and at least 2 NRTIs for participant to take
* Certain abnormal laboratory values. More information on this criterion can be found in the protocol.

Exclusion Criteria:

* Chronic, active hepatitis B virus infection (hepatitis B surface antigen positive or HBV DNA positive)
* Taking certain medications. More information on this criterion can be found in the protocol.
* Known allergy/sensitivity to components of two or more of the study-provided drugs or their formulations. For maraviroc, this includes hypersensitivity or history of allergy to soy lecithin or peanuts.
* Active drug or alcohol use that, in the opinion of the investigator, may interfere with the study
* Pregnancy or breastfeeding
* Use of any immunomodulator (interferons, interleukins, systemic corticosteroids, or cyclosporine), vaccine, or investigational therapy within 30 days prior to study treatment allocation/assignment
* Require certain medications prohibited with study treatment
* Serious illness requiring systemic treatment or hospitalization. Participants who complete therapy or are clinically stable on therapy for at least 14 days prior to study treatment allocation are not excluded.

Primary outcomes:
measure: Percent of Participants With Regimen Failure, Defined as a Confirmed Virologic Failure or Discontinuation of Randomized NRTI Component of Study Treatment
timeFrame: From study entry to end of Week 48 evaluation window
Secondary outcomes:
measure: Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality
timeFrame: From treatment dispensation to week 96 study visit
measure: Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable)
timeFrame: From treatment dispensation to week 96 study visit
measure: Time From Randomization to Discontinuation of Randomized NRTI Component of Study Treatment
timeFrame: From randomization to week 96 study visit
measure: Time From Randomization to Confirmed Virological Failure
timeFrame: From randomization to week 96 study visit
measure: Number of Participants With Plasma HIV-1 Viral Load < 50 Copies/ml
timeFrame: At Weeks 24, 48, 96
measure: Change in Plasma HIV-1 Viral Load From Baseline to Week 1
timeFrame: From baseline to Week 1 evaluation
measure: Change in Summarized Quality of Life Score
timeFrame: At study entry and Weeks 24, 48, 96
measure: Number of Participants Self-reporting Non-adherence to Assigned Study ARVS (Excluding NRTIs, if Applicable)
timeFrame: At Weeks 24 and 48
measure: Change in Cardiovascular Risk Score From Baseline
timeFrame: At Weeks 24, 48, and 96
measure: Change in CD4 Count From Baseline
timeFrame: From study entry to Weeks 48 and 96
measure: Time From Treatment Dispensation to Serious Non-AIDS-defining Events
timeFrame: From treatment initiation to week 96 study visit
measure: Number of Participants With Change in Virus Co-receptor Tropism Among Those With R5-only Tropic Virus at Study Entry
timeFrame: From study entry to time of confirmed virological failure (up to 96 weeks)
measure: Change in Fasting Non-HDL Cholesterol From Baseline
timeFrame: From study entry to Weeks 24, 48
measure: Participants With Newly Acquired HIV Drug Resistance Between Study Entry and Confirmed Virologic Failure
timeFrame: Between baseline and confirmed virologic failure (up to 96 weeks)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS
state: California
city: Los Angeles
country: United States
facility: University of Southern California CRS
state: California
city: Los Angeles
country: United States
facility: Usc La Nichd Crs
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Los Angeles
country: United States
facility: UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
state: California
city: Palo Alto
country: United States
facility: Stanford AIDS Clinical Trials Unit CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: San Francisco
country: United States
facility: Univ. of California San Francisco NICHD 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: Children's National Med. Ctr. ATN CRS
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Miami
country: United States
facility: Pediatric Perinatal HIV Clinical Trials Unit 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 University CRS
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ. New Orleans NICHD CRS
state: Louisiana
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital CRS (MGH CRS)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD 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: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) 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 Clinical Research Center CRS
state: New Jersey
city: Newark
country: United States
facility: Rutgers - New Jersey Medical School 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: Weill Cornell Chelsea 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: Nyu Ny Nichd Crs
state: New York
city: New York
country: United States
facility: Metropolitan Hosp. NICHD CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: New York
country: United States
facility: Columbia IMPAACT CRS
state: New York
city: New York
country: United States
facility: Harlem ACTG CRS
state: New York
city: Rochester
country: United States
facility: Trillium Health ACTG CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case Clinical Research Site
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Columbus
country: United States
facility: Ohio State University CRS
state: Ohio
city: Portland
country: United States
facility: The Research & Education Group-Portland CRS
state: Oregon
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ. Med. Ctr. CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital Clinical Research Site (TMH CRS) CRS
state: Rhode Island
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital CRS
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Dallas
country: United States
facility: Trinity Health and Wellness Center CRS
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital 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: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico Pediatric HIV/AIDS Research Program CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
Study officials:
affiliation: Brown University
name: Karen T. Tashima, MD
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, UCSD Antiviral Research Center
name: Richard H. Haubrich, MD
role: STUDY_CHAIR
References:
citation: Altmann A, Beerenwinkel N, Sing T, Savenkov I, Doumer M, Kaiser R, Rhee SY, Fessel WJ, Shafer RW, Lengauer T. Improved prediction of response to antiretroviral combination therapy using the genetic barrier to drug resistance. Antivir Ther. 2007;12(2):169-78. doi: 10.1177/135965350701200202.
citation: Eshleman SH, Husnik M, Hudelson S, Donnell D, Huang Y, Huang W, Hart S, Jackson B, Coates T, Chesney M, Koblin B. Antiretroviral drug resistance, HIV-1 tropism, and HIV-1 subtype among men who have sex with men with recent HIV-1 infection. AIDS. 2007 May 31;21(9):1165-74. doi: 10.1097/QAD.0b013e32810fd72e.
citation: Geretti AM. Clinical implications of HIV drug resistance to nucleoside and nucleotide reverse transcriptase inhibitors. AIDS Rev. 2006 Oct-Dec;8(4):210-20.
citation: Mallolas J, Blanco J, Labarga P, Vergara A, Ocampo A, Sarasa M, Arnedo M, Lopez-Pua Y, Garcia J, Juega J, Guelar A, Terron A, Dalmau D, Garcia I, Zarraga M, Martinez E, Carne X, Pumarola T, Escayola R, Gatell J. Inhibitory quotient as a prognostic factor of response to a salvage antiretroviral therapy containing ritonavir-boosted saquinavir. The CIVSA Study. HIV Med. 2007 May;8(4):226-33. doi: 10.1111/j.1468-1293.2007.00464.x.
citation: Gandhi RT, Tashima KT, Smeaton LM, Vu V, Ritz J, Andrade A, Eron JJ, Hogg E, Fichtenbaum CJ. Long-term Outcomes in a Large Randomized Trial of HIV-1 Salvage Therapy: 96-Week Results of AIDS Clinical Trials Group A5241 (OPTIONS). J Infect Dis. 2020 Apr 7;221(9):1407-1415. doi: 10.1093/infdis/jiz281.
citation: Tashima KT, Smeaton LM, Fichtenbaum CJ, Andrade A, Eron JJ, Gandhi RT, Johnson VA, Klingman KL, Ritz J, Hodder S, Santana JL, Wilkin T, Haubrich RH; A5241 Study Team. HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial. Ann Intern Med. 2015 Dec 15;163(12):908-17. doi: 10.7326/M15-0949. Epub 2015 Nov 24.