Optimizing Treatment for Treatment-Experienced, HIV-infected People - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator:	Adult AIDS Clinical Trials Group
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00537394

Purpose

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 is to determine the benefit of adding a nucleoside reverse transcriptase inhibitor (NRTI) to a new anti-HIV drug regimen for the suppression of HIV.

Condition	Intervention	Phase
HIV Infections	Drug: Enfuvirtide Drug: Raltegravir Drug: Darunavir Drug: Tipranavir Drug: Etravirine Drug: Maraviroc	Phase III

Study Type:	Interventional
Study Design:	Treatment, Open Label, Active Control, Parallel Assignment, Efficacy Study
Official Title:	The Optimized Treatment That Includes or Omit NRTIs Trial: A Randomized Strategy Study for HIV-1-Infected Treatment-Experienced Subjects Using the cPSS to Select an Effective Regimen

Resource links provided by NLM:

MedlinePlus related topics: AIDS

Drug Information available for: Enfuvirtide Tipranavir Darunavir Etravirine Maraviroc Raltegravir Darunavir ethanolate

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Time to regimen failure [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Toxicity, as defined as time to first Grade 3 or higher (and one grade higher than baseline) signs/symptom or laboratory abnormality [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Tolerability, as defined as time to first dose modification, time to permanent discontinuation of all study drugs [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Time to abandoning randomized NRTI strategy [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Time to virological failure, as defined by the protocol [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Binary variable indication if viral load is less than 50 copies/ml [ Time Frame: At Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
Change in viral load [ Time Frame: From study entry to Week 1 ] [ Designated as safety issue: No ]
Binary variable indicating acquisition of drug resistance mutations to any of the study agents [ Time Frame: At time of virologic failure ] [ Designated as safety issue: No ]
Change in summarized quality of life score [ Time Frame: At study entry and Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
Binomial indicator of "perfect" adherence to assigned ARVs [ Time Frame: At Weeks 24 and 48 ] [ Designated as safety issue: No ]
Change in cardiovascular risk score and fasting lipid values [ Time Frame: At Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
Change in CD4 count [ Time Frame: From study entry to Week 96 ] [ Designated as safety issue: No ]
Time to serious non-AIDS events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Change in virus coreceptor tropism among those with R5-only tropic virus in Step 1 [ Time Frame: From study entry to time of virological failure and Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
HIV-1 co-receptor tropism [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Binary indicator of undetectable CSF HIV-1 RNA [ Time Frame: At or after Week 24 ] [ Designated as safety issue: No ]
Summarized continuous neuro-cognitive performance Z-scores [ Time Frame: Through Week 96 ] [ Designated as safety issue: No ]
Binary variable indicating whether CSF ARV drug concentrations are above the population median [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
CPE score (CNS penetration effectiveness) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Estimated Enrollment:	577
Study Start Date:	January 2008
Estimated Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Experimental Regimen with higher predicted activity assigned by the study plus at least 2 NRTIs assigned by the study for 96 weeks. A 3-4 drug regimen will be selected from the drugs listed to the right.	Drug: Enfuvirtide One tablet twice daily Drug: Raltegravir 400 mg twice daily Drug: Darunavir Two 300-mg tablets twice daily Drug: Tipranavir Two 250-mg capsules twice daily Drug: Etravirine Two 100-mg tablets twice daily Drug: Maraviroc Dosage dependent on regimen in which maraviroc is included
B: Experimental Regimen with higher predicted activity assigned by the study without NRTIs for 96 weeks. A 3-4 drug regimen will be selected from the drugs listed to the right.	Drug: Enfuvirtide One tablet twice daily Drug: Raltegravir 400 mg twice daily Drug: Darunavir Two 300-mg tablets twice daily Drug: Tipranavir Two 250-mg capsules twice daily Drug: Etravirine Two 100-mg tablets twice daily Drug: Maraviroc Dosage dependent on regimen in which maraviroc is included
C: Active Comparator Regimen with higher predicted activity assigned plus at least 2 NRTIs by the study for 96 weeks. A 3-4 drug regimen will be selected from the drugs listed to the right.	Drug: Enfuvirtide One tablet twice daily Drug: Raltegravir 400 mg twice daily Drug: Darunavir Two 300-mg tablets twice daily Drug: Tipranavir Two 250-mg capsules twice daily Drug: Etravirine Two 100-mg tablets twice daily Drug: Maraviroc Dosage dependent on regimen in which maraviroc is included

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 is 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 will have treatment experience or resistance to NRTIs, nNRTIs, and PIs, and who are receiving novel agents.

This study will have 2 steps and 3 arms. It will last for at least 75 days for all participants and will last an additional 96 weeks for those who continue to Step 2. In Step 1, all participants will remain on their current drug regimen. During this time, phenotypic and genotypic HIV resistance tests will be performed on participants' blood samples, as well as a coreceptor tropism assay. Using this information and medication history, the study team will determine the best new regimen options for each participant. Each clinician, along with the study participant, will then chose a new regimen based on the recommendations of the study team and the participant's preference.

Step 2 will begin when participants begin their new regimen. Stratification between Arms A and B or Arm C will be based on predicted activity of the new regimen. Those assigned to a regimen with higher predicted activity will be randomly assigned to Arm A or B; those assigned a regimen predicted to have lower activity will be assigned to Arm C.

Participants in Arms A and C will take their new assigned study regimen plus at least 2 NRTIs for 96 weeks. Participants in Arm B will take their new assigned study regimen with no NRTIs for 96 weeks. Participants in Arms A and B who reach virologic failure before 96 weeks will discontinue the study. Participants in Arm C who reach virologic failure before 96 weeks will remain in the study.

All participants will have 11 clinical visits. At each visit, blood collection will occur. At some visits, urine collection and quality of life and adherence questionnaires will occur. A neurocognitive assessment will occur for all participants who enter Step 2. Participants may also consent to have cerebrospinal fluid collected via lumbar puncture upon entering Step 2 and/or at Week 24. Those participants who consent to cerebrospinal fluid collection will also have neurocognitive assessments at the times of collections. Participants will be responsible for obtaining certain ARVs not provided by the study, including the ARVs they take in Step 1 and depending on which arm of Step 2 they are in.

Eligibility

Ages Eligible for Study:	16 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria for Step 1:

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 entry to Step 2
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 for Step 2:

Receipt of successful phenotype/genotype resistance results within 105 days prior to entry into Step 2
Study team identification of a study regimen and at least 2 NRTIs for participant to take in Step 2
Currently on the same failing PI-containing regimen for the entire duration of Step 1 that includes at least 2 other ARVs besides the PI
Certain abnormal laboratory values. More information on this criterion can be found in the protocol.
Willing to use accepted forms of contraception

Exclusion Criteria for Step 1:

Chronic, active hepatitis B virus infection (hepatitis B surface antigen positive or HBV DNA positive)
Prior use of any integrase inhibitor
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

Exclusion Criteria for Step 2:

Has participated for 76 days or more in Step 1
Use of any immunomodulator (interferons, interleukins, systemic corticosteroids, or cyclosporine), vaccine, or investigational therapy within 30 days of entry to Step 2
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 Step 2 entry are not excluded.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00537394

Show 27 Study Locations

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Adult AIDS Clinical Trials Group

Investigators

Study Chair:	Karen T. Tashima, MD	Brown University
Study Chair:	Richard H. Haubrich, MD	Division of Infectious Diseases, UCSD Antiviral Research Center

More Information

Additional Information:

Click here for more information on Darunavir This link exits the ClinicalTrials.gov site

Click here for more information about enfuvirtide This link exits the ClinicalTrials.gov site

Click here for more information about etravirine This link exits the ClinicalTrials.gov site

Click here for more information about maraviroc This link exits the ClinicalTrials.gov site

Click here for more information about raltegravir This link exits the ClinicalTrials.gov site

Click here for more information about tipranavir This link exits the ClinicalTrials.gov site

Haga clic aquí para ver información sobre este ensayo clínico en español. This link exits the ClinicalTrials.gov site

Publications:

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.

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.

Geretti AM. Clinical implications of HIV drug resistance to nucleoside and nucleotide reverse transcriptase inhibitors. AIDS Rev. 2006 Oct-Dec;8(4):210-20. Review.

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.

Responsible Party:	DAIDS ( Rona Siskind )
Study ID Numbers:	ACTG A5241, OPTIONS
Study First Received:	September 27, 2007
Last Updated:	September 23, 2009
ClinicalTrials.gov Identifier:	NCT00537394 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Treatment Experienced

Additional relevant MeSH terms:

Anti-Infective Agents
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Molecular Mechanisms of Pharmacological Action
Infection
Darunavir
Tipranavir
Anti-Retroviral Agents
Therapeutic Uses
Retroviridae Infections
RNA Virus Infections
HIV Protease Inhibitors
Anti-HIV Agents

Immune System Diseases
Acquired Immunodeficiency Syndrome
Enzyme Inhibitors
Antiviral Agents
Enfuvirtide
Immunologic Deficiency Syndromes
Pharmacologic Actions
Protease Inhibitors
Virus Diseases
HIV Infections
Sexually Transmitted Diseases
Lentivirus Infections
HIV Fusion Inhibitors

ClinicalTrials.gov processed this record on November 05, 2009