Clinical trial NCT00011128: Salvage Treatment, Resistance Testing, and Withdrawal of Anti-HIV Drugs for HIV Patients Failing Current Anti-HIV Treatment
Official title: Phase III Evaluation of the Role of Temporary Cessation of Antiretroviral Treatment and Resistance Testing-Based Selection of Antiretroviral Drugs in the Virologic Response to Salvage Therapy for Heavily Treatment-Experienced HIV-Infected Individuals Failing Current Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: HIV Infections
Keywords: HIV-1
Drug Resistance, Microbial
Microbial Sensitivity Tests
Salvage Therapy
Anti-HIV Agents
Viral Load
Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 0
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 purpose of this study is to test another way to control the amount of HIV in the blood (viral load).

Studies show that stopping all anti-HIV drugs for a time before switching to new anti-HIV drugs may improve the response in some individuals who are failing treatment. Other studies suggest a benefit if drug-resistance tests are used in selecting a new anti-HIV drug treatment. This study tests the effect of stopping anti-HIV drugs for a time before switching to anti-HIV drugs selected using drug-resistance test results.

Detailed description: Virologic failure occurs in a large proportion of individuals receiving treatment with combination antiretroviral therapy. Studies suggest that treatment interruption prior to initiation of a multiple-drug rescue regimen may improve virologic response in individuals who have failed several prior antiretroviral regimens. Other studies suggest there is a virologic benefit derived from using genotypic or phenotypic resistance testing in selecting salvage therapy regimens for patients failing antiretroviral therapy. This study tests the hypothesis that salvage regimens selected on the basis of HIV-1 resistance genotype, phenotype \[AS PER AMENDMENT 02/19/02: virtual phenotype\], and treatment history will be more effective if there is a period of treatment interruption before initiating that regimen.

Patients continue their antiretroviral therapy until randomization. Based on the results of the pre-entry genotype and phenotype \[AS PER AMENDMENT 02/19/02: virtual phenotype\] tests and treatment history, an individualized salvage therapy regimen (not provided by the study) is selected by the site investigator(s). Additionally, patients start or continue maintenance therapy (not provided by the study) for opportunistic infections (OIs). Patients are randomized to 1 of 2 treatment arms. In Arm A, patients have antiretroviral treatment interruption for a period of 16 weeks (Step 1), followed by initiation of the \[AS PER AMENDMENT 02/19/02: best available\] salvage therapy regimen (Step 2). \[AS PER AMENDMENT 02/19/02: Patients in Arm A will be placed immediately on their individualized salvage regimen before the end of the 16-week period of treatment interruption if their CD4 count falls below a defined threshold, or if they develop a new OI\]. In Arm B, patients switch immediately to the salvage therapy regimen. \[AS PER AMENDMENT 02/15/01: Patients who become pregnant during Step 1 of Arm A must be advised to begin their selected, individualized salvage therapy regimen or a modified salvage regimen. Patients who become pregnant during Step 2 of Arm A or Arm B have therapy evaluated and undergo any changes required by their pregnancy.\] Patients in both arms are monitored for plasma HIV-1 RNA levels, CD4+ and CD8+ cell counts, and HIV drug resistance genotypes and phenotypes for a duration of 64 weeks from randomization. Patients in Arm A are also monitored for immune reactivation by measurement of T-cell subsets and plasma cytokines during treatment interruption. Patients may participate in a virology substudy (A5100s) and an immunology substudy (A5104s). \[AS PER AMENDMENT 02/19/02: Patients who volunteer to participate in the substudies must be registered to the main study at the same time they are registered to a substudy.\]

Eligibility criteria: Inclusion Criteria

Patients may be eligible for this study if they:

* Are HIV-infected.
* Are likely to have drug-resistant HIV from having taken all types of anti-HIV drugs (protease inhibitors \[PIs\], nucleoside reverse transcriptase inhibitors \[NRTIs\], and nonnucleoside reverse transcriptase inhibitors \[NNRTIs\]), and having failed treatment prior to the current treatment for reasons other than toxicity.
* Are currently receiving anti-HIV treatment with at least 3 drugs. Low doses of ritonavir (100 to 200 mg twice daily) taken with 1 other PI is counted as a single PI.
* Are currently failing treatment due to a high viral load (amount of HIV in the blood).
* Have had a new anti-HIV drug combination selected.
* Are at least 18 years old.
* This study has been changed to remove CD4 counts as an inclusion criterion. In the previous version of the protocol, patients were required to have a CD4 count of 150 cells/ml or more within 42 days prior to study entry.

Exclusion Criteria

Patients will not be eligible for this study if they:

* Have stopped treatment for more than 4 weeks in the past 6 months.
* Are pregnant or breast-feeding.
* Have cancer that requires systemic treatment or radiation.
* Have received the following medications affecting the immune system within 14 days before entry: erythropoietin; Granulocyte Colony Stimulating Factor (G-CSF), including Granulocyte Macrophage Colony Stimulating Factors (GM-CSF); interleukins; or therapeutic HIV vaccines.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Ctr
state: California
city: Menlo Park
country: United States
facility: Willow Clinic
state: California
city: San Diego
country: United States
facility: Univ of California, San Diego
state: California
city: Stanford
country: United States
facility: San Mateo AIDS Program / Stanford Univ
state: California
city: Stanford
country: United States
facility: Stanford Univ Med Ctr
state: California
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Honolulu
country: United States
facility: Univ of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Rush Presbyterian - Saint Luke's Med Ctr
state: Illinois
city: Chicago
country: United States
facility: The CORE Ctr
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp of Indiana / Life Care Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Wishard Hosp
state: Indiana
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Buffalo
country: United States
facility: SUNY / Erie County Med Ctr at Buffalo
state: New York
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Cornell Clinical Trials Unit - Chelsea Clinic
state: New York
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Cornell Univ Med Ctr
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Med Ctr
state: New York
city: Rochester
country: United States
facility: Community Health Network Inc
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Philadelphia
country: United States
facility: Univ of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Univ Med Ctr
state: Tennessee
city: Dallas
country: United States
facility: Children's Med Ctr of Dallas
state: Texas
city: San Juan
country: Puerto Rico
facility: Univ of Puerto Rico
Study officials:
affiliation: University of Colorado, Denver
name: Constance A Benson, MD
role: STUDY_CHAIR
affiliation: University of Pittsburgh
name: John Mellors, MD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Diane Havlir, MD
role: STUDY_CHAIR
References:
citation: Montaner JS, Harrigan PR, Jahnke N, Raboud J, Castillo E, Hogg RS, Yip B, Harris M, Montessori V, O'Shaughnessy MV. Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens. AIDS. 2001 Jan 5;15(1):61-9. doi: 10.1097/00002030-200101050-00010.
citation: Lorenzi P, Opravil M, Hirschel B, Chave JP, Furrer HJ, Sax H, Perneger TV, Perrin L, Kaiser L, Yerly S. Impact of drug resistance mutations on virologic response to salvage therapy. Swiss HIV Cohort Study. AIDS. 1999 Feb 4;13(2):F17-21. doi: 10.1097/00002030-199902040-00001.
citation: Hance AJ, Lemiale V, Izopet J, Lecossier D, Joly V, Massip P, Mammano F, Descamps D, Brun-Vezinet F, Clavel F. Changes in human immunodeficiency virus type 1 populations after treatment interruption in patients failing antiretroviral therapy. J Virol. 2001 Jul;75(14):6410-7. doi: 10.1128/JVI.75.14.6410-6417.2001.
citation: Clevenbergh P, Durant J, Halfon P, del Giudice P, Mondain V, Montagne N, Schapiro JM, Boucher CA, Dellamonica P. Persisting long-term benefit of genotype-guided treatment for HIV-infected patients failing HAART. The Viradapt Study: week 48 follow-up. Antivir Ther. 2000 Mar;5(1):65-70.
citation: Delaugerre C, Valantin MA, Mouroux M, Bonmarchand M, Carcelain G, Duvivier C, Tubiana R, Simon A, Bricaire F, Agut H, Autran B, Katlama C, Calvez V. Re-occurrence of HIV-1 drug mutations after treatment re-initiation following interruption in patients with multiple treatment failure. AIDS. 2001 Nov 9;15(16):2189-91. doi: 10.1097/00002030-200111090-00016.
citation: Benson CA, Vaida F, Havlir DV, Downey GF, Lederman MM, Gulick RM, Glesby MJ, Wantman M, Bixby CJ, Rinehart AR, Snyder S, Wang R, Patel S, Mellors JW; ACTG A5086 Study Team. A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086. J Infect Dis. 2006 Nov 1;194(9):1309-18. doi: 10.1086/508289. Epub 2006 Sep 22.
citation: Wang R, Bosch RJ, Benson CA, Lederman MM. Drug-resistant virus has reduced ability to induce immune activation. J Acquir Immune Defic Syndr. 2012 Dec 1;61(4):e60-3. doi: 10.1097/QAI.0b013e31827171d7. No abstract available.