Using Drug Levels in the Blood to Guide Therapy in HIV Infected Patients Taking a Protease Inhibitor

A Phase II Randomized Controlled Trial Evaluating the Impact of Therapeutic Drug Monitoring (TDM) on Virologic Response to a Salvage Regimen in Subjects With a Normalized Inhibitory Quotient (NIQ) Less Than or Equal to 1 to One or More Protease Inhibitors

Drug resistance testing can be used to see which anti-HIV drugs are likely to suppress the growth of HIV and to select an anti-HIV regimen for HIV infected patients who have failed previous drug regimens. Therapeutic drug monitoring (TDM) is a process that involves measuring blood levels of a drug and may further increase the benefits that resistance testing offers by optimizing protease inhibitor (PI) drug concentrations. The purpose of this study is to determine whether changing the dose of PIs, as indicated by TDM, reduces the viral load in PI-experienced patients.

Hypothesis: Treatment-naive study participants who undergo TDM and whose clinicians' interpret their TDM results and adjust their PI doses will have better virologic response rates and decreased toxicities (and thus better treatment outcomes) than participants who do not undergo TDM.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Procedure: Therapeutic Drug Monitoring (TDM)

Detailed Description

The use of drug resistance testing to guide the selection of an antiretroviral regimen for patients in whom current therapy is failing has gained growing acceptance in clinical practice. Genotypic and phenotypic resistance testing has been associated with improved short-term virologic outcome in prospective interventional trials. There is also growing evidence that monitoring drug levels, particularly of PIs, may add to the benefit provided by resistance testing. This study will assess the impact of TDM and resistance testing on lowering viral load in treatment-experienced patients and will also evaluate the mean change in plasma HIV RNA from study entry to Step 2 of the study.

No antiretrovirals will be provided by this study. Participants will be followed for a maximum of 48 weeks. Participants failing at least one combination antiretroviral regimen will have a screening drug resistance test performed while remaining on the failing regimen. In Step 1, participants will begin a salvage antiretroviral regimen within 7 days of study entry selected by their clinician using results of the resistance test. Two weeks after initiation of the salvage regimen, participants will have timed plasma samples obtained for PI trough levels. The results of the trough level tests will be used to calculate a normalized inhibitory quotient (NIQ) in order to determine eligibility for randomization into Step 2 at Week 4. Electrocardiograms (EKGs) and trough levels will be performed at Weeks 2, 6, and 10; support interviews to promote adherence will also be conducted by the study nurse or clinician at these times. Some participants taking tipranavir may have additional blood collection at Week 2.

In Step 2, participants with an NIQ of 1 or less will be randomly assigned to one of two arms. Arm A participants will receive standard care (SC) only, while participants in Arm B will receive SC plus dose-adjusted PIs based on the NIQ. Clinical and viral load assessment will be conducted at screening, entry, and Weeks 4, 10, 16, 24, 32, 40, and 48. Arm B participants will also have their PI trough levels checked at Weeks 6 and 10. Participants with an NIQ greater than 1 will be assigned to observational Arm C (open to up to 50 enrollees) or will stop their involvement in the study. Participants in Arms A, B, or C who have a viral load of 1000 copies/ml or higher or who experience virologic failure at or after Week 24 will be eligible to receive a second resistance test and enter Step 3.

Participants in Step 3 will begin a second salvage regimen; PI trough levels will be measured after 2, 6, and 10 weeks of salvage therapy. Those with an NIQ greater than 1, or with an NIQ of 1 or less and do not wish to escalate dose, will be followed on Step 3 for a maximum of 48 weeks after study entry.

All participants are encouraged to coenroll in ACTG A5128, Consent for Use of Stored Patient Specimens for Future Testing.

• Study Type: Interventional
• Enrollment: 360
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00936-5067
    • University of Puerto Rico
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35924-2050
      • Univ of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90095
      • UCLA School of Medicine
    • Los Angeles, California, United States, 90033-1079
      • Univ of Southern California
    • San Diego, California, United States, 92103
      • Univ of California, San Diego Antiviral Research Center (AVRC)
    • San Francisco, California, United States, 94110
      • Univ of California San Francisco
    • Stanford, California, United States, 94305-5107
      • San Mateo County AIDS Program
    • Stanford, California, United States, 94305-5107
      • Willow Clinic
    • Stanford, California, United States, 94305-5107
      • Santa Clara Valley Med Ctr
  • Colorado
    • Denver, Colorado, United States, 80262
      • Univ of Colorado Health Sciences Ctr
  • Florida
    • Miami, Florida, United States, 33136-1013
      • Univ of Miami
  • Hawaii
    • Honolulu, Hawaii, United States, 96816-2396
      • Univ of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60612
      • The CORE Ctr
    • Chicago, Illinois, United States, 60611-3015
      • Northwestern Univ
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Wishard Hosp
    • Indianapolis, Indiana, United States, 46202-5250
      • Indiana Univ Hosp
    • Indianapolis, Indiana, United States, 46202-1261
      • Methodist Hosp of Indiana
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Univ of Maryland, Institute of Human Virology
    • Baltimore, Maryland, United States, 21287-8106
      • Johns Hopkins Univ
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Brigham and Women's Hosp
    • Boston, Massachusetts, United States, 02114
      • Harvard (Masschusetts General Hosp)
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess-West Campus
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455-0392
      • Univ of Minnesota
  • Missouri
    • St. Louis, Missouri, United States, 63108-2138
      • St. Louis Connect Care
    • St. Louis, Missouri, United States, 63108-2138
      • Washington Univ (St. Louis)
  • New York
    • Buffalo, New York, United States, 14215
      • SUNY-Buffalo (Rochester)
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10011
      • Chelsea Clinic
    • New York, New York, United States, 10032
      • Columbia Univ
    • New York, New York, United States, 10016
      • New York University - Bellevue
    • New York, New York, United States, 10021
      • Long Beach Memorial (Pediatric)
    • Rochester, New York, United States, 14642
      • Univ of Rochester Medical Center
    • Rochester, New York, United States, 14642
      • Community Health Network Inc
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Univ Med Ctr
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0405
      • Univ of Cincinnati
    • Cincinnati, Ohio, United States, 45267-0405
      • Ohio State Univ
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve Univ
    • Cleveland, Ohio, United States, 44109-1998
      • MetroHealth Med Ctr
    • Cleveland, Ohio, United States, 44109-1998
      • Cleveland Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Univ of Pittsburgh
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • Stanley Street Treatment and Resource
    • Providence, Rhode Island, United States, 02906
      • Rhode Island Hosp
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hosp
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Comprehensive Care Clinic
  • Texas
    • Galveston, Texas, United States, 77555-0435
      • Univ of Texas, Galveston
  • Washington
    • Seattle, Washington, United States, 98104
      • Univ of Washington (Seattle)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Note: Enrollment into Arm C closed on 07/28/04 after reaching target accrual. Participants with a Week 2 NIQ of greater than 1 will be permanently discontinued from the study.

Inclusion Criteria for Step 1:

• HIV infected
• Viral load of 1000 copies/ml or more at study screening
• At least one viral load of 400 copies/ml or more within 6 months of study entry while on the failing antiretroviral regimen
• Virologic failure of at least one combination (two or more drugs) antiretroviral regimen, with at least one of these failing regimens containing a PI. Low dose ritonavir and hydroxyurea are not counted as antiretrovirals.
• Currently on a failing combination antiretroviral regimen
• Plan to initiate a salvage regimen containing a PI within 7 days of study entry
• Acceptable methods of contraception while receiving the study medications and for 6 weeks after stopping the medications. Participants who are currently taking efavirenz and who have undergone surgery to prevent conception (e.g., hysterectomy, tubal ligation, vasectomy) must provide physician's documentation of their current regimen and of their previous surgery.
• Resistance to at least one drug in the failing regimen, documented within 90 days of study entry
• Karnofsky performance scale of 70 or more within 30 days prior to study entry

Exclusion Criteria:

• Growth factors, interleukins, interferons (except for the treatment of hepatitis C), non-FDA approved systemic drugs, and HIV vaccines within 30 days of study entry
• Require certain medications prior to or during the study
• Certain heart conditions, if starting a PI-based regimen as the salvage regimen
• Acute illness or infection requiring treatment within 14 days of study entry
• Any condition that would limit ability to participate in the study
• Cancer requiring radiation or systemic chemotherapy
• Active drug or alcohol use or dependence that would interfere with the ability to meet study requirements
• Acute or chronic pancreatitis
• Planned use of hydroxyurea in the salvage regimen
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Change in log10 plasma HIV-1 RNA concentration from Step 2 entry (Week 4) to Week 24 (20 weeks post-randomization)
change in log10 plasma HIV-1 RNA concentration from study entry to Week 24 (20 weeks post-randomization)

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Lisa Demeter, MD, Infectious Diseases Unit, University of Rochester Medical Center; Study Chair: Mary Albrecht, MD, Division of Infectious Diseases, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Clevenbergh P, Mouly S, Sellier P, Badsi E, Cervoni J, Vincent V, Trout H, Bergmann JF. Improving HIV infection management using antiretroviral plasma drug levels monitoring: a clinician's point of view. Curr HIV Res. 2004 Oct;2(4):309-21. doi: 10.2174/1570162043351129.
• Duong M, Golzi A, Peytavin G, Piroth L, Froidure M, Grappin M, Buisson M, Kohli E, Chavanet P, Portier H. Usefulness of therapeutic drug monitoring of antiretrovirals in routine clinical practice. HIV Clin Trials. 2004 Jul-Aug;5(4):216-23. doi: 10.1310/NXJU-9ERQ-ADWW-UC5X.
• Kiser JJ, Anderson PL, Gerber JG. Therapeutic drug monitoring: pharmacologic considerations for antiretroviral drugs. Curr HIV/AIDS Rep. 2005 Jun;2(2):61-7. doi: 10.1007/s11904-005-0020-8.
• Rakhmanina NY, van den Anker JN, Soldin SJ. Therapeutic drug monitoring of antiretroviral therapy. AIDS Patient Care STDS. 2004 Jan;18(1):7-14. doi: 10.1089/108729104322740866.
• Rendon A, Nunez M, Jimenez-Nacher I, Gonzalez de Requena D, Gonzalez-Lahoz J, Soriano V. Clinical benefit of interventions driven by therapeutic drug monitoring. HIV Med. 2005 Sep;6(5):360-5. doi: 10.1111/j.1468-1293.2005.00321.x.
• DiFrancesco R, Rosenkranz S, Mukherjee AL, Demeter LM, Jiang H, DiCenzo R, Dykes C, Rinehart A, Albrecht M, Morse GD. Quality assessment for therapeutic drug monitoring in AIDS Clinical Trials Group (ACTG 5146): a multicenter clinical trial. Ther Drug Monit. 2010 Aug;32(4):458-66. doi: 10.1097/FTD.0b013e3181e4427a.

Study record dates

Study Major Dates

• Study Start: June 1, 2002
• Primary Completion (Actual): April 1, 2007
• Study Completion (Actual): August 1, 2007

Study Registration Dates

• First Submitted: July 16, 2002
• First Submitted That Met QC Criteria: July 16, 2002
• First Posted (Estimate): July 17, 2002

Study Record Updates

• Last Update Posted (Estimate): July 13, 2010
• Last Update Submitted That Met QC Criteria: July 12, 2010
• Last Verified: December 1, 2008

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Viral Load; Treatment Experienced; HIV Protease Inhibitors; Salvage Therapy
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: ACTG A5146; AACTG A5146