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

This study has been completed.
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID) Identifier:
First received: July 16, 2002
Last updated: July 12, 2010
Last verified: December 2008

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.

Condition Intervention Phase
HIV Infections
Procedure: Therapeutic Drug Monitoring (TDM)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

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

Primary Outcome Measures:
  • 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)

Estimated Enrollment: 360
Study Start Date: June 2002
Study Completion Date: August 2007
Primary Completion Date: April 2007 (Final data collection date for primary outcome measure)
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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00041769

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

Additional Information:
Publications: Identifier: NCT00041769     History of Changes
Other Study ID Numbers: ACTG A5146  AACTG A5146 
Study First Received: July 16, 2002
Last Updated: July 12, 2010
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Drug Therapy, Combination
HIV Protease Inhibitors
Salvage Therapy
Viral Load
Treatment Experienced

Additional relevant MeSH terms:
HIV Protease Inhibitors
Protease Inhibitors
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses processed this record on April 27, 2016