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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00041769
Recruitment Status : Completed
First Posted : July 17, 2002
Last Update Posted : July 13, 2010
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:

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 or disease Intervention/treatment Phase
HIV Infections Procedure: Therapeutic Drug Monitoring (TDM) Phase 3

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  (Clinical Trial)
Enrollment : 360 participants
Allocation: Randomized
Masking: None (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
Study Start Date : June 2002
Actual Primary Completion Date : April 2007
Actual Study Completion Date : August 2007

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00041769

  Show 47 Study Locations
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

Publications of Results:
Other Publications: Identifier: NCT00041769     History of Changes
Other Study ID Numbers: ACTG A5146
First Posted: July 17, 2002    Key Record Dates
Last Update Posted: July 13, 2010
Last Verified: December 2008

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 Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Protease Inhibitors
HIV Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents