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	Treatment or Intervention	Phase
HIV Infections	Procedure: Therapeutic Drug Monitoring (TDM)	Phase III

Further Study Details: 

Primary Outcomes: Change in log10 plasma HIV-1 RNA concentration from Step 2 entry (Week 4) to Week 24; change in log10 plasma HIV-1 RNA concentration from study entry to Week 24
Expected Total Enrollment:  360

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.

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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

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
• 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
• Certain medications used 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

Alabama
      Univ of Alabama at Birmingham, Birmingham,  Alabama,  35924-2050,  United States; Recruiting
California
      Univ of California San Francisco, San Francisco,  California,  94110,  United States; Recruiting
      UCLA School of Medicine, Los Angeles,  California,  90095,  United States; Recruiting
      San Mateo County AIDS Program, Stanford,  California,  94305-5107,  United States; Recruiting
      Willow Clinic, Stanford,  California,  94305-5107,  United States; Recruiting
      Santa Clara Valley Med Ctr, Stanford,  California,  94305-5107,  United States; Recruiting
      Univ of Southern California, Los Angeles,  California,  90033-1079,  United States; Recruiting
      Univ of California, San Diego Antiviral Research Center (AVRC), San Diego,  California,  92103,  United States; Recruiting
Colorado
      Univ of Colorado Health Sciences Ctr, Denver,  Colorado,  80262,  United States; Recruiting
Florida
      Univ of Miami, Miami,  Florida,  33136-1013,  United States; Recruiting
Hawaii
      Univ of Hawaii, Honolulu,  Hawaii,  96816-2396,  United States; Recruiting
Illinois
      The CORE Ctr, Chicago,  Illinois,  60612,  United States; Recruiting
      Northwestern Univ, Chicago,  Illinois,  60611-3015,  United States; Recruiting
Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  46202-5250,  United States; Recruiting
      Methodist Hosp of Indiana, Indianapolis,  Indiana,  46202-1261,  United States; Recruiting
      Wishard Hosp, Indianapolis,  Indiana,  46202,  United States; Recruiting
Maryland
      Univ of Maryland, Institute of Human Virology, Baltimore,  Maryland,  21201,  United States; Recruiting
      Johns Hopkins Univ, Baltimore,  Maryland,  21287-8106,  United States; Recruiting
Massachusetts
      Beth Israel Deaconess-West Campus, Boston,  Massachusetts,  02215,  United States; Recruiting
      Brigham and Women's Hosp, Boston,  Massachusetts,  02215,  United States; Recruiting
      Harvard (Masschusetts General Hosp), Boston,  Massachusetts,  02114,  United States; Recruiting
Minnesota
      Univ of Minnesota, Minneapolis,  Minnesota,  55455-0392,  United States; Recruiting
Missouri
      Washington Univ (St. Louis), St. Louis,  Missouri,  63108-2138,  United States; Recruiting
      St. Louis Connect Care, St. Louis,  Missouri,  63108-2138,  United States; No longer recruiting
New York
      Univ of Rochester Medical Center, Rochester,  New York,  14642,  United States; Recruiting
      Community Health Network Inc, Rochester,  New York,  14642,  United States; Recruiting
      New York University - Bellevue, New York,  New York,  10016,  United States; Recruiting
      Beth Israel Medical Center, New York,  New York,  10003,  United States; Recruiting
      Columbia Univ, New York,  New York,  10032,  United States; Recruiting
      SUNY-Buffalo (Rochester), Buffalo,  New York,  14215,  United States; Recruiting
      Long Beach Memorial (Pediatric), New York,  New York,  10021,  United States; Recruiting
      Chelsea Clinic, New York,  New York,  10011,  United States; Recruiting
North Carolina
      Duke Univ Med Ctr, Durham,  North Carolina,  27710,  United States; Recruiting
      University of North Carolina, Chapel Hill,  North Carolina,  27514,  United States; Recruiting
Ohio
      Case Western Reserve Univ, Cleveland,  Ohio,  44106,  United States; Recruiting
      MetroHealth Med Ctr, Cleveland,  Ohio,  44109-1998,  United States; Recruiting
      Univ of Cincinnati, Cincinnati,  Ohio,  45267-0405,  United States; Recruiting
      Cleveland Clinic, Cleveland,  Ohio,  44109-1998,  United States; No longer recruiting
      Ohio State Univ, Cincinnati,  Ohio,  45267-0405,  United States; Recruiting
Pennsylvania
      Univ of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
Rhode Island
      The Miriam Hosp, Providence,  Rhode Island,  02906,  United States; Recruiting
      Rhode Island Hosp, Providence,  Rhode Island,  02906,  United States; Recruiting
      Stanley Street Treatment and Resource, Providence,  Rhode Island,  02906,  United States; Recruiting
Tennessee
      Comprehensive Care Clinic, Nashville,  Tennessee,  37203,  United States; Recruiting
Texas
      Univ of Texas, Galveston, Galveston,  Texas,  77555-0435,  United States; Recruiting
Washington
      Univ of Washington (Seattle), Seattle,  Washington,  98104,  United States; Recruiting
Puerto Rico
      University of Puerto Rico, San Juan,  00936-5067,  Puerto Rico; Recruiting

Study chairs or principal investigators

Lisa Demeter, MD,  Study Chair,  Infectious Diseases Unit, University of Rochester Medical Center   
Mary Albrecht, MD,  Study Chair,  Division of Infectious Diseases, Beth Israel Deaconess Medical Center   

Study ID Numbers:  ACTG A5146; AACTG A5146
Record last reviewed:  December 2004
Last Updated:  April 1, 2005
Record first received:  July 16, 2002
ClinicalTrials.gov Identifier:  NCT00041769
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08