Clinical trial NCT00041769: Using Drug Levels in the Blood to Guide Therapy in HIV Infected Patients Taking a Protease Inhibitor
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Drug Therapy, Combination
HIV Protease Inhibitors
Salvage Therapy
Viral Load
Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2002-07-17
Enrollment: 360
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

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.

Eligibility 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. 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

Primary outcomes:
measure: Change in log10 plasma HIV-1 RNA concentration from Step 2 entry (Week 4) to Week 24 (20 weeks post-randomization)
measure: change in log10 plasma HIV-1 RNA concentration from study entry to Week 24 (20 weeks post-randomization)
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: Univ of Southern California
state: California
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: San Diego
country: United States
facility: Univ of California, San Diego Antiviral Research Center (AVRC)
state: California
city: San Francisco
country: United States
facility: Univ of California San Francisco
state: California
city: Stanford
country: United States
facility: San Mateo County AIDS Program
state: California
city: Stanford
country: United States
facility: Santa Clara Valley Med Ctr
state: California
city: Stanford
country: United States
facility: Willow Clinic
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
state: Florida
city: Honolulu
country: United States
facility: Univ of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Univ
state: Illinois
city: Chicago
country: United States
facility: The CORE Ctr
state: Illinois
city: Indianapolis
country: United States
facility: Methodist Hosp of Indiana
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Wishard Hosp
state: Indiana
city: Baltimore
country: United States
facility: Univ of Maryland, Institute of Human Virology
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Univ
state: Maryland
city: Boston
country: United States
facility: Harvard (Masschusetts General Hosp)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess-West Campus
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp
state: Massachusetts
city: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis Connect Care
state: Missouri
city: St. Louis
country: United States
facility: Washington Univ (St. Louis)
state: Missouri
city: Buffalo
country: United States
facility: SUNY-Buffalo (Rochester)
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Chelsea Clinic
state: New York
city: New York
country: United States
facility: New York University - Bellevue
state: New York
city: New York
country: United States
facility: Long Beach Memorial (Pediatric)
state: New York
city: New York
country: United States
facility: Columbia Univ
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: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Cincinnati
country: United States
facility: Ohio State Univ
state: Ohio
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Med Ctr
state: Ohio
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hosp
state: Rhode Island
city: Providence
country: United States
facility: Stanley Street Treatment and Resource
state: Rhode Island
city: Providence
country: United States
facility: The Miriam Hosp
state: Rhode Island
city: Nashville
country: United States
facility: Comprehensive Care Clinic
state: Tennessee
city: Galveston
country: United States
facility: Univ of Texas, Galveston
state: Texas
city: Seattle
country: United States
facility: Univ of Washington (Seattle)
state: Washington
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico
Study officials:
affiliation: Infectious Diseases Unit, University of Rochester Medical Center
name: Lisa Demeter, MD
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, Beth Israel Deaconess Medical Center
name: Mary Albrecht, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.