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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00041769
• Other study ID #: ACTG A5146
• Secondary ID: AACTG A5146
• Status: Completed
• Phase: Phase 3
• First received: July 16, 2002
• Last updated: July 12, 2010
• Start date: June 2002
• Est. completion date: August 2007

Study information

• Verified date: December 2008
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 360
• Est. completion date: August 2007
• Est. primary completion date: April 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections

Intervention

Procedure:
• Therapeutic Drug Monitoring (TDM)

Locations

Country	Name	City	State
Puerto Rico	University of Puerto Rico	San Juan
United States	Johns Hopkins Univ	Baltimore	Maryland
United States	Univ of Maryland, Institute of Human Virology	Baltimore	Maryland
United States	Univ of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess-West Campus	Boston	Massachusetts
United States	Brigham and Women's Hosp	Boston	Massachusetts
United States	Harvard (Masschusetts General Hosp)	Boston	Massachusetts
United States	SUNY-Buffalo (Rochester)	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Northwestern Univ	Chicago	Illinois
United States	The CORE Ctr	Chicago	Illinois
United States	Ohio State Univ	Cincinnati	Ohio
United States	Univ of Cincinnati	Cincinnati	Ohio
United States	Case Western Reserve Univ	Cleveland	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	MetroHealth Med Ctr	Cleveland	Ohio
United States	Univ of Colorado Health Sciences Ctr	Denver	Colorado
United States	Duke Univ Med Ctr	Durham	North Carolina
United States	Univ of Texas, Galveston	Galveston	Texas
United States	Univ of Hawaii	Honolulu	Hawaii
United States	Indiana Univ Hosp	Indianapolis	Indiana
United States	Methodist Hosp of Indiana	Indianapolis	Indiana
United States	Wishard Hosp	Indianapolis	Indiana
United States	UCLA School of Medicine	Los Angeles	California
United States	Univ of Southern California	Los Angeles	California
United States	Univ of Miami	Miami	Florida
United States	Univ of Minnesota	Minneapolis	Minnesota
United States	Comprehensive Care Clinic	Nashville	Tennessee
United States	Beth Israel Medical Center	New York	New York
United States	Chelsea Clinic	New York	New York
United States	Columbia Univ	New York	New York
United States	Long Beach Memorial (Pediatric)	New York	New York
United States	New York University - Bellevue	New York	New York
United States	Univ of Pittsburgh	Pittsburgh	Pennsylvania
United States	Rhode Island Hosp	Providence	Rhode Island
United States	Stanley Street Treatment and Resource	Providence	Rhode Island
United States	The Miriam Hosp	Providence	Rhode Island
United States	Community Health Network Inc	Rochester	New York
United States	Univ of Rochester Medical Center	Rochester	New York
United States	Univ of California, San Diego Antiviral Research Center (AVRC)	San Diego	California
United States	Univ of California San Francisco	San Francisco	California
United States	Univ of Washington (Seattle)	Seattle	Washington
United States	St. Louis Connect Care	St. Louis	Missouri
United States	Washington Univ (St. Louis)	St. Louis	Missouri
United States	San Mateo County AIDS Program	Stanford	California
United States	Santa Clara Valley Med Ctr	Stanford	California
United States	Willow Clinic	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (6)

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. Review. — View 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 Mon — View 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. — View 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. Review. — View 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. Review. — View Citation

Rendón A, Núñez M, Jiménez-Nácher I, González de Requena D, González-Lahoz J, Soriano V. Clinical benefit of interventions driven by therapeutic drug monitoring. HIV Med. 2005 Sep;6(5):360-5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in log10 plasma HIV-1 RNA concentration from Step 2 entry (Week 4) to Week 24 (20 weeks post-randomization)
Primary	change in log10 plasma HIV-1 RNA concentration from study entry to Week 24 (20 weeks post-randomization)

External Links

•   Click here for information on HIV treatment regimen failure
•   Click here for more information on changing your HIV treatment regimen
•   Haga clic aquí para ver información sobre este ensayo clínico en español.