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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00041769

Collaborator

(none)

360

Enrollment

Locations

Duration (Months)

7.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

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 :

Jun 1, 2002

Actual Primary Completion Date :

Apr 1, 2007

Actual Study Completion Date :

Aug 1, 2007

Outcome Measures

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) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Univ of Alabama at Birmingham	Birmingham	Alabama	United States	35924-2050
2	Univ of Southern California	Los Angeles	California	United States	90033-1079
3	UCLA School of Medicine	Los Angeles	California	United States	90095
4	Univ of California, San Diego Antiviral Research Center (AVRC)	San Diego	California	United States	92103
5	Univ of California San Francisco	San Francisco	California	United States	94110
6	San Mateo County AIDS Program	Stanford	California	United States	94305-5107
7	Santa Clara Valley Med Ctr	Stanford	California	United States	94305-5107
8	Willow Clinic	Stanford	California	United States	94305-5107
9	Univ of Colorado Health Sciences Ctr	Denver	Colorado	United States	80262
10	Univ of Miami	Miami	Florida	United States	33136-1013
11	Univ of Hawaii	Honolulu	Hawaii	United States	96816-2396
12	Northwestern Univ	Chicago	Illinois	United States	60611-3015
13	The CORE Ctr	Chicago	Illinois	United States	60612
14	Methodist Hosp of Indiana	Indianapolis	Indiana	United States	46202-1261
15	Indiana Univ Hosp	Indianapolis	Indiana	United States	46202-5250
16	Wishard Hosp	Indianapolis	Indiana	United States	46202
17	Univ of Maryland, Institute of Human Virology	Baltimore	Maryland	United States	21201
18	Johns Hopkins Univ	Baltimore	Maryland	United States	21287-8106
19	Harvard (Masschusetts General Hosp)	Boston	Massachusetts	United States	02114
20	Beth Israel Deaconess-West Campus	Boston	Massachusetts	United States	02215
21	Brigham and Women's Hosp	Boston	Massachusetts	United States	02215
22	Univ of Minnesota	Minneapolis	Minnesota	United States	55455-0392
23	St. Louis Connect Care	St. Louis	Missouri	United States	63108-2138
24	Washington Univ (St. Louis)	St. Louis	Missouri	United States	63108-2138
25	SUNY-Buffalo (Rochester)	Buffalo	New York	United States	14215
26	Beth Israel Medical Center	New York	New York	United States	10003
27	Chelsea Clinic	New York	New York	United States	10011
28	New York University - Bellevue	New York	New York	United States	10016
29	Long Beach Memorial (Pediatric)	New York	New York	United States	10021
30	Columbia Univ	New York	New York	United States	10032
31	Community Health Network Inc	Rochester	New York	United States	14642
32	Univ of Rochester Medical Center	Rochester	New York	United States	14642
33	University of North Carolina	Chapel Hill	North Carolina	United States	27514
34	Duke Univ Med Ctr	Durham	North Carolina	United States	27710
35	Ohio State Univ	Cincinnati	Ohio	United States	45267-0405
36	Univ of Cincinnati	Cincinnati	Ohio	United States	45267-0405
37	Case Western Reserve Univ	Cleveland	Ohio	United States	44106
38	Cleveland Clinic	Cleveland	Ohio	United States	44109-1998
39	MetroHealth Med Ctr	Cleveland	Ohio	United States	44109-1998
40	Univ of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
41	Rhode Island Hosp	Providence	Rhode Island	United States	02906
42	Stanley Street Treatment and Resource	Providence	Rhode Island	United States	02906
43	The Miriam Hosp	Providence	Rhode Island	United States	02906
44	Comprehensive Care Clinic	Nashville	Tennessee	United States	37203
45	Univ of Texas, Galveston	Galveston	Texas	United States	77555-0435
46	Univ of Washington (Seattle)	Seattle	Washington	United States	98104
47	University of Puerto Rico	San Juan		Puerto Rico	00936-5067

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

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