Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir

This study has been completed.
Sponsor:
Collaborators:
The University-Wide AIDS Research program
GlaxoSmithKline
University of California, Irvine
University of California, Los Angeles
University of Southern California
Santa Clara Valley Health & Hospital System
Information provided by:
California Collaborative Treatment Group
ClinicalTrials.gov Identifier:
NCT00214890
First received: September 20, 2005
Last updated: August 2, 2011
Last verified: August 2011
  Purpose

Once-daily nucleotide/nucleoside reverse transcriptase inhibitor (NtRTI/NRTI) combinations form the backbone of many regimens. Although efficacy data exists between tenofovir and the pyrimidine analogues (i.e. lamivudine and emtricitabine), recent clinical data suggests a potential interaction between tenofovir and purine analogs (i.e. abacavir and didanosine).

Specific Aim 1: To evaluate the impact of an acyclic nucleoside phosphonate, tenofovir (TDF), on the intracellular metabolism of a purine nucleoside analog, abacavir (ABC), as a determinant of the antiviral potency of this nucleotide/nucleoside reverse transcriptase inhibitor (NtRTI/NRTI) combination.

  • Hypothesis #1: ABC and TDF dosed together will have reduced antiviral activity, as measured by early plasma HIV RNA decay kinetics, than the drugs given alone.
  • Hypothesis #2: ABC dosed with TDF will have reduced intracellular concentrations, as measured by the ratio of carbovir triphosphate (active metabolite of ABC) to deoxyguanosine triphosphate (endogenous nucleotide), compared to ABC given alone.

Condition Intervention Phase
HIV Infections
Drug: Tenofovir
Drug: Abacavir
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: CCTG584: Viral Dynamics and Pharmacokinetics of Tenofovir and Abacavir Monotherapy Versus the Combination Therapy of TDF-ABC in HIV-Infected Treatment Naive Patients

Resource links provided by NLM:


Further study details as provided by California Collaborative Treatment Group:

Primary Outcome Measures:
  • To evaluate the relative potencies of two monotherapy regimens (TDF alone vs. ABC alone) compared to the dual NRTI regimen of TDF+ABC as assessed by the short-term virologic response [ Time Frame: 49 days ] [ Designated as safety issue: No ]
  • To compare the plasma and intracellular pharmacokinetic data of the two monotherapy regimens to the dual NRTI regimen [ Time Frame: 49 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To evaluate the change in cellular regulatory enzymes involved with nucleoside analogue transport across cell membranes after TDF+ABC exposure [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • To compare the relative viral potency of TDF monotherapy versus ABC monotherapy [ Time Frame: 7 weeks ] [ Designated as safety issue: No ]
  • To evaluate the long-term viral response to efavirenz + ABC + lamivudine after two 7-day sequences of mono/dual therapy [ Time Frame: 46 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: April 2005
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Tenofovir Drug: Tenofovir
300 mg once daily
Active Comparator: Abacavir Drug: Abacavir
600 mg once daily

Detailed Description:

The primary objectives of this study are to compare the virologic potency and pharmacology of TDF and ABC alone and in combination. Since it is not feasible or ethical to give mono or dual-therapy with these agents for prolonged intervals, this project was designed to take advantage of a short term drug exposure. The study performs intensive lab monitoring with a cross-over design to compare short courses of monotherapy and dual-therapy. This is an open-labeled study of a dual NRTI/NtRTI combination, ABC + TDF, compared to ABC and TDF monotherapy administered for 7 days. A total of 20 ARV-naïve subjects will be enrolled in this study. A screening genotype will be done to confirm that there are no resistance-associated mutations at baseline. Each subject will then be randomized to a 7-day sequence of monotherapy (ABC or TDF), and four measurements for plasma HIV RNA will be done to calculate the slope of the phase one viral decay. Prior to initiation of nucleoside analogues, PBMCs will be collected to measure baseline expression of nucleoside transport enzymes via RT-PCR and Western blot analysis. On days 7 and 8, serial blood specimens will be collected for plasma and intracellular levels of TDF and ABC. The monotherapy sequence will be followed by a 35-day washout period.

After the washout (day 42), subjects will initiate the dual NRTI/NtRTI therapy sequence for an additional 7 days. During dual NRTI/NtRTI therapy, again, four measurements for HIV RNA will be done to calculate the slope of the phase one viral decay. On day 48 and 49, serial plasma and intracellular levels of ABC + TDF will be evaluated. On Day 49 a second HIV genotype will be performed in real time. On day 49, after the second 7-day sequence, all subjects will receive EFV in addition to the ABC + TDF combination for 14 days. Afterwards, a second sample of PBMCs will be collected to evaluate for a potential induction or suppression of nucleoside transport enzymes. Since the long-term efficacy of the TDF + ABC nucleoside backbone is not yet known, TDF will be discontinued (day 63) and 3TC will be substituted. Subjects will then continue on the HAART portion of the study for an additional 46 weeks of EFV + ABC + 3TC.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
  2. Antiretroviral naïve defined as no prior therapy.
  3. CD4+ cell count > than 200 cells/ mm3 determined by site clinical laboratory within 90 days of screening.
  4. HIV-1 RNA level > 5000 copies/mL obtained by site clinical laboratory within 90 days of screening.
  5. Laboratory values obtained by screening laboratories within 30 days of entry:

    • Absolute neutrophil count (ANC) ≥ 750/mm3.
    • Hemoglobin ≥ 8.0 g/dL.
    • Platelet count ≥ 50,000/mm3.
    • Calculated creatinine clearance (CrCl) > 50 mL/min as estimated by the
    • AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 5 x ULN.
    • Total bilirubin ≤ 2.5 x ULN.
  6. Negative serum or urine pregnancy test within 30 days of study entry.
  7. Karnofsky performance score ≥ 70.
  8. Men and women age ≥ 18 years.
  9. Ability and willingness of subject to give written informed consent.

Exclusion Criteria:

  1. Any NRTI or NNRTI-associated resistance mutations as defined by the updated International AIDS Society-USA (IAS-USA) mutation list.
  2. Pregnancy and breast-feeding.
  3. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
  4. Urgent need to initiate antiretroviral therapy, as determined by the patient's primary provider.
  5. Serious illness (requiring systemic treatment and/or hospitalization) until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 14 days prior to study entry.
  6. Use of any immunomodulator, HIV vaccine, or investigational therapy within 30 days of study entry.
  7. Use of human growth hormone within 30 days prior to study entry.
  8. Initiation of testosterone or anabolic steroids within 30 days prior to study entry. (Exception: Chronic replacement dosages in patient's with diagnosed hypogonadism is allowed)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00214890

Locations
United States, California
UCI
Irvine, California, United States, 92668
USC
Los Angeles, California, United States, 90033
University of California San Diego
San Diego, California, United States, 92103
Santa Clara Valley Medical Center
San Jose, California, United States, 95128
Harbor-UCLA Medical Center
Torrance, California, United States, 90502
Sponsors and Collaborators
California Collaborative Treatment Group
The University-Wide AIDS Research program
GlaxoSmithKline
University of California, Irvine
University of California, Los Angeles
University of Southern California
Santa Clara Valley Health & Hospital System
Investigators
Study Chair: Richard H Haubrich, MD University California San Diego
  More Information

Publications:
Responsible Party: Richard H. Haubrich, M.D., California Collaborative Treatment Group
ClinicalTrials.gov Identifier: NCT00214890     History of Changes
Other Study ID Numbers: CCTG584
Study First Received: September 20, 2005
Last Updated: August 2, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by California Collaborative Treatment Group:
HIV
nucleoside pharmacology
drug-drug interaction
Treatment Naive
Drug resistance
Drug pharmacokinetics

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Tenofovir
Tenofovir disoproxil
Abacavir
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on August 27, 2014