Switch to Unboosted Atazanavir With Tenofovir Study (SUAT)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
University of British Columbia
ClinicalTrials.gov Identifier:
NCT01351740
First received: May 9, 2011
Last updated: March 20, 2014
Last verified: March 2014
  Purpose

A drug-drug interaction between the anti-HIV drugs tenofovir DF (TDF) and atazanavir (ATZ) results in lower ATZ plasma levels when the drugs are given together, particularly in patients not taking ritonavir to boost ATZ levels. Lower plasma drug levels may make the anti-HIV regimen less effective in controlling the HIV virus levels in the blood. For this reason, current treatment guidelines recommend that ATZ always be boosted with ritonavir in regimens also containing TDF. However, withdrawal of ritonavir is often desirable given the tolerability and toxicity issues with this agent, even at the low dose (100 mg daily) used to boost ATZ. For example, ritonavir can cause stomach upset, nausea, diarrhea, high cholesterol levels, and liver enzyme abnormalities.

However, there is evidence that plasma ATZ levels may not predict treatment success on unboosted ATZ regimens, particularly among people whose plasma HIV virus is already under control and unboosted ATZ is being used as a maintenance strategy. In the BC Centre for Excellence in HIV/AIDS Drug Treatment Program (DTP), nearly 100 patients originally treated with ritonavir-boosted ATZ + TDF (+ FTC or 3TC) are receiving successful maintenance therapy with unboosted ATZ and the same TDF-based backbone.

The study will examine the hypothesis that switching to maintenance therapy with unboosted ATZ 400mg daily will have similar 48-week virologic efficacy to continuing ATZ/ritonavir 300/100mg daily among HIV-infected adults with stable viral load suppression on regimens comprising ATZ/ritonavir 300/100mg daily with TDF plus either FTC or 3TC, despite potentially lower ATZ trough levels with the unboosted regimen. In other words, patients whose HIV viral load is undetectable while receiving TDF (+FTC or 3TC) and ATZ/ritonavir will continue to maintain an undetectable viral load after switching to unboosted ATZ without ritonavir, in the same proportions as those continuing on their boosted ATZ/ritonavir regimen.


Condition Intervention Phase
HIV Infection
Drug: atazanavir
Drug: atazanavir/ritonavir
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Switch to Unboosted Atazanavir With Tenofovir (SUAT) Study

Resource links provided by NLM:


Further study details as provided by University of British Columbia:

Primary Outcome Measures:
  • Proportions of subjects experiencing virologic failure by randomized treatment arm [ Time Frame: at or before 48 weeks. ] [ Designated as safety issue: No ]
    For the purposes of the study, virologic failure is defined as either regimen change for any reason, or plasma viral load >400 copies/mL on 2 consecutive measurements >2 weeks apart.


Secondary Outcome Measures:
  • proportions of subjects in each randomized treatment arm with atazanavir trough levels below 150ng/mL [ Time Frame: 1 month (4-8 weeks) ] [ Designated as safety issue: No ]
    Therapeutic drug monitoring (TDM) to determine atazanavir trough plasma level will be performed once on all subjects at 4-8 weeks

  • proportion of subjects experiencing virologic failure by results of 1-month TDM [ Time Frame: at or before 48 weeks ] [ Designated as safety issue: No ]
    For the purposes of the study, virologic failure is defined as either regimen change for any reason, or plasma viral load >400 copies/mL on 2 consecutive measurements >2 weeks apart. Comparison will be made between subjects with 1-month (4-8 week) on-study atazanavir trough levels <150ng/mL and those with 1-month (4-8 week) on-study atazanavir trough levels >150ng/mL.

  • proportions of subjects experiencing virologic failure by randomized treatment arm [ Time Frame: at or before 24 weeks. ] [ Designated as safety issue: No ]
    For the purposes of the study, virologic failure is defined as either regimen change for any reason, or plasma viral load >400 copies/mL on 2 consecutive measurements >2 weeks apart.

  • proportion of subjects experiencing virologic failure by results of 1-month TDM [ Time Frame: at or before 24 weeks ] [ Designated as safety issue: No ]
    For the purposes of the study, virologic failure is defined as either regimen change for any reason, or plasma viral load >400 copies/mL on 2 consecutive measurements >2 weeks apart. Comparison will be made between subjects with 1-month (4-8 week) on-study atazanavir trough levels <150ng/mL and those with 1-month (4-8 week) on-study atazanavir trough levels >150ng/mL.

  • CD4 cell count changes (absolute and fraction) [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
    Comparison will be made between randomized treatment arms.

  • safety (clinical and laboratory adverse events) [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: Yes ]
    Serious adverse events and discontinuations will be compared between randomized treatment arms

  • total serum bilirubin levels [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: Yes ]
    Comparison will be made between randomized treatment arms.

  • metabolic parameters [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: Yes ]
    Comparison will be made between randomized treatment arms with respect to changes in fasting lipids and glucose, highly sensitive C-reactive protein [hsCRP], and apolipoprotein [apo]B, and proportions of subjects developing abnormalities or crossing predefined limits (e.g. NCEP thresholds for lipids)

  • quality of life as assessed by MOS-HIV [ Time Frame: 24 and 48 weeks ] [ Designated as safety issue: No ]
    Changes in MOS-HIV scores from baseline will be compared between randomized treatment arms.


Enrollment: 50
Study Start Date: July 2011
Estimated Study Completion Date: December 2015
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Switch
switch to unboosted atazanavir 400mg daily with the same nucleoside (NRTI) backbone
Drug: atazanavir
switch to unboosted atazanavir 400 mg daily
Active Comparator: Continuation
continue on current regimen of atazanavir/ritonavir 300mg/100mg with the same nucleoside (NRTI) backbone
Drug: atazanavir/ritonavir
Continue current regimen of atazanavir 300 mg/ ritonavir 100 mg daily

Detailed Description:

Following a screening visit to establish study eligibility, eligible consenting subjects will be randomized 1:1 to one of the two treatment arms (switch to unboosted ATZ or continue ritonavir-boosted ATZ). Randomized open-label treatment will commence following study procedures at baseline. Participants will be assessed at baseline and at weeks 4, 8, 12, 24, 36, and 48. On-study evaluations will include assessment of adverse clinical events and medication changes; blood tests for HIV viral load, CD4 cell count, standard safety parameters, fasting lipids and glucose, and pregnancy testing (if applicable); and urine tests for urinalysis and albumin to creatinine ratio. In addition, a serum sample will be stored at each visit for possible future testing. A timed plasma sample for measurement of pre-dose trough ATZ levels will be obtained once per subject at 4-8 weeks. Quality of life will be assessed by completion of the MOS-HIV questionnaire at baseline and every 12 weeks. Adherence will be assessed based on prescription refill data.

In case of protocol-defined virologic failure, a plasma sample for ATZ trough level will be collected, and genotypic resistance testing will be performed on plasma samples with viral load >250 copies/mL. Subjects with confirmed virologic failure will be asked to come to the clinic and will have their HIV treatment changed to a more effective regimen, selected based on the results of genotypic testing, as soon as possible.

The anticipated rate of confirmed virologic failure in the control arm is no more than 15% over the 48 weeks of the study. Once at least 20 subjects have been assigned to the experimental (switch) treatment arm, if the observed confirmed virologic failure rate in the experimental arm is greater than twice this rate, i.e. >30%, at any time during the study, the study will be stopped. At this time, subjects in the experimental arm will be reassessed as soon as possible and will resume ritonavir-boosted atazanavir or other effective HIV therapy as appropriate. The failure rate will be reassessed at a minimum after each 20 subjects are enrolled into the experimental (switch) arm.

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HIV infected adults at least 19 years of age
  2. Willing and able to provide informed consent to study participation
  3. Currently receiving a regimen including atazanavir 300mg/ritonavir 100mg daily with either tenofovir/emtricitabine (FTC) or tenofovir/lamivudine (3TC), for at least 3 months
  4. Plasma viral load (VL) <40 copies/mL for at least 2 consecutive measurements including the screening value, and < 150 copies/mL continuously for at least 3 months prior to screening
  5. Current regimen is first antiretroviral regimen, or if not first regimen, no evidence of resistance to any nucleosides (NRTIs) or protease inhibitors (PIs) on previous resistance tests
  6. Any CD4

Exclusion Criteria:

  1. Clinically significant intolerance or toxicity with current regimen precluding regimen continuation (e.g. intolerance/toxicity to ritonavir necessitating ritonavir discontinuation)
  2. pregnancy or breast-feeding
  3. antiretroviral regimen including any nonnucleoside reverse transcriptase inhibitor (nevirapine, efavirenz, or etravirine)
  4. antiretroviral regimen including any protease inhibitor other than atazanavir and ritonavir
  5. concomitant treatment with proton pump inhibitors, rifampin, St. John's wort, or garlic supplements. (Antacids and H2 receptor antagonists will be allowed provided their dosing is separated from atazanavir administration by at least 2 and 10 hours, respectively).
  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: NCT01351740

Locations
Canada, British Columbia
Immunodeficiency Clinic, St. Paul's Hospital
Vancouver, British Columbia, Canada, V6Z1Y6
Sponsors and Collaborators
University of British Columbia
Investigators
Principal Investigator: Marianne Harris, MD Providence Health Care/ University of British Columbia
  More Information

No publications provided

Responsible Party: University of British Columbia
ClinicalTrials.gov Identifier: NCT01351740     History of Changes
Other Study ID Numbers: H10-03255, H10-03255
Study First Received: May 9, 2011
Last Updated: March 20, 2014
Health Authority: Canada: Health Canada

Keywords provided by University of British Columbia:
HIV
Anti-HIV Agents
HIV Protease Inhibitors

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
HIV Protease Inhibitors
Ritonavir
Atazanavir
Tenofovir
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 18, 2014