Efficacy and Safety of Tenofovir DF/Atazanavir Enhanced With Low Dose of Ritonavir in HIV-Infected Patients - Full Text View

Sponsors and Collaborators:	French National Agency for Research on AIDS and Viral Hepatitis Bristol-Myers Squibb Gilead Sciences
Information provided by:	French National Agency for Research on AIDS and Viral Hepatitis
ClinicalTrials.gov Identifier:	NCT00122577

Purpose

This trial is aimed at studying the antiviral activity, toxicity and pharmacokinetic (PK) interactions of tenofovir DF and atazanavir enhanced with low dose of ritonavir given alone and then concomitantly as part of a salvage regimen to HIV patients with multiple failure, under conditions allowing to tease out the specific role of atazanavir combined with low dose of ritonavir.

Condition	Intervention	Phase
HIV Infections	Drug: Tenofovir Drug: Atazanavir Drug: Ritonavir	Phase II

MedlinePlus related topics: AIDS

Drug Information available for: Ritonavir Atazanavir sulfate BMS 232632 Tenofovir Tenofovir disoproxil Tenofovir Disoproxil Fumarate

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study
Official Title:	Randomized Open Label Study Assessing the Antiviral Activity, Toxicity and Pharmacologic Interaction of Tenofovir DF/Atazanavir Enhanced With Low Dose of Ritonavir as Part of a Salvage Regimen in HIV Infected Patients With Multiple Treatment Failures (ANRS 107 Trial PUZZLE 2)

Further study details as provided by French National Agency for Research on AIDS and Viral Hepatitis:

Primary Outcome Measures:

Change in plasma HIV RNA level and percentage of patients with undetectable HIV-RNA in plasma at Week 26

Secondary Outcome Measures:

Tolerance during the study
Changes in CD4+ counts at week 26
Emergence of drug-resistant viruses
Rate of virus decay in plasma in group 2 during the initial phase (14 days) of therapy according to baseline EC50 of atazanavir
Pharmacokinetic (PK) profile of atazanavir alone at day 14
Blood samples prior to drug administration (Cmin) and after drug administration on day 14 at +1h, +2h, +3h, +5h, +8h, and +24h in 10 patients of group 2
PK assessment on Week 6, of atazanavir, after 4 weeks of co-administration with tenofovir DF. (Blood samples prior to drug administration (Cmin) and after drug administration at +1h, +2h, +3h, +5h, +8h, and +24h in the same 10 patients of group 2)

Estimated Enrollment:	50
Study Start Date:	March 2002
Estimated Study Completion Date:	July 2004

Detailed Description:

When licensed, new drugs are widely used in patients failing antiretroviral therapy, including patients with multiple failures. In such patients, having multi-resistant virus, the introduction of one new drug only in the salvage regimen will infrequently result in undetectable virus load in the plasma. Tenofovir DF and atazanavir appear promising because of their pharmacokinetic profile, activity, safety and resistance properties. In addition, pharmacokinetic data in healthy volunteers suggest that atazanavir could be optimized by adding ritonavir at low dose. Thus, one may speculate that atazanavir pharmacokinetic and antiviral activity could be optimized by adding ritonavir at low dose in patients exhibiting high rate of protease inhibitor mutations.

This protocol is aimed at studying the antiviral activity, toxicity and PK interactions, of tenofovir DF and atazanavir enhanced with low dose of ritonavir given alone and then concomitantly as part of a salvage regimen to patients with multiple failure, under conditions allowing to tease out the specific role of atazanavir combined with low dose of ritonavir.

EKG abnormalities (increased PR and QTc intervals) were observed in normal volunteers treated with atazanavir, therefore EKG safety monitoring will be performed on all subjects during this study

Eligibility

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

Criteria

Inclusion Criteria:

Males and non pregnant females 18 years of age and older who have confirmed laboratory diagnosis of HIV infection and documented failure (plasma HIV RNA level over 10,000 copies/ml) to at least two protease inhibitors (ritonavir [RTV] must have been given at a dose over 400 mg twice a day (bid), in order to qualify for a protease inhibitor in this study) and one non-nucleoside reverse transcriptase inhibitor (NNRTI)
Ongoing antiretroviral therapy at inclusion without change within the last month
No threshold of CD4 cell count
Patients naive of atazanavir and tenofovir DF

Exclusion Criteria:

Cardiomyopathy
QTc interval over 450 msec and pause length over 3 seconds on screening EKG
Heart rate below 40 bpm
Third degree heart block, and clinical symptoms potentially related to heart block
Ongoing immunotherapy including IL2, interferon or HIV specific vaccine
Ongoing opportunistic infection

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00122577

Locations

France
Service d'Immunologie clinique Hopital Europeen Georges Pompidou
Paris, France, 75015

Sponsors and Collaborators

French National Agency for Research on AIDS and Viral Hepatitis

Bristol-Myers Squibb

Gilead Sciences

Investigators

Principal Investigator:	Christophe Piketty, MD	Hopital Européen Georges Pompidou Paris, service d'immunologie clinique
Study Chair:	Jean Pierre Aboulker, MD	Inserm SC10

More Information

Publications of Results:

Piketty C, Gerard L, Chazallon C, Calvez V, Clavel F, Taburet AM, Girard PM, Aboulker JP; ANRS 107 Puzzle 2 Study Group. Virological and immunological impact of non-nucleoside reverse transcriptase inhibitor withdrawal in HIV-infected patients with multiple treatment failures. AIDS. 2004 Jul 2;18(10):1469-71.

Taburet AM, Piketty C, Chazallon C, Vincent I, Gerard L, Calvez V, Clavel F, Aboulker JP, Girard PM. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2004 Jun;48(6):2091-6.

Study ID Numbers:	ANRS 107 Puzzle 2
Study First Received:	July 19, 2005
Last Updated:	July 27, 2005
ClinicalTrials.gov Identifier:	NCT00122577
Health Authority:	France: Afssaps - French Health Products Safety Agency

Keywords provided by French National Agency for Research on AIDS and Viral Hepatitis:

HIV infections
Treatment Failure
tenofovir
atazanavir

Study placed in the following topic categories:

Virus Diseases
Sexually Transmitted Diseases, Viral
Ritonavir
HIV Infections
Sexually Transmitted Diseases
Acquired Immunodeficiency Syndrome

Tenofovir
Atazanavir
Retroviridae Infections
Immunologic Deficiency Syndromes
Tenofovir disoproxil

Additional relevant MeSH terms:

Anti-Infective Agents
RNA Virus Infections
HIV Protease Inhibitors
Slow Virus Diseases
Anti-HIV Agents
Immune System Diseases
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Infection

Antiviral Agents
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Protease Inhibitors
Anti-Retroviral Agents
Therapeutic Uses
Lentivirus Infections
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on January 16, 2009