Safety and Efficacy of Switching a Stable Combined Antiretroviral Therapeutic Regimen to Atazanavir With Ritonavir Plus Lamivudine in Treatment Experienced HIV Positive Patients With Full and Stable Virological Suppression (ATLAS)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Simona Di Giambenedetto, Catholic University of the Sacred Heart
ClinicalTrials.gov Identifier:
NCT01599364
First received: May 14, 2012
Last updated: July 31, 2014
Last verified: July 2014
  Purpose

The purpose of this study is to evaluate the virological efficacy of maintenance therapy with atazanavir with ritonavir combined with lamivudine in treatment experienced HIV positive patients with full and stable virological suppression.


Condition Intervention Phase
Human Immunodeficiency Virus
Drug: Atazanavir, ritonavir, lamivudine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Switching a Stable Combined Antiretroviral Therapeutic Regimen to Atazanavir With Ritonavir Plus Lamivudine in Treatment Experienced HIV Positive Patients With Full and Stable Virological Suppression

Resource links provided by NLM:


Further study details as provided by Catholic University of the Sacred Heart:

Primary Outcome Measures:
  • Proportion of patients with viral load < 50 copies/mL [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
    Proportion of patients with viral load < 50 copies/mL at week 48 at the intention-to-treat with switch = failure analysis


Secondary Outcome Measures:
  • Efficacy and the safety of atazanavir with ritonavir combined with lamivudine in treatment experienced HIV positive patients with full and stable virological suppression [ Time Frame: 48 and 96 weeks ] [ Designated as safety issue: No ]

Enrollment: 266
Study Start Date: July 2011
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Switch
Switch to Atazanavir 300 mg with ritonavir 100 mg plus lamivudine 300 mg
Drug: Atazanavir, ritonavir, lamivudine
Lamivudine 300 mg 1 pill once-a-day, atazanavir 300 mg 1 pill with ritonavir 100 mg 1 pill once-a-day, taken together orally with a light meal
Other Name: Lamivudine (Epivir, GSK), Atazanavir (Reyataz, BMS), Ritonavir (Norvir, Abbott)
No Intervention: continue
Continue Atazanavir 300 mg with ritonavir 100 mg with the same NRTI backbone

Detailed Description:

The introduction of combined antiretroviral therapy (cART) dramatically improved the prognosis of HIV infection [1]; nowadays, virological suppression (viral load < 50 copies/mL) can be obtained in the vast majority of patients receiving cART. Nevertheless, antiretroviral drugs have short- and long-term side effects mainly regarding mitochondrial toxicity, impaired lipid and glucose metabolism, impairment of renal function and bone density and may contribute to increase the patients' cardiovascular risk.

Current treatment guidelines recommend three drug regimens with a "backbone" of 2 nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs) and a "third drug" to be chosen among non-nucleoside reverse transcriptase inhibitors (NNRTIs) and ritonavir-boosted protease inhibitors (PIr). Regimens containing less than three antiretroviral drugs are currently not recommended based on the high risk of virological failure and selection of drug resistance mutations (DRM) with previous experience of NRTI-only based approaches with the exception of boosted PIs monotherapy which is optional in patients with intolerance to NRTIs or requiring treatment simplification provided that they never experienced virological failures or admitted in exceptional circumstances.

Nevertheless, the investigation of possible new treatment paradigms remains attractive due to the high potency and low risk of selection of drug resistance mutations with PIr based therapies and the established long term toxicity of even newer and currently preferred N(t)RTIs, in particular the renal and bone toxicity of tenofovir and the debated potential association with increased cardiovascular risk of abacavir, which has been described in some cohort studies. Studies evaluating N(t)RTI-sparing treatment strategies are thus increasing in order to try to respond to the unmet medical needs of HIV-infected patients with metabolic complications and increasing risk of cardiovascular or renal diseases.

These studies will need to investigate the safety and efficacy of these alternative strategies, also evaluating their possible effects on renal function, bone mass density and risk of premature osteoporosis.

Atazanavir with ritonavir is a generally well tolerated lipid-friendly protease inhibitor with mild effects on lipid metabolism even when combined with low-dose ritonavir and is the only drug who achieved a non-significant difference in virological efficacy compared to efavirenz; like all other PIr-based regimens, failure of an atazanavir/ritonavir containing cART seems to protect against the development of drug resistance mutations to both the PI and the backbone. Lamivudine is a well tolerated NRTI which showed no significant toxicity in the short and long term and, together with its analog emtricitabine, is now a preferred option in most of the major international treatment guidelines; it has a good CNS penetration score and its only signature resistance mutation (M184V) deeply impairs the viral fitness and does not compromise the future treatment options.

The combination of these two drugs could therefore be an appealing possibility for treatment switch in stably virologically suppressed treatment-experienced patients with toxicity-related issues. The results of a previously planned 24 weeks interim analysis of a monocentric 48 weeks Italian pilot study evaluating this strategy in 40 patients has recently been presented at IAS conference in Vienna and showed no virologic failures without any "blip" and good tolerability with a significant improvement of renal function as measured by MDRD. These data look very promising and allow us to be confident in designing a randomized study in order to confirm these findings.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • HIV positive patients 18 years of age or older who signed an informed consent form
  • Already on cART, without any treatment interruption.
  • Treated with a cART regimen containing atazanavir boosted with ritonavir since at least 3 months
  • With full virological suppression (VL<50 copies/mL) for a minimum of six months and in at least in two consecutive determination 3 months +/-2 weeks apart from each other
  • With CD4 cell count >200 since at least 6 months and without opportunistic infections or other AIDS-related events since at least one year before screening

Exclusion Criteria:

  • Previous virological failure on a lamivudine- or PI-containing regimen or previous exposure to lamivudine-containing suboptimal antiretroviral regimens
  • Patients with at least a single viral load blip over 200 copies/mL
  • Patients with M184V or major atazanavir resistance mutation at previous genotypic resistance test (historical genotype)
  • Pregnancy or lactation, planned pregnancy in the short-term
  • Patients with HBsAg positive chronic HBV infection
  • Patients who experienced major toxicities related to any of the study drugs in the past
  • Patients with grade 4 laboratory abnormalities at baseline (excluding lipid profile and plasma bilirubin concentration).
  • Patients with non-AIDS related illnesses which could, in the Clinician's judgement, jeopardize the patient's compliance to the study procedures (i.e. Child-Pugh B or higher liver cirrhosis, active cancers on treatment…).
  • Patients treated with proton-pump inhibitors or other concomitant medication with potential for interactions reducing exposure to atazanavir
  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: NCT01599364

Locations
Italy
Ospedale S. M. Annunziata - U.O. Malattie Infettive
Bagno a Ripoli, Firenze, Italy, 50011
P.O. "S. Caterina Novella" - UOC di Malattie Infettive
Galatina, Lecce, Italy, 73013
Azienda Ospedaliero Universitaria - Ospedali Riuniti di Ancona Struttura Organizzativa Dipartimentale (S.O.D) Clinica di Malattie infettive
Ancona, Italy, 60126
Azienda Ospedaliera Spedali Civili - Istituto di Malattie Infettive e Tropicali
Brescia, Italy, 25123
Azienda Ospedaliera di Rilievo Nazionale di alta specializzazione Garibaldi di Catania - Istituto Malattie infettive
Catania, Italy, 95122
Azienda Ospedaliera Universitaria San Martino - Clinica Malattie Infettive
Genova, Italy, 16132
Ospedale San Raffaele
Milano, Italy, 20127
Ospedale Luigi Sacco di Milano Azienda ospedaliera e Polo Universitario - Dip. di Scienze Cliniche L. Sacco / Sez. Malattie Infettive
Milano, Italy, 20157
Ospedale Luigi Sacco di Milano - Malattie infettive I Divisione
Milano, Italy, 20157
A.O. Ospedale Niguarda Cà Granda - Malattie Infettive
Milano, Italy, 20126
A.O. Universitaria Policlinico Paolo Giaccone di Palermo - Malattie Infettive
Palermo, Italy, 9127
Ospedale S. Maria della Misericordia
Perugia, Italy, 06129
Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli - Istituto di Clinica delle Malattie Infettive
Roma, Italy, 00168
IRCCS Istituto Dermatologico S. Gallicano (IFO) - UOC Dermatologia Infettiva
Roma, Italy, 00144
I.N.M.I. L. Spallanzani I.R.C.C.S. - .O.C. Malattie Infettive e Tropicali IV Divisione
Roma, Italy, 00149
Università' degli studi di Roma La Sapienza - Dipartimento di Malattie Infettive e Tropicali
Roma, Italy, 00161
I.N.M.I. L. Spallanzani I.R.C.C.S. - U.O.C. Infezioni Sistemiche e dell'Immunodepresso II Divisione
Roma, Italy, 00149
Università degli studi di Sassari - Reparto Malattie Infettive
Sassari, Italy, 07100
Ospedale Amedeo di Savoia - Divisione A Malattie Infettive
Torino, Italy, 10149
Azienda ULSS 9 Treviso Ospedale S. Maria di Ca'Foncello - U.O. Malattie infettive
Treviso, Italy, 31100
Azienda Ospedaliera Universitaria Integrata di Verona - U.O.C. Malattie infettive
Verona, Italy, 37134
Sponsors and Collaborators
Catholic University of the Sacred Heart
Investigators
Study Chair: Mauro MM Moroni, MD Università di Milano Direttore clinica Malattie infettive
Study Chair: Pierluigi PZ Zoccolotti, MD Università di Roma La Sapienza Dipartimento di Psicologia
Study Chair: Stafano SV Vella, MD Dipartimento del farmaco all'Istituto Superiore della Sanità
Principal Investigator: Roberto RC Cauda, MD Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli
  More Information

Additional Information:
No publications provided

Responsible Party: Simona Di Giambenedetto, MD, Catholic University of the Sacred Heart
ClinicalTrials.gov Identifier: NCT01599364     History of Changes
Other Study ID Numbers: ATLAS 2, 2011-001060-21
Study First Received: May 14, 2012
Last Updated: July 31, 2014
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by Catholic University of the Sacred Heart:
HIV infection
Atazanavir
Lamivudine
Ritonavir
virological suppression
non-inferiority
Combined antiretroviral therapy

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
HIV Seropositivity
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immune System Diseases
Lamivudine
Ritonavir
Atazanavir
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
HIV Protease Inhibitors
Protease Inhibitors

ClinicalTrials.gov processed this record on August 01, 2014