Atazanavir/r + Lamivudine Dual Therapy (ATLAS)

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

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.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Atazanavir, ritonavir, lamivudine

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.

• Study Type: Interventional
• Enrollment (Actual): 266
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy, 60126
    • Azienda Ospedaliero Universitaria - Ospedali Riuniti di Ancona Struttura Organizzativa Dipartimentale (S.O.D) Clinica di Malattie infettive
  • Brescia, Italy, 25123
    • Azienda Ospedaliera Spedali Civili - Istituto di Malattie Infettive e Tropicali
  • Catania, Italy, 95122
    • Azienda Ospedaliera di Rilievo Nazionale di alta specializzazione Garibaldi di Catania - Istituto Malattie infettive
  • Genova, Italy, 16132
    • Azienda Ospedaliera Universitaria San Martino - Clinica Malattie Infettive
  • Milano, Italy, 20127
    • Ospedale San Raffaele
  • Milano, Italy, 20126
    • A.O. Ospedale Niguarda Cà Granda - Malattie Infettive
  • Milano, Italy, 20157
    • Ospedale Luigi Sacco di Milano - Malattie infettive I Divisione
  • Milano, Italy, 20157
    • Ospedale Luigi Sacco di Milano Azienda ospedaliera e Polo Universitario - Dip. di Scienze Cliniche L. Sacco / Sez. Malattie Infettive
  • Palermo, Italy, 9127
    • A.O. Universitaria Policlinico Paolo Giaccone di Palermo - Malattie Infettive
  • Perugia, Italy, 06129
    • Ospedale S. Maria Della Misericordia
  • Roma, Italy, 00144
    • IRCCS Istituto Dermatologico S. Gallicano (IFO) - UOC Dermatologia Infettiva
  • Roma, Italy, 00149
    • I.N.M.I. L. Spallanzani I.R.C.C.S. - .O.C. Malattie Infettive e Tropicali IV Divisione
  • Roma, Italy, 00149
    • I.N.M.I. L. Spallanzani I.R.C.C.S. - U.O.C. Infezioni Sistemiche e dell'Immunodepresso II Divisione
  • Roma, Italy, 00161
    • Università' degli studi di Roma La Sapienza - Dipartimento di Malattie Infettive e Tropicali
  • Roma, Italy, 00168
    • Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli - Istituto di Clinica delle Malattie Infettive
  • Sassari, Italy, 07100
    • Università degli studi di Sassari - Reparto Malattie Infettive
  • Torino, Italy, 10149
    • Ospedale Amedeo di Savoia - Divisione A Malattie Infettive
  • Treviso, Italy, 31100
    • Azienda ULSS 9 Treviso Ospedale S. Maria di Ca'Foncello - U.O. Malattie infettive
  • Verona, Italy, 37134
    • Azienda Ospedaliera Universitaria Integrata di Verona - U.O.C. Malattie infettive
  • Firenze
    • Bagno a Ripoli, Firenze, Italy, 50011
      • Ospedale S. M. Annunziata - U.O. Malattie Infettive
  • Lecce
    • Galatina, Lecce, Italy, 73013
      • P.O. "S. Caterina Novella" - UOC di Malattie Infettive

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with viral load < 50 copies/mL	Proportion of patients with viral load < 50 copies/mL at week 48 at the intention-to-treat with switch = failure analysis	at week 48

Secondary Outcome Measures

Outcome Measure	Time Frame
Efficacy and the safety of atazanavir with ritonavir combined with lamivudine in treatment experienced HIV positive patients with full and stable virological suppression	48 and 96 weeks

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• Fabbiani M, Gagliardini R, Ciccarelli N, Quiros Roldan E, Latini A, d'Ettorre G, Antinori A, Castagna A, Orofino G, Francisci D, Chinello P, Madeddu G, Grima P, Rusconi S, Del Pin B, Lombardi F, D'Avino A, Foca E, Colafigli M, Cauda R, Di Giambenedetto S, De Luca A; ATLAS-M Study Group. Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed HIV-infected patients: 96 week outcomes of a randomized trial. J Antimicrob Chemother. 2018 Jul 1;73(7):1955-1964. doi: 10.1093/jac/dky123.
• Di Giambenedetto S, Fabbiani M, Quiros Roldan E, Latini A, D'Ettorre G, Antinori A, Castagna A, Orofino G, Francisci D, Chinello P, Madeddu G, Grima P, Rusconi S, Di Pietro M, Mondi A, Ciccarelli N, Borghetti A, Foca E, Colafigli M, De Luca A, Cauda R; Atlas-M Study Group. Treatment simplification to atazanavir/ritonavir + lamivudine versus maintenance of atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M). J Antimicrob Chemother. 2017 Apr 1;72(4):1163-1171. doi: 10.1093/jac/dkw557.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): February 23, 2018

Study Registration Dates

• First Submitted: May 14, 2012
• First Submitted That Met QC Criteria: May 15, 2012
• First Posted (Estimate): May 16, 2012

Study Record Updates

• Last Update Posted (Actual): July 24, 2019
• Last Update Submitted That Met QC Criteria: July 23, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Lamivudine; Atazanavir; Ritonavir; HIV infection; non-inferiority; virological suppression; Combined antiretroviral therapy
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lamivudine; Atazanavir Sulfate
• Other Study ID Numbers: ATLAS 2; 2011-001060-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No