Atazanavir/r + Lamivudine Dual Therapy (ATLAS)

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	Phase
Human Immunodeficiency Virus	Drug: Atazanavir, ritonavir, lamivudine	Phase 4

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	266 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (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
Study Start Date :	April 2014
Actual Primary Completion Date :	April 2016
Estimated Study Completion Date :	November 2016

Arms and Interventions

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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 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

Outcome Measures

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Primary Outcome Measures :

1. Proportion of patients with viral load < 50 copies/mL [ Time Frame: at week 48 ]
   Proportion of patients with viral load < 50 copies/mL at week 48 at the intention-to-treat with switch = failure analysis

Secondary Outcome Measures :

1. 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 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
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

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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
A.O. Ospedale Niguarda Cà Granda - Malattie Infettive
Milano, Italy, 20126
Ospedale San Raffaele
Milano, Italy, 20127
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
Milano, Italy, 20157
A.O. Universitaria Policlinico Paolo Giaccone di Palermo - Malattie Infettive
Palermo, Italy, 9127
Ospedale S. Maria della Misericordia
Perugia, Italy, 06129
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
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 Roma La Sapienza - Dipartimento di Malattie Infettive e Tropicali
Roma, Italy, 00161
Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli - Istituto di Clinica delle Malattie Infettive
Roma, Italy, 00168
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

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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, Focà 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 Apr 12. doi: 10.1093/jac/dky123. [Epub ahead of print]

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, Focà 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.

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 ( EudraCT Number )
First Posted:	May 16, 2012
Last Update Posted:	August 16, 2016
Last Verified:	August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Simona Di Giambenedetto, 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; Immunologic Deficiency Syndromes; Immune System Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Slow Virus Diseases; Ritonavir; Atazanavir Sulfate	Lamivudine; HIV Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors