Atazanavir/r + Lamivudine Dual Therapy

NCT ID: NCT01599364

Last Updated: 2019-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 266 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-30
• Study Completion Date: 2018-02-23

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.

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.

Conditions

Human Immunodeficiency Virus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Switch

Switch to Atazanavir 300 mg with ritonavir 100 mg plus lamivudine 300 mg

Group Type: EXPERIMENTAL

Atazanavir, ritonavir, lamivudine

Intervention Type: DRUG

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

continue

Continue Atazanavir 300 mg with ritonavir 100 mg with the same NRTI backbone

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Lamivudine (Epivir, GSK), Atazanavir (Reyataz, BMS), Ritonavir (Norvir, Abbott)

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Catholic University of the Sacred Heart

OTHER

Sponsor Role: lead

Responsible Party

Simona Di Giambenedetto

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mauro MM Moroni, MD

Role: STUDY_CHAIR

Università di Milano Direttore clinica Malattie infettive

Pierluigi PZ Zoccolotti, MD

Role: STUDY_CHAIR

Università di Roma La Sapienza Dipartimento di Psicologia

Stafano SV Vella, MD

Role: STUDY_CHAIR

Dipartimento del farmaco all'Istituto Superiore della Sanità

Roberto RC Cauda, MD

Role: PRINCIPAL_INVESTIGATOR

Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli

Locations

Ospedale S. M. Annunziata - U.O. Malattie Infettive

Bagno a Ripoli, Firenze, Italy

P.O. "S. Caterina Novella" - UOC di Malattie Infettive

Galatina, Lecce, Italy

Azienda Ospedaliero Universitaria - Ospedali Riuniti di Ancona Struttura Organizzativa Dipartimentale (S.O.D) Clinica di Malattie infettive

Ancona, , Italy

Azienda Ospedaliera Spedali Civili - Istituto di Malattie Infettive e Tropicali

Brescia, , Italy

Azienda Ospedaliera di Rilievo Nazionale di alta specializzazione Garibaldi di Catania - Istituto Malattie infettive

Catania, , Italy

Azienda Ospedaliera Universitaria San Martino - Clinica Malattie Infettive

Genova, , Italy

A.O. Ospedale Niguarda Cà Granda - Malattie Infettive

Milan, , Italy

Ospedale San Raffaele

Milan, , Italy

Ospedale Luigi Sacco di Milano - Malattie infettive I Divisione

Milan, , Italy

Ospedale Luigi Sacco di Milano Azienda ospedaliera e Polo Universitario - Dip. di Scienze Cliniche L. Sacco / Sez. Malattie Infettive

Milan, , Italy

A.O. Universitaria Policlinico Paolo Giaccone di Palermo - Malattie Infettive

Palermo, , Italy

Ospedale S. Maria della Misericordia

Perugia, , Italy

IRCCS Istituto Dermatologico S. Gallicano (IFO) - UOC Dermatologia Infettiva

Roma, , Italy

I.N.M.I. L. Spallanzani I.R.C.C.S. - .O.C. Malattie Infettive e Tropicali IV Divisione

Roma, , Italy

I.N.M.I. L. Spallanzani I.R.C.C.S. - U.O.C. Infezioni Sistemiche e dell'Immunodepresso II Divisione

Roma, , Italy

Università' degli studi di Roma La Sapienza - Dipartimento di Malattie Infettive e Tropicali

Roma, , Italy

Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli - Istituto di Clinica delle Malattie Infettive

Roma, , Italy

Università degli studi di Sassari - Reparto Malattie Infettive

Sassari, , Italy

Ospedale Amedeo di Savoia - Divisione A Malattie Infettive

Torino, , Italy

Azienda ULSS 9 Treviso Ospedale S. Maria di Ca'Foncello - U.O. Malattie infettive

Treviso, , Italy

Azienda Ospedaliera Universitaria Integrata di Verona - U.O.C. Malattie infettive

Verona, , Italy

Countries

Italy

References

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.

Reference Type: DERIVED

PMID: 29668978 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28093483 (View on PubMed)

Related Links

http://atlas.cr-technology.com/

Related Info

Other Identifiers

2011-001060-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ATLAS 2

Identifier Type: -

Identifier Source: org_study_id