Atazanavir/r + Lamivudine Dual Therapy

Human Immunodeficiency Virus Clinical Trial

— ATLAS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01599364
• Other study ID #: ATLAS 2
• Secondary ID: 2011-001060-21
• Status: Completed
• Phase: Phase 4
• Start date: April 2014
• Est. completion date: February 23, 2018

Study information

• Verified date: July 2019
• Source: Catholic University of the Sacred Heart
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 266
• Est. completion date: February 23, 2018
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus
• Immunologic Deficiency Syndromes

Intervention

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

Locations

Country	Name	City	State
Italy	Azienda Ospedaliero Universitaria - Ospedali Riuniti di Ancona Struttura Organizzativa Dipartimentale (S.O.D) Clinica di Malattie infettive	Ancona
Italy	Ospedale S. M. Annunziata - U.O. Malattie Infettive	Bagno a Ripoli	Firenze
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	P.O. "S. Caterina Novella" - UOC di Malattie Infettive	Galatina	Lecce
Italy	Azienda Ospedaliera Universitaria San Martino - Clinica Malattie Infettive	Genova
Italy	A.O. Ospedale Niguarda Cà Granda - Malattie Infettive	Milano
Italy	Ospedale Luigi Sacco di Milano - Malattie infettive I Divisione	Milano
Italy	Ospedale Luigi Sacco di Milano Azienda ospedaliera e Polo Universitario - Dip. di Scienze Cliniche L. Sacco / Sez. Malattie Infettive	Milano
Italy	Ospedale San Raffaele	Milano
Italy	A.O. Universitaria Policlinico Paolo Giaccone di Palermo - Malattie Infettive	Palermo
Italy	Ospedale S. Maria della Misericordia	Perugia
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	IRCCS Istituto Dermatologico S. Gallicano (IFO) - UOC Dermatologia Infettiva	Roma
Italy	Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli - Istituto di Clinica delle Malattie Infettive	Roma
Italy	Università' degli studi di Roma La Sapienza - Dipartimento di Malattie Infettive e Tropicali	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

Sponsors (1)

Lead Sponsor	Collaborator
Catholic University of the Sacred Heart

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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

External Links

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