A Study of a Nucleoside Sparing Regimen in HIV-1 Infected Patients With Detectable Viremia

Study Overview
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Brief Summary
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Research ipotesis is to assess the efficacy and safety of a nucleos(t)ide sparing regimen of atazanavir/ritonavir 300 mg /100 mg QD + Dolutegravir 50 mg QD for the management of virological failure in HIV-1 infected patients. The Primary Objective is to explore the 24-week efficacy of a nucleos(t)ide sparing regimen of atazanavir 300 mg QD/ ritonavir 100 mg QD + Dolutegravir 50 mg QD for the management of virologic failure in HIV-1 infected, integrase inhibitor-naïve subjects.

Detailed Description
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Study design; • 24-week prospective, single-arm, monocentric, open label, pilot study Participants will be seen at screening, baseline, day 8 and at week 4, 8, 12, 16, 24. At each visit the following evaluations will be performed: clinical assessment. routine laboratory tests (hematological tests and clinical chemistry) including hemochromocytometric examination with leukocytic formula, creatinine, creatine kinase, transaminases, phosphorus, calcium, alkaline phosphatase, total and direct bilirubin, gammaGT, uric acid, lactate dehydrogenase, urine analysis, glucose, lipid profile, HIV-RNA and CD4 cell counts. Additional blood samples will be collected at each visit for storage and further determinations. During follow-up, at different timepoints, patients will additionally undergo: HbA1c and fasting insulin levels and HOMA-IR determination (baseline, week 12, week 24) Adherence assessment (questionnaire and/or pills counts) at week 4, 12 and 24. ECG (baseline and week 24) Protocol virologic failure is defined as < 1 log10 decrease in plasma HIV-1 RNA by week 12, with subsequent confirmation, unless plasma HIV-RNA < 200 copies/ml OR a confirmed rebound in plasma HIV-RNA levels ≥ 50 copies/ml after prior confirmed suppression to < 50 copies/ml OR a confirmed plasma increase in HIV-1 RNA levels > 1log10 copies/ml above the nadir value where nadir is ≥ 50 copies/ml OR a plasma HIV-1 RNA level ≥ 50 copies/ml at week 24 Subjects who meet a protocol-defined virologic failure during follow-up will be discontinued from the study. Patients who suppress HIV-1 RNA < 50 cp/ml before week 24 and have a viral blip ≥ 50 copies/ml at week 24 will undergo a plasma HIV-1 RNA re-test to confirm the virologic failure. At virologic failure subjects will perform genotypic and phenotypic tests and a plasma determination of ATV and DTG Cthrough. No changes in study treatment are allowed with the exception of ritonavir (RTV) discontinuation in patients with hyperbilirubinemia and/or gastrointestinal adverse events judged as RTV-related by the Investigator. In this case, subjects will remain on study using the regimen ATV 400mg QD + DTG 50mg QD. The discontinuation of RTV will not be considered as treatment failure. In subjects with plasma HIV-RNA < 50 copies/ml at week 24, the study treatment will be successively provided by Italian National Health system.

Official Title
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A Pilot Phase II Study of a Nucleoside Sparing Regimen of Dolutegravir + Atazanavir/r in HIV-1 Infected Patients With Detectable Viremia (DOLATAV Study)

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: atazanavir 300 mg + ritonavir 100 mg + dolutegravir 50 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with age more than 18 years Willing and able to provide informed consent Failing a stable (at least 3 months) antiretroviral therapy (HIV-RNA more than 200 copies/ml) Any CD4 cell count Virus susceptible to atazanavir, defined as a genotypic mutation score inferior to 15 according to the HIV drug resistance database (Stanford University) No previous documented virologic failure during an atazanavir-containing regimen No previous exposure to integrase inhibitors Absolute neutrophil count (ANC) more than 500/mm3 Haemoglobin more than 8.0 g/dL Platelet count more than 60,000/mm3 e-GFR> 60 ml/min using CKD-EPI equation Exclusion Criteria: Active AIDS-defining condition at Screening Serious illness requiring systemic treatment and/or hospitalization Current use of immunomodulant or immunosuppressive drugs Requirement for any concomitant medications that are prohibited with any study drugs (protocol section 3.6) History or presence of hypersensitivity to any of the active substances or to the excipients Alanine aminotransferase (ALT) more than 5 times the upper limit of normal (ULN), OR ALT more than 3xULN and bilirubin more than 1.5xULN (with more than 35 percent direct bilirubin) Subjects positive for Hepatitis B at screening (HBsAg positive) Subjects with anticipated need for Hepatitis C virus (HCV) therapy during the study Presence of moderate or severe hepatic impairment (defined as a Class B or C at Child Pugh Classification) or presence of unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice) or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Pregnancy or pregnancy wish; breastfeeding Moreover, all clinical conditions reported as an absolute contraindication in the summary of product characteristics of the study drugs, will be considered as exclusion criteria.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open label single arm<br>Introduction of treatment regimen with atazanavir 300mg qd + ritonavir 100mg qd + dolutegravir 50mg qd | Drug: atazanavir 300 mg + ritonavir 100 mg + dolutegravir 50 mg<br>* Switch to single arm treatment atazanavir-ritonavir 300-100 mg + dolutegravir 50 mg therapy for 24 weeks<br>* Other names: Reyataz 300 mg + norvir 100 mg + tivicay 50 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary endpoint - The proportion of patients with undetectable HIV RNA viral load ( < 50 copies/ml) at week 24 | The proportion of patients with undetectable HIV RNA viral load ( < 50 copies/ml) at week 24. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of patient with undetactable HIV RNA at week 4 (Virologic efficacy) | proportion of patient with undetactable HIV RNA at week 4 | 4 week | 
| Change from baseline CD4 cell counts (Immunological efficacy) | Change from baseline CD4 cell counts | 4,8,12,16,24 weeks | 
| Time to achieve undetectability (Virologic efficacy) | Time to achieve undetectability | Day 8, weeks 4,8,12,16,24 | 
| Occurrence of genotyping resistance mutations for PI and INSTI in isolates from patients with virological failure. | Occurrence of genotyping resistance mutations for PI and INSTI in isolates from patients with virological failure. | 24 week | 
| Atazanavir and Dolutegravir Ctrough (PK evaluation) | Atazanavir and Dolutegravir Ctrough | Day 8, weeks 4,8,12,16,24 | 
| Proportion of patients with adverse events (safety and tolerability). | Proportion of patients with adverse events (any grade, proportion of patients with more than or equal than grade 2 AE, proportion of patients with side effects leading to discontinuation, reason for treatment discontinuation. | Day 8, weeks 4,8,12,16,24 | 
| Changes in lipid, clearance creatinine and glycemic profile from baseline (safety and tolerability) | Changes in lipid, clearance creatinine and glycemic profile from baseline | weeks 4,8,12,16,24 | 
| Change in ECG parameters (safety and tolerability) | Change in ECG parameters | 24 week | 
| Adherence evaluation | Adherence changes since first evaluation using questionnaire | 8,12,16,24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1