Cohort Study of HIV-positive People, Treated With Long Acting Antiretroviral Therapy

Study Overview
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Brief Summary
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Systematic, continuative collection of clinical and laboratory data on patients followed at lnfectious Diseases Unit of the IRCCS San Raffaele Hospital in Milan, receiving long-acting ART (Phase IV, single-center, prospective, cohort study) PRIMARY ENDOPOINT: Treatment failure over 48 weeks, defined as virological failure (VF) or therapy discontinuation for any reason (TD) SECONDARY ENDPOINTS: Clinical and pharmacological determinants of efficacy, tolerability, toxicity Modifications in risk and incidence of comorbidities Description of drug-resistance in case of VR Efficacy of rescue regimens in case of VF Quality of life and patient's satisfaction

Detailed Description
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The SCohoLART Study consists of the systematic, continuative collection of clinical and laboratory data on patients followed at the Centro San Luigi (lnfectious Diseases) of the IRCCS Ospedale San Raffaele in Milano, receiving long-acting ART regimens. Currently the Centro San Luigi follows-up·5122 HIV-infected patients; we hypothesize that at least one third of them (roughly 1500) could be initially eligible for a long-acting ART with cabotegravir and rilpivirine The collection of study related clinical and laboratory information, as well as study specific blood samples, will start only after the patient has given and dated/signed his/her informed consent to participate in the study. Patients enrolled in this cohort will be followed according to the standard of care; they will receive the prescribed long-acting regimen according to the indication and posology authorized by AIFA and described in the technical sheet of the drug(s). Follow-up ambulatory visits and laboratory tests will be generally performed every 6 months (earlier, if necessary, on patient's demand or physician's opinion). According to EACS guidelines, patients with obesity, metabolic syndrome or persistent ALT elevation will be evaluated for suspected non-alcoholic fatty liver disease (NAFLD) by ultrasonography and then by liver transient elastography (fibroscan), if NAFLD suggested by ultrasonography. The following information will be checked and recorded at baseline: HIV viral load, CD4+ cell count, co-infection with viruses causing hepatitis (in particular HBV), history of AIDS-defining events; Smoking habit, alcohol consumption; Current comorbidity (including cancers, diabetes, cardio-vascular, kidney and liver diseases, psychiatric disorders (with focus on depression), sexually transmitted diseases; concomitant medications; lipid profile, glycemic metabolisms; if previously performed, results of drug resistance testing. The following information will be acquired at each follow-up visit: general clinical evaluation (e.g. symptoms, new clinical events, including adverse events, vital signs); results of the last routine laboratory tests; results of other investigations (e.g. radiological evaluations, ultrasonography); concomitant medications; Abdominal circumference and weight; Systolic and diastolic blood pressure; Drug plasma concentrations; lnterval since last injection; Quality of life and patient's satisfaction. Adjunctive blood samples (28 ml) will be collected and then stored at the following timepoints: Baseline (start of the long-acting regimen) Every 1 year thereafter or at the stop the long-acting regimen. Investigations that will be performed on stored blood samples are not fully anticipated; they will be gradually defined in consequence of clinical issues that will emerge during patients' follow-up. It can be anticipated that these investigations will include biomarkers of central nervous system toxicity and of HBV monitoring in patients who are HBsAg-negative, but HBcAb-positive. The study is observational; if necessary, the antiretroviral therapy will be modified by the reference physician, according to the standard of care; the participation in the protocol will not influence any therapeutic decision. Adverse events will be managed according to the post-marketing legislation: it is responsibility of the promoter/investigator to notify (as normai clinical practice) any adverse reaction occurring during the study according to the norm issued by AIFA on 20/03/2008, which applies to any adverse reaction observed by doctors or other healthcare professional, on the basis of the Decreto Ministeriale del DM issued on 30/04/2015 and following updates. In parallel, the investigator will also notify the person in charge of the pharmacovigilance of Ospedale San Raffaele (the Director of the hospital pharmacy), by completing the adverse reaction form within two days from being aware of the reaction or within 36 hours if the reaction follows the administration of biological drugs, including vaccines. The cumulative probabilities of treatment failure or virological failure or discontinuation at 12, 24, 48 weeks since the start of the study regimen will be estimated overall and according to a number of baseline characteristics by the Kaplan-Meier curve and compared by the log-rank test. These analyses will consider as baseline the date of start of the long-acting ART regimen with cabotegravir and rilpivirine; follow-up will accrue from the baseline date to the date of treatment failure/virological failure/discontinuation or last available visit. Univariate and multivariate Cox proportional hazard regression models will be performed to identify baseline factors associated with treatment failure. Baseline covariates with a statistically significant (p<0.05) or marginally significant (p-value <0.20) difference between people with or without treatment failure at univariate analyses and other baseline characteristics known to be associated with the study outcome will be entered into the multivariate model. Variables will be assessed for multicollinearity before inclusion into the final multivariate model. The analysis will also assess significant changes in laboratory parameters occurred during the treatment with the study regimen by univariate mixed linear models (with random slope and random intercept), if more than 2 determinations will be available during the considered follow-up; otherwise absolute changes between the baseline and last available determination (untimed) will be calculated and tested by the Wilcoxon signed-rank test. The analyses will be conducted using two-sided test at 0.05 alpha level of significance and using SAS v 9.4 (Cary, NC). Data will be collected and filed by means of the electronic clinical chart for ambulatory patients currently in use at the Centro San Luigi (Malattie Infettive), IRCCS Ospedale San Raffaele in Milano for the routine management of HIV-infected patients followed at the aforementioned center. All data extracted from patient charts will be de-identified. Only the investigators, and the clinical staff involved in this study, will have access to the de-identified data. All data will be protected from unauthorized access. The data will be stored and recorded in an electronic database in pseudo-anonymous form. The details of the names or initials will be replaced by a number and/or an alphabetic code, possibly with the year of birth of the patients. All documents will be stored in a protected place.

Official Title
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Cohort Study of HIV-positive People, Treated With Long Acting Antiretroviral Therapy (SCohoLART)

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Cabotegravir 600mg/3mL, Rilpivirine 900mg/3mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infection; Age > 18 years; HIV-RNA <50 copies/ml; Stable ART; Planned start of a long-acting regimen approved by AIFA (initially, cabotegravir and rilpivirine); Written informed consent provided. Exclusion Criteria: - Any contraindication to the use of one or more long-acting drug, according to the technical sheet of the long-acting drug(s) planned to be started (including pregnancy, current or planned).

Ages Eligible for Study
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Minimum Age: 18 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HIV-positive people virologically suppressed without resistance/failure to NNRTI and INI<br>Initial administration of two separate intramuscolar injection of cabotegravir 400mg/3mL and rilpivirine 600mg/3mL in opposite gluteal muscles, repeated one month later and then every two months. | Drug: Cabotegravir 600mg/3mL, Rilpivirine 900mg/3mL<br>* Initial administration of two separate intramuscolar injection of cabotegravir 400mg/3mL and rilpivirine 600mg/3mL in opposite gluteal muscles, repeated one month later and then every two months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative proportion of people with treatment failure | The primary study endpoint will be the cumulative proportion of people with treatment failure over 48 weeks. Treatment failure is defined by the occurrence of virological failure (2 consecutive HIV-RNA values >50 copies/mL or a single HIV-RNA value >1000 copies/mL after the start of a long-acting ART with cabotegravir and rilpivirine) or discontinuation for any reason of the study regimen. The SCohoLART Study wants to collect clinical data on HIV-infected patients treated with long-acting regimens approved by AIFA (cabotegravir and rilpivirina), in order to optimize during a long-term follow-up their clinical management. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative proportion of people with experience of toxic effects | The secondary outcome is the cumulative proportion of people who experience toxic effects in order to define tolerability and toxicity (including reasons for stopping). | 48 weeks | 
| Cumulative proportion of individuals with HIV-RNA <50 copies/mL at 1 and 2 years | As secondary outcome we want to define clinical and pharmacological determinants of efficacy at 1 and 2 years | 48 weeks | 
| Triglycerides (mg/dl) as values of risk comorbidities | As secondary outcome we want to describe possible modifications in the risk of comorbidities (including BMI, lipid profile, renal function and liver fibrosis) | 48 weeks | 
| Total cholesterol (mg/dl) as values of risk comorbidities | As secondary outcome we want to describe possible modifications in the risk of comorbidities (including BMI, lipid profile, renal function and liver fibrosis) | 48 weeks | 
| High density lipoprotein cholesterol (HDL, mg/dl) as values of risk comorbidities | As secondary outcome we want to describe possible modifications in the risk of comorbidities (including BMI, lipid profile, renal function and liver fibrosis) | 48 weeks | 
| Low density lipoprotein cholesterol (LDL, mg/dl) as values of risk comorbidities | As secondary outcome we want to describe possible modifications in the risk of comorbidities (including BMI, lipid profile, renal function and liver fibrosis) | 48 weeks | 
| Creatinine (mg/dl) as values of risk comorbidities | As secondary outcome we want to describe possible modifications in the risk of comorbidities (including BMI, lipid profile, renal function and liver fibrosis) | 48 weeks | 
| Glucose (mg/dl) as values of risk comorbidities | As secondary outcome we want to describe possible modifications in the risk of comorbidities (including BMI, lipid profile, renal function and liver fibrosis) | 48 weeks | 
| BMI (kg/m^2) as values of risk comorbidities | As secondary outcome we want to describe possible modifications in the risk of comorbidities (including weight in kilograms, BMI, lipid profile and changes in fat accumulation in the liver) | 48 weeks | 
| Incidence of new comorbidities | Incidence of new comorbidities | 48 weeks | 
| Cumulative proportion and features of drug-resistance | Description of drug-resistance in case of virological failure | 48 weeks | 
| Proportion of individuals achieving virological success (HIV-RNA <50 copies/mL) with new ART regimens in case of virological failure | Efficacy of rescue regimens in case of virological failure | 48 weeks | 
| w-bq12 questionnaire | Quality of life and patient's satisfaction | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV therapy, PLWH, long-acting antiretroviral drugs, cabotegravir, rilpivirine