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

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.

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).

The study will include HIV-infected patients, followed at IRCCS Ospedale San Raffaele in Milano, who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class.

Patients will be included in the cohort only after having agreed with the reference physician to switch from the current to a long-acting ART regimen, only after AIFA has approved the long-acting regimen planned to be started, and only after having given their informed consent to participate in the cohort and to have their anonymized clinical and laboratory data analyzed for scientific purpose.