**1. Introduction**

The worldwide incidence and prevalence of Hepatitis C virus (HCV) infection has been decreasing since the introduction of the new direct antiviral agents (DAAs) as a form of standard of care [1,2] and the World Health Organization (WHO) has established the global goal of eradicating hepatitis C infection as a public health threat by 2030 [3].

Currently, injection drug use represents the primary route of transmission of HCV infection and the main viral reservoir consists of people who inject drugs (PWID) [4,5], among whom a global anti-HCV seroprevalence of 52.3% has been estimated [6].

Prevalence studies have reported that also homeless persons are at high risk for HCV, mostly as a result of injection drug use [7]. Indeed, PWID tend to experience homelessness or unstable housing with prevalence ranging from 6.7% in Eastern Europe to 50.3% in North America [6].

Homelessness and unstable housing have been recently associated to a greater risk for acquiring infections such as HCV and human immunodeficiency virus (HIV) among PWID when compared to PWID who had stable house [8]. A large meta-analysis has estimated an overall prevalence of HCV infection ranged from 3.9% to 36.2% in homeless people, based

**Citation:** Granozzi, B.; Guardigni, V.; Badia, L.; Rosselli Del Turco, E.; Zuppiroli, A.; Tazza, B.; Malosso, P.; Pieralli, S.; Viale, P.; Verucchi, G. Out-of-Hospital Treatment of Hepatitis C Increases Retention in Care among People Who Inject Drugs and Homeless Persons: An Observational Study. *J. Clin. Med.* **2021**, *10*, 4955. https://doi.org/ 10.3390/jcm10214955

Academic Editors: Maria Carla Liberto and Nadia Marascio

Received: 9 October 2021 Accepted: 21 October 2021 Published: 26 October 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

on the results of 12 eligible studies [7]. However, there is a scarcity of epidemiological data on the real prevalence of HCV infection in these difficult to treat subgroups [5]. Since HCV elimination programs barely reach these populations, targeted screening programs are necessary to achieve the goal set by the WHO [4]. For a long time, PWID has been regarded as a neglected population due to the concerns about adherence to treatments and poor treatment outcome. Among others, the MISTRAL study has shown how a safe and effective pan-genotypic treatment regimen, particularly with a short duration, could facilitate an increase in accessing treatments for high-risk populations [9,10]. Currently, guidelines for hepatitis C treatment from both the American and the European Association for the Study of Liver Diseases recommends to treat PWID with chronic HCV infection [11,12].

Factors complicating access to care in this population must be addressed including the stigma, the risk for reinfection in PWID, challenges related to incarceration, and housing instability [5,13].

It is also widely recognized that an integrated harm reduction strategy is needed to control HCV transmission and to reduce community viral load [6,14]. By reducing risk behaviors, HCV testing programs that combine screening and counseling can decrease HCV transmission and reinfection after treatment with DAAs [15,16]. The provision of sterile injecting equipment through needle and syringe programs and the enrolment in opioid substitution treatment (OST) are among the primary interventions for reducing HCV reinfection rate among PWID [17].

Recent data have shown that the incidence of HCV reinfections in PWID after achieving sustained viral response (SVR) is low (1.85–22.32/1000 person-years), with higher rates in active drug users [18,19].

Screening and confirmation tests, linkage to care, retention in care, prescription of DAAs, and adherence to HCV treatment are priorities for fighting the silent epidemic of chronic HCV infection in PWID and homeless people [9,20].

However, PWID and homeless persons have poor access to hospital care due to reduced retention in care and difficulties in accessing traditional screening programs. Therefore, alternative treatment approaches for PWID and homeless people are emerging across Europe [17,20–23].

In Italy, out-of-hospital care models are emerging with the presence of dedicated doctors, nurses, and peer-educators with experience in drug addiction [24–26]. In Italy, the "Stop HCV" project was conceived and conducted in the city of Bologna with the help of the "Open Group-Unità di Strada", a non-profit organization of harm reduction. The project consisted in offering HCV screening and treatment for hepatitis C using DOT (directly observed therapy), in a population of PWID and homeless people, with this occurring in an out-of-hospital setting.

The primary aim of our retrospective study was to measure and compare the retention in care rate, (defined as the completion of DAAs therapy) achieved in a group consisting of PWID and/or homeless persons with hepatitis C managed in a traditional hospital setting (i.e., outpatient services) with the retention in care rate achieved in a group of PWID and/or homeless persons but managed in an out-of-hospital setting.

The secondary aim of the study was to estimate prevalence of patients who started treatment after their linkage-to-care, the time between first visit and the scheduled start of therapy (defined as expected waiting time), and the rate of sustained virological response 12 weeks after the end of treatment (SVR 12).

#### **2. Materials and Methods**

We carried out a retrospective observational study including patients with HCV chronic infection (i.e., with documented detectable HCV RNA), considered eligible for DAAs treatment, who were active or past intravenous drug users and/or who were experiencing homelessness. In order to test our hypothesis that an out-of-hospital setting might ensure a greater retention in care in difficult-to-treat populations, we compared our

outcomes between patients with similar characteristics but treated for HCV in different circumstances (i.e., out-of-hospital and in-hospital services).

Therefore, we included in the study all the patients with confirmed current HCV infection and history of injection drug use or homelessness who access the out-of-hospital facility where "Senza la C" project was established from January to June 2019.

This outpatient care model included an initial screening for HCV using saliva rapid tests (OraQuick® Rapid HCV Antibody by OraSure Technologies, Bethlehem, PA, USA) and a pre-test peer counseling offered by educators from Open Group Onlus, the communitybased service for harm reduction we mentioned beforehand. Patients also received face-toface counselling on HCV treatment, prevention, and re-infection risk.

In case of reactive saliva HCV-Ab test, a point of care HCV-RNA test on whole blood (Xpert® HCV VL Fingerstick by Cepheid, Sunnyvale, CA, USA), transient elastography (Fibroscan® by Echosens, Paris, France) and liver ultrasound were performed. Those who resulted HCV-RNA positive were tested through standard blood tests for liver and kidney function and HCV genotype and they were scheduled to start HCV treatment within three to four weeks.

Each of the following visits was conducted at DAAs initiation, after 4 weeks, at the end of therapy, and 12 weeks and 24 weeks after the end of therapy. HCV RNA viremia was performed at each visit in order to rule out any possible relapse or reinfection.

All diagnostic procedures, drug supplying, treatment monitoring, and post-treatment follow-up were conducted in a low-threshold, extra hospital setting by a team of peer educators, medical doctors, and trained nurses.

We considered as a comparison, a group of patients who met the inclusion criteria and with demographics (age and sex) similar to the group of interest, who had referred to a traditional hospital setting for a visit from May 2017 to August 2018 at our clinic of Infectious Diseases in Bologna (Italy), and were invited by clinicians to start DAAs treatment.

In the out-of-hospital setting, DOT (under the supervision of medical and not-medical staff) was applied, with the support of peer-educators with expertise in managemen<sup>t</sup> of PWID, in the context of the "Stop HCV" project, which we have already mentioned.

All of the patients included in the study who started anti-HCV treatment, received DAAs for 8 or 12 weeks, according to international guidelines.

We assessed retention in care, defined as the completion of the established DAAs therapy, among our study population. We also measured the expected waiting time, which was defined as the time between the first visit and the scheduled start of therapy with DAAs. With regard to the proportion of population who started and completed treatment for hepatitis C, we observed them for six months after end of treatment. For each subject, we collected the following data at baseline: demographics (age, sex, BMI), stage of liver fibrosis (measured by transient elastography, FibroScan® by Echosens, Paris, France), prior failures to anti-HCV treatment, HCV genotype, HCV RNA viremia, DAAs regimen, data on HIV coinfection when present (i.e., HIV RNA viremia, CD4+T-cells count, current antiretroviral regimen), HBV coinfection (i.e., HBsAg positivity), psychiatric comorbidity, OST, and drug use status (i.e., current PWID or not). INR, bilirubin level, ALT level, creatinine level, and HCV RNA viremia were then evaluated at each scheduled visit.
