**4. Discussion**

HCV infection is efficiently spread by injection drug use, and this represents an important public health issue. Furthermore, PWID are very challenging patients to treat due to their difficulties in accessing traditional care in hospital settings and the frequent co-occurrence of alcohol abuse, HIV infection, and psychiatric comorbidities [5,6]. Due to the difficulties in treating PWID, along with often asymptomatic course of HCV infection, there is a risk of underestimating individuals affected by hepatitis C [1]. Similarly, hepatitis C infection represents one of the most prevalent infectious disease among homeless people, and therefore they should be considered a high-risk group and for whom diagnosis and treatment of HCV should be a priority [7]. This lack of data on the real prevalence of HCV infection limits the WHO's goal of eradicating hepatitis C around the world [2]. Attempts to associate harm reduction interventions simultaneously with the administration of safe and short therapeutic regimens may favor a lowered transmission of the virus and a reduction of liver damage in these populations [9,10]. For these reasons, alternative models of care in out-of-hospital setting are spreading in Europe and Italy, with encouraging results [24–26]. Our study showed how an out-of-hospital care model might guarantee a greater percentage of patients starting DAAs with an overall better retention in care for difficult-to-reach groups with HCV infection. In our population, the patients with diagnosis of chronic hepatitis C managed in the out-of-hospital setting were more likely to initiate and complete the therapy, achieving the primary outcome, in comparison to the individuals treated in hospital (*p* = 0.002). Consistently with that, those who were scheduled to start a treatment with DAAs earlier after their first visit were more likely to complete the treatment for HCV infection than those who had to start DAAs with delay (*p* = 0.003). The significantly longer waiting time between the first access to hospital and the scheduled therapy initiation in comparison to the waiting time in out-of-hospital services (216 vs. 28 days) could have represented the major barrier to the "in-hospital" treatment and could explain the lower rate of DAAs treatment in this specific group. All the patients who started therapy were able to complete it (33/33). Therefore, treatment, per se, did not represent an obstacle in completing DAAs therapy in our population. A shorter expected waiting time seemed to increase the retention in care in active PWID (as anticipated). Also, when we focused our analysis on this specific subset of study population (although not statistically significant). We can reasonably assume from our analysis and results that a shorter waiting time is the key for the success of out-of-hospital approach, suggesting that it may play a role as a mediator for a higher proportion of retention in care in the

out-of-hospital setting. Moreover, the presence of peer educators may have contributed to improve the linkage to care in the out-of-hospital setting. Starting treatment quickly and in a more individualized way improved the retention in care of PWID [17,20,24,26]. In agreemen<sup>t</sup> with our findings, recent research conducted in Vienna on DAAs administration as DOT (given at OST facilities) in PWID showed excellent SVR12 rates (99%) in this difficult-to-treat population, similar to patients with expected high treatment compliance in a standard setting [27]. In our study, although the rate of DAAs therapy completion was lower among patients treated in hospital, when we consider the entire subset of subjects who completed treatment, we observed similarly high virological success rates regardless from treatment setting with no statistically significant differences. The 93.9% of SVR 12 in our overall treated population confirmed the efficacy of regimens with DAAs as reported in the real-world published studies [28]. Small sample size and its retrospective nature are limitations of the study. Moreover, this is a real-world study and we have to acknowledge some baseline differences between the two groups that we compared in the analysis. In particular, all of the patients in the in-hospital group were active intravenous drug users, while less than 50% of the out-of-hospital group was currently using intravenous drugs: for this reason, we ran the same analysis including only active PWID. The presence of educators with expertise in the managemen<sup>t</sup> of PWID, which are usually lacking in a traditional hospital setting, might also have contributed to the better retention in care achieved in the out-of-hospital facility. In addition, the "Stop HCV project" was interrupted due to a lack of funds. A prolongation of this program would have added relevant data, such as reinfection rate. The results of an effective anti-HCV treatment can be compromised by the risk of reinfection, associated with the persistence of risk behaviors after achieving SVR. For this reason, for a long time, PWID has been regarded as a neglected. However, recent published data have showed how the incidence of HCV reinfection in PWID after the achievement of SVR is low (1.85 to 22.32/1000 person-years) [18,29]. Longer follow-up periods could have certainly provided further data on this population.

In conclusions, our study demonstrated that underserved patients with chronic hepatitis C, historically defined as "difficult-to-treat" groups due to their social instability and risky behaviors, might benefit from new integrated healthcare approaches, such as an out-of-hospital setting where patients may be diagnosed with chronic HCV infection and cured shortly afterwards. The choice of treatment models that can better adapt to difficult populations, such as PWID and homeless people, will be important for achieving the WHO's goal and therefore further studies are needed.

**Author Contributions:** Conceptualization, B.G. and V.G.; methodology, V.G.; software, V.G.; investigation, B.G., L.B., B.T., S.P. and P.M.; data curation, V.G. and A.Z.; writing—original draft preparation, B.G.; writing—review and editing, V.G. and E.R.D.T.; supervision, G.V. and P.V.; project administration, L.B.; funding acquisition, P.V., L.B. and G.V. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Gilead Sciences (Fellowship Program/Digital Health Program 2018), gran<sup>t</sup> number 04284.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of Declaration of Helsinki, and approved by the Ethics Committee of Policlinico S. Orsola-Malpighi in Bologna (Italy), with the code CE 663/2019/Oss/AOUBo (date 20 November 2019).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data that support the findings of this study are available from the corresponding author, (VG), upon reasonable request.

**Acknowledgments:** We thank Gilead Sciences that supported this work by Gilead Fellowship Program 2018.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
