key: cord-0024632-jhb8k9si
authors: Mangia, Alessandra; Rina, Maria Franca; Canosa, Antonio; Piazzolla, Valeria; Squillante, Maria Maddalena; Agostinacchio, Ernesto; Cocomazzi, Giovanna; Visaggi, Egidio; Augello, Nazario; Iannuzziello, Camilla; Falcone, Mattia; De Giorgi, Angelo; Campanozzi, Fausto
title: Increased Hepatitis C virus screening, diagnosis and linkage to care rates among people who use drugs through a patient‐centered program from Italy
date: 2021-10-26
journal: United European Gastroenterol J
DOI: 10.1002/ueg2.12156
sha: 9b2cbbdd5479c9066a6f7469926fd48588851a05
doc_id: 24632
cord_uid: jhb8k9si

BACKGROUND: Rates of Hepatitis C virus (HCV) testing and diagnosis are variable among people who use drugs (PWUD). In Puglia in 2018, of 871 subjects screened, 38% had HCV antibodies (HCVAb). Despite sustained virologic response at week 12 Sustained virologic response (SVR12) rates >95%, addiction centers in Italy are not allowed to prescribe direct‐acting antivirals (DAA). AIM: To increase testing and linkage to care a dedicated program including “ad hoc” transportation and fast‐track access to care was offered to PWUD from Puglia. METHODS: Over 12 months, 1,470 individuals seen at 15 Services for Dependence (SERDs) underwent screening. For HCVAb positive, a fast‐track evaluation was offered at our Hepatology Unit. Patients were subsequently taken to their pharmacists to receive the prescribed DAA regimen. Treatment and adherence were supervised by SERDs physicians, SVR12 assessed at our unit. The scalability of the process was based on both, number of patients screened in our region in 2018, and number of PWUD diagnosed and treated at our center during 2018–2019. RESULTS: Of 1,470 individuals screened, 634 (43.1%) tested HCVAb positive. Overall, 231 were RNA positive, 54% of whom on opioid agonist therapy (OAT) and 32% with cirrhosis. Median interval between RNA assessment and treatment start was 22 days (0–300). Patients received 12‐week sofosbuvir/velpatasvir regimen without Ribavirin; in 220 patients who completed treatment, SVR12 was 98.6%. Among GT3, SVR12 was 98%. No re‐infection was observed. Improvements in screening, and linkage to care were registered. CONCLUSIONS: A PWUD‐tailored service led to HCV care cascade improvement and high SVR12 rates. Despite history of drug addiction, social instability and logistic barriers, micro‐elimination programs providing dedicated care are key drivers of success.

Globally 71 million people live with Hepatitis C virus (HCV) infection, a major cause of end-stage liver disease. With recent advances in antiviral therapy, HCV has become curable and HCV elimination foreseeable, allowing for major health, societal, and economic benefits. 1 Nevertheless, it has been recently reported that even among high-income countries, only 11 are on track to eliminate HCV by 2030, five more countries are on track for elimination by 2040, while all the remaining will eliminate HCV by 2050 or later. 2 This is mostly due to an insufficient number of diagnosed patients, low linkage to care and treatment rates across the majority of countries. In addition, the COVID-19 pandemic is having deep impact on chronic liver diseases management. 3 Screening campaigns appear more difficult to implement, and testing and access to treatment are reduced. 4 It is clear that one size fits all strategy to achieve global elimination would be unsuccessful and that different populations with chronic HCV infection require dedicated programs. 5 Micro-elimination consisting in achieving elimination in a well-defined group currently appears more feasible and measurable than macro-elimination. 6 A key aspect of HCV micro-elimination is to individualize interventions according to local needs.

HCV infection is common among people using substances people who use drugs (PWUD), and PWUD mean young age is a major risk factor for HCV transmission. 7 Although being an underserved and challenging population for several reasons -including lack of updated information on undiagnosed cases, low linkage to care rate, difficulties in engaging and completing treatment courses, and risk of reinfections-PWUD represent a group to prioritize when aiming at achieving global HCV elimination.

In Italy, in 2018 up to 70% prevalence of HCV infection has been reported among PWUD, 8 however, data on HCV screening rate are unclear and variable. Addiction centers are not allowed to prescribe direct-acting antivirals (DAA) and are often located in areas far from prescription centers. In our geographical region, despite 32 DAA prescribing centers, the number of PWUD screened remains low. Based on a recent estimate, less than 10% of PWUD living in Puglia underwent HCV screening in 2020 over an expected number of substance users of about 9,000. 9 Barriers to treatment include poor venous access, fear of screening and of treatment side effects driven by previous IFN-based regimens; however, the most impactful appears to be distance from specialist centers. Moreover, lack of direct public transportations linking our prescribing center to the peripheral SERDs, together with complexity and duration of baseline pre-treatment assessments represent a major obstacle to HCV cure in this population. To increase screening and linkage to care in PWUD, we designed a tailored strategy including educational sessions at 15 different SERDs located in our geographical area, fast-track local screening

Micro-elimination in a well-defined group of patients or pathological context is required to achieve global HCV elimination. PWUD represents an underserved group to prioritize. Data on PWUD screened and diagnosed in Puglia remain suboptimal and limited by distance from Services for dependence (SERDs) not allowed to prescribe DAA and prescribing centers. A strategy tailored on the local needs and including a dedicated shuttle service to reduce logistic barriers and a fast-track baseline assessment to simplify patients pathway was designed to increase the number of PWUD screened, diagnosed and linked to treatment. A strict collaboration between SERD's screening patients and monitoring their treatment, and our center diagnosing HCV infection, prescribing sofosbuvir/velpatasvir combination and assessing SVR12 response was established and resulted helpful in minimizing the effect of the COVID-19 pandemic.

In comparison to the 9.8% screening rate reported in Puglia in 2018, the 62.9% screening rate registered in our study was a significant improvement. Significantly higher was also the rate of HCVAb positive subjects identified. The rate of PWUD linked to care increased at our center from 83.9% in 2018 to 99% in this study. SVR12 was attained in 96% of patients regardless of cirrhosis or genotype. Patient-tailored multidisciplinary approaches enhance scalability and lead to many patients benefits including prioritize access to care, rapid start of treatment and high SVR12 rates. After this program, SERDs implemented a shuttle service for their patients.

UNITED EUROPEAN GASTROENTEROLOGY JOURNAL activities, and a dedicated transportation service between the SERDs and our prescribing center.

An outreach program targeting individuals with substance addiction history, followed at 15 SERDs in Puglia was implemented.

Subjects underwent HCV screening at each SERD using rapid The study started on July 1, 2019 and was expected to be completed by June 30, 2020. However, due to the COVID-19 pandemic lockdown (that in Italy in 2020 was complete and mandatory from March 9 to May 18, and partial for 69 days), the study was put on hold. We consequently extended the study end date, and patients treatment completion was planned by the end of October 2020. However, the second wave of COVID-19 pandemic once again forced a temporary halt to our project and the end of the study was further extended to January 30, 2021 in order to complete a 12 full months duration. Last study visit was performed on January 29, 2021. Re-infection was assessed by genotyping when required at the time of SVR12 assessment.

Primary outcome measures include (1) number of hepatitis C antibody testing performed by both OraQuick 10 and of HCV RNA assessments by COBAS TaqMan HCV Test versus 2.0 and (2) number of patients linked to care. Due to the fluctuating number of patients followed at each SERD, the screening test was offered to 100 PWUD per SERD. Patients resulting HCV RNA reactive had genotype assessment and were offered treatment. SVR12 and post-treatment follow-up were considered secondary outcomes. SVR12 was assessed for patients starting treatment by effectiveness analysis. Intention to Treat analysis (ITT) was also evaluated.

In order to establish scalability, the number of PWUD screened within this project was compared to the number of those screened at regional level published in the annual report of Health Ministry for 2018. 9 The increase in number of patients linked to care and treated was calcu- 

At the time of the study commencement, 2,358 PWUD were followed at the 15 participating SERDs. Of them, 1,470 agreed to be tested by OraQuick (62.3%) and 634 HCVAbs carriers were identified (43.1%; Figure 1 ). Up to 56% of them were aware of their condition but could not produce previous testing result, for this reason they were included in the general analysis. Overall, 42.4% had received the first diagnosis a mean of 15 years earlier, 45.4% had received standard interferon monotherapy or in combination with ribavirin but had not been tested for HCV RNA after treatment. Baseline characteristics of patients testing HCVAb positive are reported in Table 1 . The vast majority (90.9%) were male. The median age was relatively high (48.1 years), but in keeping with the mean age of Italian PWUD. 12 Overall, 34.8% were on opioid agonist therapy (OAT), this rate suggests that linking screening to OAT increases patients motivation. All had history of previous substance use and 28.4% were active intravenous drug users. All but five attended the first appointment. Overall, 231 patients of the 629 HCVAb positive who accepted to come to our center to be diagnosed 

Baseline characteristics of patients with active infection are reported in Table 2 

All 231 HCV RNA reactive patients were offered treatment. Patients received sofosbuvir/velpatasvir (SOF/VEL) treatment. As shown in Figure 2 , and Table 3 , only two did not accept, one due to the simultaneous diagnosis of cancer, the other due to relocation to a different geographical area. All remaining patients accepted to start treatment, however three did not pick up the drug at their local pharmacy and were lost to follow-up. Of 226 

Overall, 220 patients completed the assigned treatment and all but three achieved SVR12 (98.6%).

The three patients who did not achieve SVR12 were also alcohol abusers and they did not return the bottle of pills for the planned monthly drug counts to their SERDs physician. No difference in SVR12 rates between patients with or without cirrhosis was observed ( Figure 3 ). SVR rates were higher than 95%, irrespective of 

In comparison to the 9.8% screening rate reported by the Regional Health Authorities in 2018 in Puglia, 9 Simplified models of care are key aspects in the success of HCV treatment programs in community settings, and enable scaling up. 14,15 Among diverse strategies adopted to allow HCV elimination, the most successful appear those based on a personalized intervention. Based on these evidence, we designed and implemented a dedicated micro-elimination program focusing on PWUD.

Of a total number of 2,358 PWUD followed at 15 SERDs, up to 62.3% were screened. Although the screening acceptance rate in our study remain suboptimal, this rate appears significantly higher as compared to data attained in the entire Puglia in the very recently published 2021 national report. In that report, among 8,819 PWUD followed by SERDs in our region, only 710 had received HCV screening. 9 Reason for the suboptimal acceptance rate might be related to a center effect, as in larger centers the rate of screening was lower than in smaller ones due to the patients burden (data not shown).

Our results appear well in keeping with those by Linnet et al 16 showing a 50% increase in testing using a decentralized model in which hospital infectious disease department were responsible for prescription and monitoring, and other healthcare providers were responsible for testing, dispensing and adherence support. Among subjects screened during 2018, 38% were found HCVAb positive, according to updated Health Ministry reports. 9 Our results show 5% increase in diagnosis despite a current reduction in the number of patients seeking HCV treatment in Italy, proven by the flattered MANGIA ET AL. There have been recent developments in point of care tests including the rapid oral HCV antibodies test. Incorporation of rapid detection testing (RDT) in the diagnostic pathways can reduce the time from screening to start of treatment. 25 The use of sensitive RDT together with the fast-track procedure and the dedicated transportation service make different approaches as those based on pharmacist intervention unnecessary 26 and ensure the complete baseline work-up to be homogeneously performed at the same center. 27 In addition, this strategy entails a sort of positive selection as only patients who accept to come to our center are motivated to continue on their linkage to care pathways. 28 Given the chaotic lifestyle of these patients, treatment discontinuations or lost to follow-up can be expected. The success of this patient-tailored approach was due to the close monitoring by physicians and nurse personnel at addiction centers and proven by the high treatment adherence rate and few patients lost of follow-up despite the recent drug use. Notably, the rate of loss to follow-up was comparable to that reported in controlled studies. 29, 30 Of course the very marginal number of homeless among our patients is an undeniable advantage as compared to other similar reports.

Moreover, another key of success is the decentralized screening and monitoring. Indeed, in recent reports from Spain where the linkage to treatment was lower than 4%, a centralized approach was used and the rate of patients with mental disorders was higher. 31, 32 In this study, SVR12 rates were extremely high irrespective of HCV genotypes and of disease severity. SVR12 in GT3 patients with cirrhosis was similar to that reported in previous studies using the same treatment regimen. 33 36 The main difference between that and our own experience was the lack of appropriate provider support in our study. Despite that, adherence and SVR were similarly high.

At variance with reports from other European countries as, for example, Spain, the rate of re-infection within a short post-treatment

follow-up appears negligible. 30, 37 These results are of course due to the patients' motivation to carry out a lifestyle change; they need to be confirmed during a prolonged follow-up. The strength of this study is represented by the evidence that tailoring micro-elimination strategies on the local patients needs may be more successful than simply applying national or international guidelines. The strict and direct collaboration (every day phone calls) between the different physicians involved in difficult to treat patients management ensure both decentralization and achievement of pre-determined objectives despite exceptional and unexpected events as COVID-19 pandemic. Finally, the project was shown to be self-sustainable as the shuttle funded by our Institution is from the study end onward funded by some local SERDs.

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Increased Hepatitis C virus screening, diagnosis and linkage to care rates among people who use drugs through a patientcentered program from Italy. United