Real-world effectiveness of sofosbuvir/velpatasvir for the treatment of hepatitis C virus in prison settings

Plain language summary Achievement of elimination of HCV as a major public health threat requires focus on vulnerable populations such as people in prison. The prison population is at high risk of HCV infection but their treatment is complicated by social issues such as mental health disorders and drug use. Simple and effective treatment regimens are required to increase access to treatment and improve cure rates. This real-world analysis across Europe and Canada analyzed data from 20 prison populations. HCV-infected individuals were treated with sofosbuvir/velpatasvir, a once daily treatment which requires minimal monitoring. This regimen achieved high cure rates in the prison population despite the existence of complicating social issues. Background: People in prison are at high risk of hepatitis C virus (HCV) infection and often have a history of injection drug use and mental health disorders. Simple test-and-treat regimens which require minimal monitoring are critical. Methods: This integrated real-world analysis evaluated the effectiveness of once daily sofosbuvir/velpatasvir (SOF/VEL) in 20 prison cohorts across Europe and Canada. The primary outcome was sustained virological response (SVR) in the effectiveness population (EP), defined as patients with a valid SVR status. Secondary outcomes were reasons for not achieving SVR, adherence and time between HCV RNA diagnosis and SOF/VEL treatment. Results: Overall, 526 people in prison were included with 98.9% SVR achieved in the EP (n = 442). Cure rates were not compromised by drug use or existence of mental health disorders. Conclusion: SOF/VEL for 12 weeks is highly successful in prison settings and enables the implementation of a simple treatment algorithm in line with guideline recommendations and test-and-treat strategies.

The «place» of the regional law in the legal order of the Emergency

During the early stages of the Pandemic, a minor Alpine Region, the Valle d’Aosta, has introduced a local legislation for the containment and control of the pandemic emergency, in derogation to the d.P.C.M. system introduced by National Government. The paper moves from Corte cost. 37/2021, which declares null and void the Valle d’Aosta Act, to propose an interpretation of the innovative Executive Orders (d.P.C.M.) issued by central Government to manage the pandemic crisis, in terms of an autonomous system of acts, which resembles some features of the XVIIIth Century. Administrative State. Compares the legal system of the 1848 Piedmontese and then Italian Constitution to the system of the Constitutional State established in 1948. Offers some considerations about the differences between «Emergency» and «Exception» with regard to the XXth Century. Staatsrecht’s notions of Ausnahme- und Notzustand. And finally remarks how thin the borders may be between State of Emergency and State of Exception. © Società editrice il Mulino

Spike specific immune response to sars-cov-2 bnt162b2 mrna-based vaccination in patients with liver cirrhosis

Background: Patients with advanced liver disease have well recognized deficiencies in innate and humoral immunity. Phase 3 trials on both BNT162b2 and mRNA-1273 included an extremely limited number of patients with liver disease, and ChAdOx1-nCoV-19 vaccine completely omitted patients with pre-existing liver diseases. Real life data on vaccine response in cirrhotic patients are lacking. To characterize the vaccine response in patients with liver cirrhosis (LC) considered possibly susceptible to SARS-CoV-2 after vaccination. Methods: Levels of binding antibodies and antigen specific B cells against a recombinant GFP tagged SARS-CoV-2 vaccine S protein and total T and NK in patients with established diagnosis of cirrhosis were evaluated by a combined approach based on serological anti-SARS-CoV-2 QuantiVac ELISA (EUROIMMUN) for IgG to the receptor binding domain (RBD) of viral spike protein (S-protein) and flow cytometry analyses. Both assays were performed at baseline before the first BNT162b2 dose, 7 days after the first dose and 10 days after the second dose. Results were compared with those of a group of healthcare workers (HW) comparable for age and gender. The study is ongoing. Further samples will be collected 60 and 180 days after the second dose. Results: Levels of circulating antibodies, antigen specific B cells and total T and NK-T cells were evaluated in 30 LC mostly of HCV- or HBV- related etiology, naive to COVID-19 infection, vaccinated with BNT162b2 mRNA. The majority of patients were male (58%), mean age was 64.36 ± 5.1 yrs. In 30% of LC, as compared to 40% of HW, antiS1 spike IgG antibodies at day 7 were above the positivity threshold. Mean titers were not different from those observed in HW at the same time-point (154.79±10.9 BAU/ml vs 153.5±29.0 BAU/ml). Levels of antigen specific B cells were increased as compared to healthcare workers (p=0.05). B cell response is shown in the Figure. In addition, helper T-cells and cytotoxic T-cells response was increased in LC as compared to HW (p=0.06). These differences were age-independent. Ten days after the second dose mean anti S1 antibody levels were significantly lower than those observed in HW: 836.60± 657.7 vs 1001±705.7 (p<0.0001). Conclusion: Patients with liver cirrhosis showed an initial cellular immune response to SARS-CoV-2 vaccination stronger than that of HW. This ongoing study will shed light on a possible clonal exhaustion phenomenon occurring in LC patients of viral etiology.

HCV elimination in active PWID: SOF/VEL as a simple tool to implement a test and treat approach in this vulnerable population

Background: The treatment of high priority populations, including patients actively using intravenous drugs (active PWID), must be prioritized to accomplish the WHO HCV elimination goals by 2030. Simplification of the treatment cascade is key to reaching this goal, even more so in the COVID-19 era Sofosbuvir/velpatasvir (SOF/VEL) is a protease inhibitor-free, pangenotypic, panfibrotic, single duration, single tablet regimen, to be taken without regards to food and with limited drug-drug interactions This real-world analysis evaluates SOF/VEL as a simple strategy to implement a testand- treat approach in HCV-infected active PWID Methods: Adult active PWID treated for HCV with 12 weeks SOF/VEL in different clinical settings were included from 25 cohorts in 6 countries Patients with a history of decompensation or prior NS5A-inhibitor exposure were excluded The endpoints were HCV cure (undetectable HCV RNA ≥12 after the end of therapy, SVR12) and time-to-treatment (TT) between most recent HCV RNA measurement and SOF/VEL treatment start Results: Analysis included 340 patients, mean age 44±10years, 84% male, 15% compensated cirrhotic (CC) and 8% treatment-experienced, with 43% genotype (GT) 1 and 41% GT3 73% of patients were diagnosed with a mental disorder, 27% were homeless and 21% incarcerated Of patients with TT available (n=334), 10% were treated the same day of diagnosis, 16% within 1 week, 39% within 1 month, and 69% within 3 months Treatment adherence below 90% was observed in 24 patients (8%) SVR12 is available for 254 patients (75%), as non-virological or unknown cause of failure was documented in 86 patients (25%), 79% due to lost-to-follow-up (LTFU) SVR12 was 98% overall (249/254), 98% (80/82) in non-cirrhotic and 95% (20/21) in CC patients Active PWID with mental disorders showed 97% SVR12 (181/186) Of active PWID with GT3 infection, 96% (104/180) were cured, including 95% (20/21) of those with CC Of 31 patients starting treatment within 1 week of diagnosis, all achieved SVR12 compared to 126/129 (98%) starting within 3 months of diagnosis Conclusion: SOF/VEL is a simple HCV treatment resulting in high cure rates in active PWID, including patients with multiple complicating factors LTFU remains a challenge in this population The simplicity of the SOF/VEL approach allowing for shortening of the patient care cascade and rapid treatment starts with high cure rates may help address this important issue.

Are hcv antibodies positive cirrhotic patients at lower risk of death as compared to cirrhotic of different etiologies when infected by COVID-19?

Background: liver injury has been reported at variable rate during COVID-19 outbreak, but the impact of pre-existing liver damage and related etiology has not been detailed so far Methods: we studied the reciprocal impact of COVID-19 and viral or metabolic pre-existing advanced liver diseases in patients consecutively admitted at 3 Italian hospitals during the COVID-19 emergency In this preliminary analysis we analyzed the results of patients enrolled in the observational study from February 28th to April 10th 2020;further analyses will be presented at the meeting Simultaneously, we investigated the prevalence of COVID-19 in patients with all HCV genotypes and any stage of fibrosis or HCV genotype 3 and cirrhosis prospectively enrolled in two real world studies on sofosbuvir/velpatasvir pangenotypic treatment recently published by our collaborative group Results: in the observational study, prevalence of HCVAbs and HBsAg positivity, among 332 COVID-19 infected patients matched recently reported national data Demographic and laboratory results in the table Overall 27 4% and 24 3%, respectively showed increased ALT and AST levels Only 10 patients (3 0%) had HCVAbs, 1 with detectable HCV-RNA, the remaining with spontaneously or treatment-induced HCVRNA clearance The frequency of HCVAbs among subjects with increased ALT at baseline (6.6%) was significantly higher than in patients with normal liver enzymes (1 8%) (p=0 038) Pre-existing cirrhosis was reported in 10, 7 had non viral origin cirrhosis, 70% of non viral origin died Overall mortality was 27 1% Cirrhosis, older age, low white blood cell (WBC) and lymphocyte count were independent predictors of death (OR=6 14, 95%CI 1 11-34 15, p=0 038;OR=1 05, 95%CI 1 03-1 07, p=0 0001, OR=1 10, 95% CI 1 01-1 16;OR=1 06, 95%CI 0 39-0 90, p=0 015) Among HCV patients recently treated with pangenotypic regimen, only 1 (0 07%) with cirrhosis in the pangenotypic study and 2 (1%) in the GT3 cirrhosis study reported COVID-19 ascertained infection, all of them recovered Conclusion: in the observational study, prevalence of HCVAbs is low among patients with COVID-19 Pre-existing cirrhosis is associated with high mortality Whether patients recently cured for HCV infection had a smaller exposure or were less vulnerable to COVID-19 as compared to patients with cirrhosis of metabolic origin deserves further investigation.

Time from diagnosis to treatment in vulnerable populations versus general population: Do we testand-treat our HCV patients in the same way?

Background: Stigma and poor linkage to care, amplified in the setting of the COVID-19 pandemic, are significant barriers for treating hepatitis C (HCV) in vulnerable patients, reducing our ability to implement a rapid test and treat (TnT) strategy with minimal monitoring within a simple patient cascade, as currently available HCV therapies would allow us to do This real-world analysis evaluates our ability to implement this approach in both general (GP) and vulnerable (VP) populations Methods: HCV-infected patients from 32 clinical cohorts in 8 countries treated with sofosbuvir/ velpatasvir without a history of decompensation or prior NS5A-inhibitor exposure were included in this analysis The VP included prisoners, homeless patients and patients with mental disorders Time to treatment (TT) between the most recent HCV RNA measurement and treatment initiation was estimated based on available data Results: A total of 2449 patients were included, 937 in GP (58% males), 1512 (72% males) in VP (59% with mental disorders, 31% homeless, 10% imprisoned) Mean age [standard deviation] was 55 [14] and 50 [14] years in GP and VP respectively Genotype 3 was observed in 35% and 33% respectively, compensated cirrhosis confirmed in 20% and 18% of GP versus VP. The median TT [MTT, interquartile range] was 55 days [23- 107] in GP and 60 days [27-132] in VP The longest MTT of 66 days [32-134] was observed in patients with mental disorders MTT was 63 days [29-149] in prisoners and 27 days [13-71] among the homeless Only 13% of GP and 8% of VP were treated the same day of diagnosis, and 70% of GP and 63% of VP were treated within 3 months In patients with mental disorders only 4% were treated the same day of diagnosis Cure rates were high and consistent with previously reported cure rates Conclusion: MTT varies across HCV patient groups, from over 6 months to 1 day This analysis shows that a quick treatment start is possible, both in general population and in vulnerable populations, supporting the feasibility of a TnT approach in all populations New strategies should be considered to engage patients with mental disorders in this model of care more effectively.