A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort.

BACKGROUND AND AIMS: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. METHODS: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. RESULTS: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. CONCLUSIONS: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Switching patterns of biological drugs in patients with psoriasis and psoriatic arthritis: insight from the VALORE database network.

BACKGROUND: Switch patterns among different biologics and from originators to biosimilars (and vice versa) can be complex in patients with psoriasis (PsO) and psoriatic arthritis (PsA). OBJECTIVE: The aim of this study was to describe switching patterns of biological drugs in PsO/PsA patients and to explore predictors of multiple switches and switch-back. RESEARCH DESIGN AND METHODS: A large-scale retrospective cohort study was conducted using the Italian VALORE database. Bio-naïve users treated for PsO/PsA during 2010-2022 were included. Time to switch/swap and predictors of multiple switches and switch-back were analyzed. RESULTS: Thirty-thousand seven hundred bio-naïve users were included. At 3 and 5 years of follow-up, patients with at least one switch/swap were 37.1% and 47.8%, respectively. The median time to first switch/swap was significantly shorter (p< 0.001) for TNF-α inhibitors (2,068 days) than anti-IL (2,780 days). At 1 year of follow-up patients starting with IL-23 switched/swapped biological therapy less frequently than those with anti-IL-12/23 and anti-IL-17 (4.9% vs. 8.7% and 9.4%, respectively). Patients starting with anti-IL-12/23 reported a significantly lower risk of multiple switches and switch-back (0.74, 95% CI, 0.67-0.83; 0.58, 95% CI, 0.44-0.77, respectively) than those with TNF-α inhibitors. CONCLUSIONS: Patients with PsO/PsA starting with TNF-α inhibitors switch/swap more rapidly and frequently than those with anti-IL, which are also associated with a reduced risk of multiple switches during follow-up.

Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV).

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan-Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23-0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16-0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02-2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

CCL18, CHI3L1, ANG2, IL-6 systemic levels are associated with the extent of lung damage and radiomic features in SARS-CoV-2 infection.

OBJECTIVE AND DESIGN: We aimed to identify cytokines whose concentrations are related to lung damage, radiomic features, and clinical outcomes in COVID-19 patients. MATERIAL OR SUBJECTS: Two hundred twenty-six patients with SARS-CoV-2 infection and chest computed tomography (CT) images were enrolled. METHODS: CCL18, CHI3L1/YKL-40, GAL3, ANG2, IP-10, IL-10, TNFα, IL-6, soluble gp130, soluble IL-6R were quantified in plasma samples using Luminex assays. The Mann-Whitney U test, the Kruskal-Wallis test, correlation and regression analyses were performed. Mediation analyses were used to investigate the possible causal relationships between cytokines, lung damage, and outcomes. AVIEW lung cancer screening software, pyradiomics, and XGBoost classifier were used for radiomic feature analyses. RESULTS: CCL18, CHI3L1, and ANG2 systemic levels mainly reflected the extent of lung injury. Increased levels of every cytokine, but particularly of IL-6, were associated with the three outcomes: hospitalization, mechanical ventilation, and death. Soluble IL-6R showed a slight protective effect on death. The effect of age on COVID-19 outcomes was partially mediated by cytokine levels, while CT scores considerably mediated the effect of cytokine levels on outcomes. Radiomic-feature-based models confirmed the association between lung imaging characteristics and CCL18 and CHI3L1. CONCLUSION: Data suggest a causal link between cytokines (risk factor), lung damage (mediator), and COVID-19 outcomes.

The meaning of dignity in care during the COVID-19 pandemic: a qualitative study in acute and intensive care.

BACKGROUND: The pandemic Era has forced palliative care professionals to use a dignity-in-care approach in different settings from the classic ones of palliative care: acute and intensive care. We explored the meanings of dignity for patients, their family members, and clinicians who have experienced COVID-19 in the acute and intensive care setting. METHODS: A qualitative, prospective study by means of semi-structured interviews with patients hospitalized for COVID-19, family members, and clinicians who care for them. FINDINGS: Between March 2021 and October 2021, we interviewed 16 participants: five physicians, three nurses, and eight patients. None of the patients interviewed consented for family members to participate: they considered it important to protect them from bringing the painful memory back to the period of their hospitalization. Several concepts and themes arose from the interviews: humanity, reciprocity, connectedness, and relationship, as confirmed by the literature. Interestingly, both healthcare professionals and patients expressed the value of informing and being informed about clinical conditions and uncertainties to protect dignity. CONCLUSIONS: Dignity should be enhanced by all healthcare professionals, not only those in palliative care or end-of-life but also in emergency departments.

Profiling the risk of hepatocellular carcinoma after long-term HCV eradication in patients with liver cirrhosis in the PITER cohort.

BACKGROUND AND AIMS: Severe liver disease markers assessed before HCV eradication are acknowledged to usually improve after the SVR. We prospectively evaluated, in the PITER cohort, the long-term HCC risk profile based on predictors monitored after HCV eradication by direct-acting antivirals in patients with cirrhosis. METHODS: HCC occurrence was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the post-treatment variables associated with de-novo HCC; their predictive power was presented in a nomogram. RESULTS: After the end of therapy (median follow-up:28.47 months), among 2064 SVR patients, 119 (5.8%) developed de-novo HCC. The HCC incidence was 1.90%, 4.21%, 6.47% at 12-, 24- and 36-months from end-of-therapy, respectively (incidence rate 2.45/100 person-years). Age, genotype 3, diabetes, platelets (PLT)≤120,000/µl and albumin ≤3.5g/dl levels were identified as pre-treatment HCC independent predictors. Adjusting for age, the post-treatment PLT≤120,000/µl (AdjHR 1.92; 95%CI:1.06-3.45) and albumin≤3.5g/dl (AdjHR 4.38; 95%CI 2.48-7.75) values were independently associated with HCC occurrence. Two different risk profiles were identified by combining long-term post-therapy evaluation of PLT ≤ vs. >120,000/µl and albumin ≤ vs. >3.5g/dl showing a significant different HCC incidence rate of 1.35 vs. 3.77/100 p-y, respectively. CONCLUSIONS: The nomogram score based on age, PLT and albumin levels after SVR showed an accurate prediction capability and may support the customizing management for early HCC detection.

Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro.

OBJECTIVE: Exhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function. DESIGN: HBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients. RESULTS: Severely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2. CONCLUSIONS: The possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project.

BACKGROUND: Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. OBJECTIVE: The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. METHODS: A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010-2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. RESULTS: From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015-2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. CONCLUSION: The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010-2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings.

Patients with HIV and cirrhosis: the risk for hepatocellular carcinoma after direct-acting antivirals for hepatitis C virus.

OBJECTIVES: Hepatocellular carcinoma (HCC) has become a major issue in coinfected HIV/HCV patients with liver cirrhosis. We aimed to determine the rate of HCC occurrence after a direct-acting antiviral (DAA) treatment and to evaluate the factors associated with the risk of HCC in this population. DESIGN: We conducted a retrospective multicenter observational study including cirrhotic HIV/HCV-coinfected patients treated with DAAs, between October 2014 and January 2017. METHODS: We collected demographics characteristics, data regarding HIV and HCV infections and treatment with DAAs. We investigated the rate and the time of occurrence of HCC. Statistical analysis explored the factors associated to development of liver cancer. RESULTS: During a median follow-up of 55 months, 24 out of 232 patients developed HCC, after a median of 22.5 months from starting DAAs. Factors associated with HCC were a higher Child--Pugh Turcotte (CPT) score (P = 0.002), HCV genotype 3 (P = 0.04), previous HCC (P < 0.001) and CD4+ cell count nadir greater than 350 cells/µl (P = 0.001), whereas antiretroviral therapy (ART) was associated to a lower rate of cancer (P = 0.02). At multivariable analysis CPT score and a history of HCC remained independently associated with HCC after DAAs (P = 0.003 and P < 0.001, respectively), and ART administration maintained its protective role (P = 0.047), regardless of HIV RNA at baseline. CONCLUSION: Our study highlights the importance of a long-lasting follow-up for HCC after HCV eradication, mostly in those patients with advanced cirrhosis and history of HCC. Furthermore, our data showed a potential role of ART itself (and not of undetectable HIV RNA) in reducing the risk for HCC development.

Feasibility and efficiency of European guidelines for NAFLD assessment in patients with type 2 diabetes: A prospective study.

AIM: We aimed to evaluate the feasibility and efficiency of a guidelines-compliant NAFLD assessment algorithm in patients with newly diagnosed type 2 diabetes (T2D). METHODS: Consecutive patients aged < 75 newly diagnosed with T2D without coexisting liver disease or excessive alcohol consumption were enrolled. Patients were stratified based on liver enzymes, fatty liver index, ultrasound, fibrosis scores and liver stiffness measurement. Referral rates and positive predictive values (PPVs) for histological non-alcoholic steatohepatitis (NASH) and significant fibrosis were evaluated. RESULTS: Of the 171 enrolled patients (age 59 ± 10.2 years, 42.1% females), 115 (67.3%) were referred to a hepatologist due to abnormal liver enzymes (n = 60) or steatosis plus indeterminate (n = 37) or high NAFLD fibrosis score (n = 18). Liver biopsy was proposed to 30 patients (17.5%), but only 14 accepted, resulting in 12 NASH, one with significant fibrosis. The PPV of hepatological referral was 12/76 (15.8%) for NASH and 1/76 (1.3%) for NASH with significant fibrosis. The PPV of liver biopsy referral was 12/14 (85.7%) for NASH and 1/14 (7.1%) for NASH with significant fibrosis. CONCLUSIONS: By applying a guidelines-compliant algorithm, many patients with T2D were referred for hepatological assessment and liver biopsy. Further studies are necessary to refine non-invasive algorithms.

Hepatitis C virus cascade of care in the general population, in people with diabetes, and in substance use disorder patients.

BACKGROUND: The aim was to evaluate the hepatitis C virus (HCV) cascade of care in the general population (GP) and in two high-risk populations: patients with diabetes mellitus (DM) and substance users (AS) in treatment in Reggio Emilia Province, Italy. METHODS: A population-based cross-sectional study was conducted that included 534,476 residents of the Reggio Emilia Province, of whom 32,800 were DM patients and 2726 AS patients. Age-adjusted prevalence was calculated using the direct method of adjustment based on the age-specific structure of EU population. RESULTS: The prevalence of HCV testing was 11.5%, 13.8%, and 47.8% in GP, DM, and AS patients respectively, while HCV prevalence was 6.5/1000, 12.6/1000, and 167/1000, respectively. The prevalence of HCV RNA positivity was 4.4/1000, 8.7/1000, and 114/1000 in the three populations, respectively. The rates of HCV RNA-positive individuals not linked to care were 27.9%, 27.3%, and 26% in GP, DM, and AS patients, respectively, while the rates of those cured or cleared were 70.9%, 71%, and 69.9%, respectively. The prevalence of HCV testing was higher for females of reproductive age than for males the same age: 218.4/1000 vs. 74.0/1000, respectively. While more foreigners than Italians underwent the HCV test and were HCV positive, fewer foreigners than Italians received HCV treatment and were cured. CONCLUSIONS: The low HCV testing and linkage to care rates remain an important gap in the HCV cascade of care in Northern Italy. The prevalence of cured/cleared residents remains lower among foreigners than among Italians.

Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B.

BACKGROUND & AIMS: In chronic HBV infection, mitochondrial functions and proteostasis are dysregulated in exhausted HBV-specific CD8 T cells. To better characterise the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion, we analysed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to simultaneously target both mitochondrial functions and proteostasis were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in patients with chronic HBV infection. METHODS: Lysosome-mediated degradation pathways were analysed by flow cytometry in virus-specific CD8 T cells from patients with chronic HBV infection. Mitochondrial function, intracellular proteostasis, and cytokine production were evaluated in HBV-peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol (RSV) and oleuropein (OLE) and their metabolites, either alone or in combination with other bioactive compounds. RESULTS: HBV-specific CD8 T cells from patients with CHB showed impaired autophagic flux. RSV and OLE elicited a significant improvement in mitochondrial, proteostasis and antiviral functions in CD8 T cells. Cytokine production was also enhanced by synthetic metabolites, which correspond to those generated by RSV and OLE metabolism in vivo, suggesting that these polyphenols may also display an effect after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalising effect of mitochondria-targeted antioxidants and of programmed cell death protein 1/programmed cell death ligand 1 blockade. CONCLUSIONS: Simultaneously targeting multiple altered intracellular pathways with the combination of mitochondria-targeted antioxidants and natural polyphenols may represent a promising immune reconstitution strategy for the treatment of chronic HBV infection. LAY SUMMARY: In chronic hepatitis B, antiviral T lymphocytes are deeply impaired, with many altered intracellular functions. In vitro exposure to polyphenols, such as resveratrol and oleuropein, can correct some of the deregulated intracellular pathways and improve antiviral T cell function. This effect can be further strengthened by the association of polyphenols with antioxidant compounds in a significant proportion of patients. Thus, the combination of antioxidants and natural polyphenols represents a promising strategy for chronic hepatitis B therapy.

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Advanced liver disease outcomes after hepatitis C eradication by human immunodeficiency virus infection in PITER cohort.

BACKGROUND: Liver disease progression after Hepatitis C Virus (HCV) eradication following direct-acting antiviral (DAA) treatment in the real-life setting according to Human Immunodeficiency Virus (HIV) coinfection was evaluated. METHODS: Patients consecutively enrolled in PITER between April 2014 and June 2019 and with at least 12-weeks follow-up following treatment were analysed. Cox regression analysis were used to evaluate HIV coinfection and factors independently associated with liver disease outcomes following viral eradication in DAA treated patients with pre-treatment liver cirrhosis. RESULTS: 93 HIV/HCV coinfected and 1109 HCV monoinfected patients were evaluated during a median follow-up of 26.7 (range 6-44.6) and 24.6 (range 6.8-47.3) months, respectively. No difference in the cumulative HCC incidence and hepatic decompensation was observed between coinfected and monoinfected patients. Age (Hazard Ratio [HR] = 1.08; 95% CI 1.04-1.13), male sex (HR = 2.76; 95% CI 1.28-5.96), lower albumin levels (HR = 3.94; 95% CI 1.81-8.58), genotype 3 (HR = 5.05; 95% CI 1.75-14.57) and serum anti-HBc positivity (HR = 1.99, 95% CI 1.01-3.95) were independently associated with HCC incidence. Older age (HR = 1.03; 95% CI 1.00-1.07), male sex (HR = 2.13; 95% CI 1.06-4.26) and lower albumin levels (HR = 3.75; 95% CI 1.89-7.46) were independently associated with the appearance of a decompensating event after viral eradication. CONCLUSION: Different demographic, clinical and genotype distribution between HIV coinfected vs those monoinfected, was observed in a representative cohort of HCV infected patients in Italy. Once liver cirrhosis is established the disease progression is decreased, but still persists regardless of viral eradication in both coinfected and monoinfected patients. In patients with cirrhosis, HIV coinfection was not associated with a higher probability of liver complications, after viral eradication.

Risk of cancer in individuals with alcohol and drug use disorders: a registry-based study in Reggio Emilia, Italy.

Aims of this population-based cohort study was to compare the overall and site-specific cancer incidence in individuals with alcohol or drug use disorders with incidence of the general population, and to estimate excess cancer risk in a subgroup of individuals who have hepatitis C virus or HIV infection. The study included 4373 residents of Reggio Emilia province diagnosed with alcohol or drug use disorders during the period from 1 January 1985 to 31 December 2014. All newly diagnosed cancers registered from 1 January 1996 to 31 December 2014 were taken into account to calculate the standardised incidence ratio (SIR) of cancers of any site and of site-specific cancers. SIR of cancer at any site was 1.6 (95% confidence interval [CI] 1.4-1.9). Anogenital cancers were associated with the highest excess risk (SIR=11.9; 95% CI 4.9-28.5), followed by oesophageal (SIR=9.5; 95% CI 3.6-25.3) and cervical cancer (SIR=8.6; 95% CI 2.8-26.7). Excess risk of all cancer sites, except for breast cancer, was observed among individuals with alcohol use disorders and of all cancer sites, except breast and kidney cancers, among individuals with drug use disorders. Among hepatitis C virus-positive individuals, cancer at any site risk was 1.9 (95% CI 1.2-3.1) and among HIV-infected individuals it was 3.3 (95% CI 1.8-5.7). Individuals with alcohol and drug use disorders face a higher risk of various cancers. Effective interventions to prevent or reduce the harm of substance abuse and risky behaviours in this population are warranted.

Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection.

Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.

Forecasting Hepatitis C liver disease burden on real-life data. Does the hidden iceberg matter to reach the elimination goals?

BACKGROUND & AIMS: Advances in direct-acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked-to-care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030. METHODS: Using a modelling approach grounded in Italian real-life data of diagnosed and treated patients, different linkage-to-care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals. RESULTS: Under the 40% linked-to-care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948-1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0-F3 cases. Under the 60% linked-to-care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958-1978 birth cohorts could capture 55% of F0-F3 individuals. Under the 80% linked-to-care scenario, screening limited in 1968-1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals. CONCLUSION: In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required.

The potential impact of multidimesional geriatric assessment in the social security system.

AIM: To evaluate the efficacy of multidimensional geriatric assessment (MGA/CGA) in patients over 65 years old in predicting the release of the accompaniment allowance (AA) indemnity by a Local Medico-Legal Committee (MLC-NHS) and by the National Institute of Social Security Committee (MLC-INPS). METHODS: In a longitudinal observational study, 200 Italian elder citizens requesting AA were first evaluated by MLC-NHS and later by MLC-INPS. Only MLC-INPS performed a MGA/CGA (including SPMSQ, Barthel Index, GDS-SF, and CIRS). This report was written according to the STROBE guidelines. RESULTS: The data analysis was performed on January 2016. The evaluation by the MLC-NHS and by the MLC-INPS was in agreement in 66% of cases. In the 28%, the AA benefit was recognized by the MLC-NHS, but not by the MLC-INPS. By the multivariate analysis, the best predictors of the AA release, by the MLC-NHS, were represented by gender and the Barthel Index score. The presence of carcinoma, the Barthel Index score, and the SPMQ score were the best predictors for the AA release by MLC-INPS. CONCLUSIONS: MGA/CGA could be useful in saving financial resources reducing the risk of incorrect indemnity release. It can improve the accuracy of the impairment assessment in social security system.

The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations.

AIMS: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. METHODS: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. RESULTS: In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. CONCLUSIONS: One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective.