Objective: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. Design: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. Results: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I ² =74.6%) and 5.7 (2.5 to 15.3, I ² =54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). Conclusion: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

Background and Aims: In patients with non-severe acute or chronic autoimmune hepatitis (AIH) without cirrhosis, clinical practice guidelines recommend indistinct use of prednisone or budesonide. However, budesonide is infrequently used in clinical practice. We aimed to describe its use and compare its efficacy and safety with prednisone as first-line options. Approach and Results: This was a retrospective, multicenter study of 105 naive AIH patients treated with budesonide as the first-line drug. The control group included 276 patients treated with prednisone. Efficacy was assessed using logistic regression and validated using inverse probability of treatment weighting propensity score. The median time to biochemical response (BR) was 3.1 months in patients treated with budesonide and 4.9 months in those with prednisone. The BR rate was significantly higher in patients treated with prednisone (87% vs. 49% of patients with budesonide, p < 0.001). The probability of achieving BR, assessed using the inverse probability of treatment weighting propensity score, was significantly lower in the budesonide group (OR = 0.20; 95% CI: 0.11–0.38) at any time during follow-up, and at 6 (OR = 0.51; 95% CI: 0.29–0.89) and 12 months after starting treatment (0.41; 95% CI: 0.23–0.73). In patients with transaminases <2 × upper limit of normal, BR was similar in both treatment groups. Prednisone treatment was significantly associated with a higher risk of adverse events (24.2% vs. 15.9%, p = 0.047). Conclusions: In the real-life setting, the use of budesonide as first-line treatment is low, and it is generally prescribed to patients with perceived less disease activity. Budesonide was inferior to prednisone as a first-line drug but was associated with fewer side effects.

Background: The impact of vitamin D supplementation on cardiovascular outcomes and mortality risk reduction remains unclear due to conflicting study findings. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), published between 1983 and 2022, that reported the effect of vitamin D supplementation in adults versus placebo or no treatment on all-cause mortality (ACM), cardiovascular mortality (CVM), non-cardiovascular mortality (non-CVM), and cardiovascular morbidities. Only studies with a follow-up period longer than one year were included. The primary outcomes were ACM and CVM. Secondary outcomes were non-CVM, myocardial infarction, stroke, heart failure, and major or extended adverse cardiovascular events. Subgroup analyses were performed according to low-, fair- and good-quality RCTs. Results: Eighty RCTs were assessed, including 82,210 participants receiving vitamin D supplementation and 80,921 receiving placebo or no treatment. The participants’ mean (SD) age was 66.1 (11.2) years, and 68.6% were female. Vitamin D supplementation was associated with a lower risk of ACM (OR: 0.95 [95%CI 0.91–0.99] p = 0.013), was close to statistical significance for a lower risk of non-CVM (OR: 0.94 [95%CI 0.87–1.00] p = 0.055), and was not statistically associated with a lower risk of any cardiovascular morbi-mortality outcome. Meta-analysis of low-quality RCTs showed no association with cardiovascular or non-cardiovascular morbi-mortality outcomes. Conclusions: The emerging results of our meta-analysis present evidence that vitamin D supplementation appears to decrease the risk of ACM (especially convincing in the fair- and good-quality RCTs), while not showing a decrease in the specific cardiovascular morbidity and mortality risk. Thus, we conclude that further research is warranted in this area, with well-planned and executed studies as the basis for more robust recommendations.

Summary: Background: The positive results of the REFLECT trial in terms of survival (sorafenib vs lenvatinib) offer a new first‐line option for hepatocellular carcinoma. Additionally, the expected results of immunotherapy could change the first‐line treatment in hepatocellular carcinoma or the clinical trial design in first and second‐line.Aims: To evaluate the impact of dermatologic adverse events under sorafenib in hepatocellular carcinoma patients as a clinical marker to predict prognosis and critically evaluate outcomes within trials.Methods: A systematic search of original articles published until October 2018 was performed using PubMed/MEDLINE and a meta‐analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement.Results: A total of 393 studies were identified and 13 articles with 2035 patients (79.5% Child‐Pugh‐A, 73.2% BCLC‐C) were selected for qualitative and quantitative analysis. The main type of dermatologic adverse events was hand‐foot skin reaction (47.7%) but other dermatologic adverse events were reported in 31.7% of the cases. Presence of dermatologic adverse events was associated with a lower mortality when compared with those patients without them (pooled Hazard Ratio for the univariate analysis 0.45 (95% CI: 0.38‐0.53) and there was no heterogeneity for the analysis (P = 0.511; I² = 0.0%). Refuting this association would require the future report of 1370 negative studies.Conclusions: This meta‐analysis shows a clinically meaningful association between dermatologic adverse events and a higher probability of longer survival. These data support the use of dermatologic adverse events in the clinical decision‐making when informing the prognosis and when systemic treatment is decided.