Trends in liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a cholestatic disease with a low prevalence in Italy. Indications for liver transplantation and the time of listing are not stated. AIM: We performed a national survey to investigate the listing criteria, comorbidities, and outcomes. METHODS: In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years. RESULTS: From 2007 to 2021, 445 patients were included on waiting lists, and 411 had undergone liver transplants. The median age at transplantation was 46 years (males 63.9%); 262 patients (59%) presented an inflammatory bowel disease. Transplants increased over the years, from 1.8 % in 2007 to 3.0 % in 2021. Cholangitis (51%) and hepatic decompensation (45%) were the main indications for listing. The disease recurred in 81 patients (20%). Patient survival after the first transplant was 94 %, 86% and 84% at one, five, and ten years. Twenty-four died in the first year (50% surgical complications, 25% infections); 33 between one to five years (36% recurrence, 21% cholangiocarcinoma recurrence) and nine after five years (56% de novo cancer, 44% recurrence). CONCLUSIONS: Primary sclerosing cholangitis has been an increasing indication for transplantation in Italy. Cholangitis and decompensation were the main indications for listing. Recurrence and cancer were the leading causes of death.

Patients with HCV genotype-1 who have failed a direct-acting antiviral regimen: virological characteristics and efficacy of retreatment.

BACKGROUND: This real-world clinical setting study characterized the virological patterns in genotype-1 patients failing interferon (IFN)-free regimens and evaluated the efficacy of re-treatment. METHODS: A total of 73 consecutive patients failing IFN-free regimens were enrolled (17 genotype-1a and 56 -1b). At failure Sanger sequencing of NS3, NS5A and NS5B regions was performed by home-made protocols. RESULTS: In patients having failed an NS3 inhibitor, the prevalence of NS3-RASs was higher in the 10 with genotype-1a than in the 24 with genotype-1b (80% versus 41.6%). In patients treated with an NS5A inhibitor, the prevalence of NS5A-RASs was very high in the 14 with genotype-1a and the 27 with genotype-1b (78.6% and 92.5%, respectively). In patients having failed sofosbuvir, the prevalence of NS5B-RASs was more frequently identified in the 45 with genotype-1b than in the 10 with genotype-1a (37.7% versus 10%). The prevalence of NS5B-RASs in patients having failed dasabuvir was high in both genotypes, 66.6% in the 6 with genotype-1a and 45.5% in the 11 with genotype-1b. The 6 patients re-treated with genotype-1a less frequently (50%) showed sustained virological response (SVR) than the 18 with genotype-1b (88.8%; P=0.07). SVR was more frequent in the 21 patients with an effective second-line direct-acting antiviral (DAA) regimen than the 3 without (90.4% versus 0%; P<0.005). CONCLUSIONS: The prevalence of RASs was high in our real-world population. NS3, NS5A and NS5B sequencing seems mandatory in the choice of DAA re-treatment.

Dual therapy with peg-interferon and ribavirin in thalassemia major patients with chronic HCV infection: Is there still an indication?

BACKGROUND: Iron overload and hepatitis C virus (HCV) infection together can lead to chronic liver damage in thalassemia major (TM) patients. AIMS: We investigated viral, genetic, and disease factors influencing sustained virological response (SVR) after peg-interferon and ribavirin therapy in TM patients with HCV infection. METHODS: We analyzed 230 TM patients with HCV infection (mean age 36.0±6.3 years; 59.1% genotype 1; 32.2% genotype 2; 3.4% genotype 3; and 5.3% genotype 4; 28.7% carried CC allele of rs12979860 in IL28B locus; 79.6% had chronic hepatitis and 20.4% cirrhosis; 63.5% naive and 36.5% previously treated with interferon alone) treated in 14 Italian centers. RESULTS: By multivariate regression analysis SVR was independently associated with CC allele of IL28B SNP (OR 2.98; CI 95% 1.29-6.86; p=0.010) and rapid virologic response (OR 11.82; CI 95% 3.83-36.54; p<0.001) in 136 genotype 1 patients. Combining favorable variables the probability of SVR ranged from 31% to 93%. In genotype 2 patients, only RVR (OR 8.61; CI 95% 2.85-26.01; p<0.001) was associated with SVR higher than 80%. In 3 patients with cirrhosis a decompensation of liver or heart disease were observed. Over 50% of patients increased blood transfusions. CONCLUSION: Dual therapy in TM patients with chronic HCV infection is efficacious in patients with the best virological, genetic and clinical predictors. Patients with cirrhosis have an increased risk of worsening liver or heart disease.

Sorafenib off-target effects predict outcomes in patients treated for hepatocellular carcinoma.

AIM: Sorafenib is the standard of care in advanced hepatocellular carcinoma. This study was aimed to identify clinical parameters that may predict survival in these patients. MATERIALS & METHODS: In this observational study, a training (226 patients) and validation cohorts (54 patients) were analyzed for evaluating pretreatment and on-treatment parameters. RESULTS: At multivariate analysis, only on-treatment variables (skin toxicity, diarrhea and arterial hypertension - sorafenib off-target effects), alphafetoprotein and radiological responses predicted survival. Using the occurrence of off-target effects, a prognostic index able to distinguish three groups of patients with different survival was constructed and externally validated. CONCLUSION: In hepatocellular carcinoma patients, on-treatment variables are the best predictors of survival. Among these, sorafenib off-target effects may be the most useful indicators for prognostication in field practice.

Safety and effectiveness of sorafenib in patients with hepatocellular carcinoma in clinical practice.

BACKGROUND: Sorafenib is currently the only approved systemic treatment for hepatocellular carcinoma. AIM: to evaluate safety and effectiveness of sorafenib in the field of practice. METHODS: We report a single-centre experience on 116 advanced hepatocellular carcinoma patients treated with sorafenib between February 2008 and March 2011. Every 4 weeks, adverse events were graded using Common Toxicity Criteria version 3.0, and every 3 months tumour response was assessed according to modified Response Evaluation Criteria in Solid Tumours for hepatocellular carcinoma. RESULTS: Cirrhosis was present in 95.7% of patients (83.6% Child-Pugh A class), hepatitis C was the main etiological factor. Median therapy duration was 3 months and median daily dose was 642 mg. Median time-to-radiological progression in the per-protocol population was 12 months and median overall survival in the intention-to-treat population was 13 months. 91.4% of patients experienced mild adverse events (grade 1 or 2), the most frequent were gastrointestinal and dermatological. Jaundice and bleeding were the main causes of definitive drug discontinuation. 3-month overall disease control rate was 70.6%: stable disease in 37.2%, partial response in 30.8%, and complete response in 2.6% patients. The 3-month radiological response correlated with overall survival. CONCLUSIONS: In daily clinical practice, sorafenib confirmed its safety and efficacy in hepatocellular carcinoma patients.

The impact of previous or concomitant IFN therapy on deferiprone-induced agranulocytosis and neutropenia: a retrospective study.

OBJECTIVE: Although IFN therapy is known to cause neutropenia, data on the risk of deferiprone (DFP)-induced haematological complications in patients receiving IFN are lacking. RESEARCH DESIGN AND METHODS: This was a retrospective single-centre study to assess the association between exposure to IFN for hepatitis C virus treatment and haematological side effects of DFP therapy in patients with thalassemia major and intermedia using a large database spanning 2001 ­ 2008. During observation time, a total of 66 patients, including 63 affected by thalassemia major and 3 by thalassemia intermedia, were treated with chelation DFP-based regimens. A subset of 25 patients was treated at least for 3 months also with IFN (6 were cotreated and 19 were pretreated). RESULTS: Overall, the incidence of neutropenia and agranulocytosis was 9.83 and 1.14/100 patient/year, respectively. Receipt of IFN was significantly associated with increased risk of haematological complications of DFP therapy: among patients receiving IFN, 48 and 12% experienced at least one episode of neutropenia and agranulocytosis, respectively. CONCLUSIONS: These results suggest that IFN therapy may increase the risk of complications of DFP-based iron chelation therapy in patients with thalassemia. Further research is needed to assess whether the association observed in this retrospective single-centre observational study is due to IFN or other factors.

Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection.

BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection are frequently treated with a combination of pegylated interferon (peginterferon) and ribavirin. This study compared the efficacy and safety of peginterferon alfa-2a and peginterferon alfa-2b, each in combination with ribavirin. METHODS: A total of 320 consecutive, treatment-naive, HCV RNA-positive patients with chronic hepatitis were randomly assigned to once-weekly peginterferon alfa-2a (180 microg, group A) or peginterferon alfa-2b (1.5 microg/kg, group B) plus ribavirin 1000 mg/day (body weight <75 kg) or 1200 mg/day (body weight >or=75 kg) for 48 weeks (genotype 1 or 4) or 24 weeks (genotype 2 or 3). The primary end point was sustained virological response (SVR) by intention-to-treat. RESULTS: More patients in group A than group B achieved an SVR (110/160 [68.8%] vs 87/160 [54.4%]; P = .008). Higher SVR rates were obtained in group A than group B among patients with genotype 1/4 (51/93 [54.8%] vs 37/93 [39.8%]; P = .04), with genotype 2/3 (59/67 [88.1%] vs 50/67 [74.6%]; P = .046), without cirrhosis (96/127 [75.6%] vs 75/134 [55.9%]; P = .005), and with baseline levels HCV RNA >500,000 IU/mL (58/84 [69%] vs 43/93 [46.2%]; P = .002). SVR rates in groups A and B were not statistically different among patients with baseline HCV RNA

Chlamydia pneumoniae induces interleukin-6 and interleukin-10 in human gingival fibroblasts.

Chlamydia pneumoniae is an obligate intracellular Gram-negative bacterium with a unique biphasic developmental cycle that can cause persistent infections. In humans, Chlamydia causes airway infection and has been implicated in chronic inflammatory diseases, such as asthma and atherosclerosis. In addition, recent studies demonstrated that patients with severe periodontitis can harbor C. pneumoniae, which can increase the risk for a host inflammatory response with weighty clinical sequelae. Previous studies have established that periodontal pathogenic bacteria (i.e. Gram-negative bacteria) can induce the synthesis and release of cytokines and other inflammatory mediators in human gingival fibroblasts. HGF are resident cells of the periodontium that respond to receptor stimulation by producing a variety of substances including cytokines and growth factors. Our results demonstrate that after 48 hr of incubation with viable C. pneumoniae HGF showed a proliferative response, as seen by both colorimetric MTT assay and direct cell count (30% and 35%, respectively). In addition, HGF incubated with viable or UV light-inactivated C. pneumoniae organisms showed an increase in the levels of IL-6 and IL-10, but not IL-4; on the contrary, HGF infected with heat-killed bacteria did not show a significant production of any of the cytokines considered. In conclusion, the present study suggests that C. pneumoniae may modulate the expression of IL-6 and IL-10 by human gingival fibroblasts. Further studies are warranted to clarify the molecular mechanisms of C. pneumoniae in the regulation of cytokine expression by host cells and to elaborate the relevant clinical implications.

Effect of alcohol, cigarette smoking, and diabetes on occurrence of hepatocellular carcinoma in patients with transfusion-acquired hepatitis C virus infection who develop cirrhosis.

AIM: Alcohol drinking, cigarette smoking, and diabetes have been claimed as risk factors for hepatocellular carcinoma in case-control studies. The aim of this study was to define the impact of these risk factors on the development of hepatocellular carcinoma in hepatitis C virus-related liver cirrhosis. METHODS: A historical cohort of 138 patients with posttransfusion hepatitis C virus-related cirrhosis was selected by reviewing all files of patients referred to our liver unit. Sixty-three of them (46%) developed hepatocellular carcinoma. RESULTS: At univariate analysis, risk factors for hepatocellular carcinoma were observed in patients aged above 59 years [P=0.004; relative risk (RR): 2.08, 95% confidence interval (CI): 1.19-3.68], male sex (P<0.001; RR: 2.48, 95% CI: 1.59-3.87), habit of alcohol drinking (P=0.001; RR: 1.89, 95% CI: 1.24-2.88), and duration of alcohol consumption of more than 30 years (P=0.02; RR: 2.08, 95% CI: 0.98-4.40). At Cox regression analysis, only male sex was an independent predictive factor (beta=0.86; P=0.002; hazard ratio=2.4, 95% CI: 1.3-4.1). CONCLUSION: Diabetes, smoking, and alcohol drinking were not independently related to the risk of developing hepatocellular carcinoma in hepatitis C virus-related cirrhosis.

Modulation of cytokine and beta-defensin 2 expressions in human gingival fibroblasts infected with Chlamydia pneumoniae.

Human beta-defensin 2 is an antimicrobial peptide that is produced by several epithelial cells after stimulation with micro-organisms and inflammatory mediators. Gram-negative bacteria, which are typically detected in periodontal pockets in periodontitis, elicit a stronger antibacterial peptide response of human beta-defensin 2 by epithelial cells. In this study, we investigated whether Chlamydia pneumoniae is able both to enter and grow in human gingival fibroblasts (HGF), to modify the production of cytokines, and is involved in regulation of beta-defensin 2 expression. Gingival fibroblasts discarded from periodontal procedures on healthy young individuals were infected with viable C. pneumoniae or with heat- or ultraviolet-inactivated organisms at a multiplicity of infection of 4 inclusion-forming units per cell. Our results demonstrate that after 48 h of incubation with viable C. pneumoniae, gingival fibroblasts showed a proliferative response as seen by both colorimetric assay and direct cell count (40% and 45%, respectively). Moreover, cells incubated with viable or ultraviolet light-inactivated C. pneumoniae organisms showed an increase in the levels of interleukin-6, interleukin-10 and human beta-defensin 2 in a time-dependent fashion, while the cells infected with heat-killed bacteria did not show a significant production either of the cytokines or beta-defensin 2 at any time. In conclusion, we demonstrate the correlation between multiplication of C. pneumoniae in human gingival fibroblasts and release of interleukin-6, interleukin-10 and up-regulation of beta-defensin 2, suggesting that gingival fibroblasts may be a periodontium niche for obligate intracellular C. pneumoniae and may play a role in innate gingival immune system and inflammatory response mechanisms of periodontitis.

Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation.

BACKGROUND/AIMS: HCV infection recurs almost in all HCV-positive patients receiving liver transplantation and carries a poor prognosis. Aim of this study was to analyze efficacy and effect on survival of antiviral therapy in this clinical setting. METHODS: Pegylated-interferon alpha-2b and ribavirin were administered at a dose of 1 microg/kg of bwt weekly and 600-800 mg/day. Planned duration of treatment was 24 or 48 weeks according to HCV genotype. Patients who failed to respond at week 24 were considered as non-responders. RESULTS: 61 patients were enrolled. According to intention-to-treat analysis, 44 (72%) patients were considered as treatment failure (31 non-responders, 4 relapsers, 9 dropout). Sustained virological response was achieved in 17 cases (28%). Genotype 2, higher doses of antivirals and absence of histological cirrhosis were predictors of sustained virological response. In the follow up, patients with sustained virological response had a significantly lower mortality compared to patients with treatment failure (chi2=6.9; P<0.01). CONCLUSIONS: Response rate to antiviral therapy in HCV reinfection after liver transplantation is higher if a full dose of antiviral drugs is administered and if treatment starts before histological cirrhosis has developed. Sustained virological response improves patient survival.

Factors influencing outcome of lamivudine in anti-HBe-positive chronic hepatitis B.

BACKGROUND/AIMS: Lamivudine has been shown to benefit patients with anti-HBe/HBV-DNA-positive chronic hepatitis B. The aim of the study was to evaluate factors influencing outcome of lamivudine therapy during two years of post-treatment follow-up in a prospective clinical trial. METHODOLOGY: Thirty-one consecutive patients, submitted to liver biopsy, were treated with lamivudine at 100mg/daily for twelve months and followed-up for twenty-four months. The patients were never treated before with interferon or stopped at least six months before starting lamivudine. ALT was measured monthly and HBV-DNA every three months. RESULTS: At the end of therapy 25 (81%) patients had both biochemical and virological response; 2 (6%) patients showed persistent viremia and 4 (13%) patients developed viral resistance during treatment. Twenty-three (92%) out of 25 responders relapsed during the follow-up; over 50% of all cases relapsed within 6 months. The relapse is related to higher HBV-DNA baseline levels. At relapse, 4/23 (17%) patients had symptomatic acute hepatitis. CONCLUSIONS: Lamivudine is associated with the risk of developing viral mutants and, after therapy discontinuation, to high rate of relapse. In relapsing patients severe acute recurrence of hepatitis B may occur. Decisions about lamivudine monotherapy should take into account the limited long-term efficacy, effects of relapse, costs and predictive factors for response.

Incidence of side effects during therapy with different types of alpha interferon: a randomised controlled trial comparing recombinant alpha 2b versus leukocyte interferon in the therapy of naive patients with chronic hepatitis C.

BACKGROUND: Alpha interferon (IFN) alone or in combination with Ribavirin (RBV) is the treatment of choice for HCV related chronic liver disease. There are many types of alpha IFN and to date only few reports are available comparing different types of alpha interferon. We run a randomised controlled trial with the aim to compare tolerability and efficacy of two different types of IFN: recombinant alpha 2b interferon (IFN-R) and leukocyte alpha n-3 interferon (IFN-L) at the same dosage of 3 MU subcutaneously thrice weekly for one year. METHODS: one hundred sixty eight consecutive anti-HCV positive naive patients, 34 mild chronic active hepatitis (MCH), 81 moderate-severe hepatitis (MSCR) and 53 active cirrhosis (CIRR) that met the inclusion criteria were enrolled into the study. The diagnosis of HCV chronic liver disease was established by liver biopsy performed on patients with abnormal serum alanine aminotransferase (ALT) value for at least one year. HCV serology: all patients were tested for confirmatory test RIBA II, HCV-RNA, and identification of viral genotype. Patients were randomised to receive either IFN-R or IFN-L. Follow-up continued for at least two years after stopping treatment. RESULTS: no significant differences were observed between the two groups of treatment as far as the incidence of side effects is concerned. Tolerability was good: only 11 in IFN-R and 8 patients IFN-L group respectively had to stop therapy due to side effects. The two types of IFN showed a comparable efficacy: an end of therapy response was observed in 34% of IFN-R and 30% of IFN-L patients; a sustained response was seen in 16% of IFN-R and in 19% of IFN-L patients. CONCLUSIONS: in the treatment of patients with chronic hepatitis C there was no statistically significant difference in tolerability and efficacy between the two IFNs tested.