Long-term Clinical Outcome of Treatment for Chronic Hepatitis C

Worldwide, 170 million people are chronically infected with the hepatitis C virus. The infection leads to inflammation and fibrosis of the liver and may eventually lead to liver failure or development of hepatocellular carcinoma. It is known that treatment with pegylated interferon and ribavirin may lead to sustained suppression of the hepatitis C virus. The aim of this thesis is to investigate whether patients with a sustained virological response have a prolonged life expectancy and whether they have a decreased risk of developing liver failure and hepatocellular carcinoma. In a first study we compared the survival of chronic hepatitis C patients from different European centers with the general population. Patients with a sustained virological response had a life expectancy similar to the general population, matched for age and gender. We also investigated patients with advanced liver fibrosis. In this study, data were collected from more than 500 European and Canadian patients. Among sustained virological responders there was a spectaculair decrease in the risk of developing liver failure and the 5-year risk of dying from a liver-related cause had decreased from 12.9 to 4.4 percent, compared to non-responders. Finally, the course of the disease in treated patients with advanced fibrosis was compared to the natural history, as predicted by a mathematical model. This comparison also suggested an improved outcome for patients who had undergone treatment with peginterferon and ribavirin. For this work, B.J. Veldt received a stipend from the Netherlands organisation for health research and development

The treatment of hepatitis C: history, presence and future

The treatment of chronic hepatitis C has made remarkable progress over the past two decades. For interferon-alpha monotherapy, sustained virological response rates were between 2 and 9% in genotype 1 and between 16 and 23% in genotypes 2 and 3. By adjusting treatment duration up to 48 weeks for genotype 1 and combining regular interferon-alpha with ribavirin, sustained response rates could be improved to 28 to 31% in genotype 1 and around 65% in genotypes 2 and 3. Attempts to further increase efficacy included the addition of amantadine without conclusive evidence up till now. With the recent introduction of long-acting pegylated interferon-alpha in combination with ribavirin, sustained virological response rates of 8o% can be obtained in genotypes 2 and 3. However, sustained virological response rates for patients with either genotype 1, nonresponse to prior treatment, cirrhosis or a combination of these characteristics are still less than 50%. In view of results with daily high-dose interferon-alpha induction in combination with prolongation of treatment duration up to 18 months, such patients might benefit from induction and prolonged PEG-IFN-alpha treatment and should be treated in an experimental setting

Management of Thrombocytopenia in Chronic Liver Disease: Focus on Pharmacotherapeutic Strategies

Thrombocytopenia (platelet count <150 × 109/L) often complicates chronic liver disease, impeding optimal management of these patients. The prevalence of this manifestation ranges from 6 % among non-cirrhotic patients with chronic liver disease to 70 % among patients with liver cirrhosis. It has also been shown that the severity of liver disease is associated with both prevalence and level of thrombocytopenia. Its development is often multifactorial, although thrombopoietin is thought to be a major factor. The discovery of and ability to clone thrombopoietin led to new treatment opportunities for this clinical manifestation. This review discusses data on the three most important thrombopoietin receptor agonists: eltrombopag, avatrombopag, and romiplostim. Currently, only eltrombopag is approved for usage among patients with thrombocytopenia and chronic hepatitis C virus infection in order to initiate and maintain interferon-based antiviral treatment. Nevertheless, the optimal management of hematologic abnormalities among patients with chronic liver disease, and its risk for bleeding complications, is still a matter of discussion. Thrombocytopenia definitely contributes to hemostatic defects but is often counterbalanced by the enhanced presence of procoagulant factors. Therefore, a thorough assessment of the patient's risk for thrombotic events is essential when the use of thrombopoietin receptor agonists is considered among patients with chronic liver disease and thrombocytopenia

Recipient IL28B polymorphism is an important independent predictor of posttransplant diabetes mellitus in liver transplant patients with chronic hepatitis C

IL28B polymorphisms are strongly associated with response to treatment for HCV infection. IL28B acts on interferon-stimulated genes via the JAK-STAT pathway, which has been implicated in development of insulin resistance. We investigated whether IL28B polymorphisms are associated with posttransplant diabetes mellitus (DM). Consecutive HCV patients who underwent liver transplantation between 1-1995 and 1-2011 were studied. Genotyping of the polymorphism rs12979860 was performed on DNA collected from donors and recipients. Posttransplant DM was screened for by fasting blood glucoses every 1-3 months. Of 221 included patients, 69 developed posttransplant DM (31%). Twenty-two patients with recipient IL28B genotype TT (48%), 25 with IL28B genotype CT (25%) and 22 with IL28B genotype CC (29%) developed posttransplant DM. TT genotype was statistically significantly associated with posttransplant DM over time (log rank p = 0.012 for TT vs. CT and p = 0.045 for TT vs. CC). Multivariate Cox regression analysis correcting for donor age, body mass index, baseline serum glucose, baseline serum cholesterol, recipient age and treated rejection, showed that recipient IL28B genotype TT was independently associated with posttransplant DM (hazard ratio 2.51; 95% confidence interval 1.17-5.40; p = 0.011). We conclude that the risk of developing posttransplant DM is significantly increased in recipients carrying the TT polymorphism of the IL28B gene. An analysis of liver transplant recipients with hepatitis C virus infection finds that the risk of developing posttransplant diabetes mellitus is significantly increased in recipients carrying the TT polymorphism of the IL28B gene

ITPA polymorphisms are associated with hematological side effects during antiviral therapy for chronic HCV infection

Background/Objective Genetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV. Patients and Methods This cohort study included all consecutive Caucasian patients treated for chronic HCV infection with PegIFN and RBV between 2000 and 2009 for whom a serum sample was available for genetic testing. The predicted inosine triphosphate pyrophosphatase (ITPase) activity was based on the genotypes of the SNPs rs1127354 and rs7270101. Decline in hemoglobin (Hb) during antiviral therapy, as well as dose reductions, blood transfusions and use of erythropoietin were assessed. Results In total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04-0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64-1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024). Conclusion Genetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently

Retreatment of hepatitis C non-responsive to Interferon. A placebo controlled randomized trial of Ribavirin monotherapy versus combination therapy with Ribavirin and Interferon in 121 patients in the Benelux [ISRCTN53821378]

BACKGROUND: Evidence based medicine depends on unbiased selection of completed randomized controlled trials. For completeness it is important to publish all trials. This report describes the first large randomised controlled trial where combination therapy was compared to placebo therapy and to ribavirin monotherapy, which has not been published untill now. METHODS: One hundred and twenty one patients with chronic hepatitis C and elevated transaminases who did not respond to previous treatment with standard interferon monotherapy, were included from 16 centers in Belgium, the Netherlands and Luxembourg between 1992 and 1996. Patient poor-response characteristics were: genotype 1 (69%), HCV RNA above 2 × 10(6 )copies/ml (55%) and cirrhosis (38%). Patients were randomized to 6 months combination therapy with interferon alpha-2b (3 MU tiw) and ribavirin (1000–1200 mg / day), 6 months ribavirin monotherapy (1000–1200 mg / day) or 6 months ribavirin placebo. The study was double blinded for the ribavirin / placebo component. One patient did not fit the entry criteria, and 3 did not start. All 117 patients who received at least one dose of treatment were included in the intention to treat analysis. RESULTS: At the end of treatment, HCV RNA was undetectable in 35% of patients on combination therapy and in none of the patients treated with ribavirin monotherapy or placebo. The sustained virological response rate at 6 months after therapy was 15% for patients treated with interferon and ribavirin. During the 6 months treatment period 13% of patients on interferon ribavirin combination therapy, 13% of patients on ribavirin monotherapy and 11% of patients on placebo withdrew due to side effects or noncompliance. At 24 weeks of treatment the mean Hb level was 85% of the baseline value, which means a mean decrease from 9.1 mmol/l to 7.8 mmol/l. The Hb levels at the end of treatment were not significantly different from patients treated with ribavirin monotherapy (p = 0.76). End of treatment WBC was significantly lower in patients treated with combination therapy, compared to ribavirin (p < 0.01) as well as for patients treated with ribavirin monotherapy compared to placebo (p < 0.01). DISCUSSION: This belated report on the only placebo controlled study of interferon ribavirin combination therapy in non responders to standard doses of interferon monotherapy documents the effectiveness, be it limited, of this approach as well as the dynamics of the effects on blood counts

Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

BACKGROUND: Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort. METHODS: Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome. RESULTS: 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44). CONCLUSION: Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12072-021-10151-4

Diagnostic accuracy of endoscopic ultrasonography-guided tissue acquisition prior to resection of pancreatic carcinoma:a nationwide analysis

Introduction: Endoscopic ultrasonography guided tissue acquisition (EUS + TA) is used to provide a tissue diagnosis in patients with suspected pancreatic cancer. Key performance indicators (KPI) for these procedures are rate of adequate sample (RAS) and sensitivity for malignancy (SFM). Aim: assess practice variation regarding KPI of EUS + TA prior to resection of pancreatic carcinoma in the Netherlands. Patients and methods: Results of all EUS + TA prior to resection of pancreatic carcinoma from 2014–2018, were extracted from the national Dutch Pathology Registry (PALGA). Pathology reports were classified as: insufficient for analysis (b1), benign (b2), atypia (b3), neoplastic other (b4), suspected malignant (b5), and malignant (b6). RAS was defined as the proportion of EUS procedures yielding specimen sufficient for analysis. SFM was calculated using a strict definition (malignant only, SFM-b6), and a broader definition (SFM-b5+6). Results: 691 out of 1638 resected patients (42%) underwent preoperative EUS + TA. RAS was 95% (range 89–100%), SFM-b6 was 44% (20–77%), and SFM-b5+6 was 65% (53–90%). All centers met the performance target RAS&gt;85%. Only 9 out of 17 met the performance target SFM-b5+6 &gt; 85%. Conclusion: This nationwide study detected significant practice variation regarding KPI of EUS + TA procedures prior to surgical resection of pancreatic carcinoma. Therefore, quality improvement of EUS + TA is indicated

Diagnostic accuracy of endoscopic ultrasonography-guided tissue acquisition prior to resection of pancreatic carcinoma:a nationwide analysis

Introduction: Endoscopic ultrasonography guided tissue acquisition (EUS + TA) is used to provide a tissue diagnosis in patients with suspected pancreatic cancer. Key performance indicators (KPI) for these procedures are rate of adequate sample (RAS) and sensitivity for malignancy (SFM). Aim: assess practice variation regarding KPI of EUS + TA prior to resection of pancreatic carcinoma in the Netherlands. Patients and methods: Results of all EUS + TA prior to resection of pancreatic carcinoma from 2014–2018, were extracted from the national Dutch Pathology Registry (PALGA). Pathology reports were classified as: insufficient for analysis (b1), benign (b2), atypia (b3), neoplastic other (b4), suspected malignant (b5), and malignant (b6). RAS was defined as the proportion of EUS procedures yielding specimen sufficient for analysis. SFM was calculated using a strict definition (malignant only, SFM-b6), and a broader definition (SFM-b5+6). Results: 691 out of 1638 resected patients (42%) underwent preoperative EUS + TA. RAS was 95% (range 89–100%), SFM-b6 was 44% (20–77%), and SFM-b5+6 was 65% (53–90%). All centers met the performance target RAS&gt;85%. Only 9 out of 17 met the performance target SFM-b5+6 &gt; 85%. Conclusion: This nationwide study detected significant practice variation regarding KPI of EUS + TA procedures prior to surgical resection of pancreatic carcinoma. Therefore, quality improvement of EUS + TA is indicated.</p