Real-Life Use of 3 Direct-Acting Antiviral Regimen in a Large Cohort of Patients with Genotype-1b HCV Compensated Cirrhosis.

BACKGROUND AND AIMS: Ombitasvir/Paritaprevir/ritonavir/Dasabuvir (OBV/PTV/r+DSV) is one of the elective direct-acting antivirals (DAAs) recommended by international guidelines and the only one covered by the National Insurance System in Romania until November 2016. Our aim was to present the first prospective Romanian cohort evaluating the effectiveness and safety in clinical practice of this 3DAA combination in patients with HCV genotype-1b Child A liver cirrhosis. METHODS: 681 patients received OBV/PTV/r+DSV+RBV for 12 weeks and were assessed clinically and biologically at baseline, week 4, 8, 12 (end of treatment, EOT), and 12 weeks after therapy (sustained viral response, SVR). RESULTS: Per protocol, EOT virological response was 99.8% and SVR12 rate was 99.4%. Adverse events were present in 36.4% of patients. Permanent discontinuation of 3DAA regimen due to side effects was reported in 11 patients (1.6%). In 47.6% (185/389) of patients, Transient Elastography values were >20kPa (defined as clinically significant portal hypertension, CSPH) at baseline. Independent variables associated with CSPH were: baseline cholesterol level (p=0.003), platelet count <120,000/mm³ (p=0.02), MELD score (p=0.01). Liver stiffness measurement has significantly improved between baseline (26.6+/-12.7kPa) and SVR12 (21.6+/-11.8kPa) (p<0.0001). The same was true for APRI score (2.66+/-0.15 at baseline vs 0.85+/-0.02 at SVR12, p<0.0001) and FIB4 score (5.53+/-0.28 vs 3.24+/-0.08, p<0.0001), but not for Lok score (0.57+/-0.01 vs 0.63+/-0.01, p<0.0001). CONCLUSIONS: We report a high efficacy of the 3DAA regimen in a homogeneous compensated HCV genotype-1b liver cirrhosis population, in a real-life setting. Noninvasive fibrosis scores significantly improved at SVR12.

A real life boceprevir use in treatment-experienced HCV genotype 1 patients with advanced fibrosis.

BACKGROUND: A number of high quality randomized clinical trials examining the efficacy and safety of triple therapy in genotype-1 HCV-infected patients have been published. However, these trials included a small number of patients with advanced fibrosis, and selected a population different from that in real-world settings. AIM: To determine the efficacy of boceprevir, pegInterferon and ribavirin regimen in genotype-1 treatment-experienced HCV-infected patients with cirrhosis and bridging fibrosis in real-life setting. METHOD: 167 treatment-experienced patients (85.6% relapsers) out of which 33.5% had cirrhosis, with a mean age of 52.6 years, registered in the Romanian Name Patient Program Database were included into the study. RESULTS: 16.7% of patients had a viral load >100 IU/mL. Undetectable HCV RNA was encountered in 77.3% of patients at week 12. Multiple logistic regression analysis revealed the following independent predictors, measured at week 8, for an HCV RNA ≥100 IU/mL at week 12 of triple therapy: alanine aminotransferase values (p=0.01), hemoglobin level (p=0.04) and <2 log drop of viral load (p<0.0001). A stopping score at 8 weeks was created as the sum of these 3 parameters, with a total of 4 possible points. AUROC of this score was 0.84, with a sensitivity of 75% and a specificity of 86.2%. CONCLUSION: Triple therapy in this cohort of real-life genotype-1 HCV-infected patients with advanced fibrosis showed robust early virological response (EVR) rates. A week 8 model predicting lack of EVR was created, with good clinical utility that can be validated in prospective larger cohorts.

Fluoropyrimidines plus cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma - a retrospective study.

AIM: This is a retrospective study of patients with advanced biliary tract carcinoma (BTC), who were treated with different regimens of chemotherapy. METHODS: We studied patients with advanced BTC registered at the Department of Oncology at the Fundeni Clinical Institute between 2004 and 2008. The following data were analyzed: rate of response, progression free survival (PFS) to first and second line of chemotherapy, overall survival (OS) and drug toxicity. Ninety-six patients were eligible having either advanced intra or extrahepatic cholangiocarcinoma, or gallbladder cancer with no prior chemotherapy. RESULTS: Out of 96 patients, 57 (59.4%) received fluoropyrimidines (FP)+cisplatin and 39 (40.6%) gemcitabine (Gem)+/-cisplatin. The median PFS for FP+cisplatin was 5.9 months (95%CI 5-6.9) and for Gem+/-cisplatin 6.3 months (95%CI 5.4-7.1), p=0.661. Median OS for FP+cisplatin was 10.3 months (95%CI 7.5-13.1) and for Gem+/-cisplatin 9.1 months (95%CI 7.0-11.2), p=0.098. On disease progression, 46 patients received second line CT (Gem or FP+/-platinum compounds). Median OS for patients with FP based first line and Gem+/-cisplatin in second line was 19 months (95%CI 8.9-29) higher than for the reverse sequence: 13.2 months (95%CI 12-14.4), but not statistically significant (p=0.830). All patients were evaluated for toxicities. Most patients (75.5%) reported at least one adverse event. CONCLUSION: Our results through direct comparison of FP+cisplatin with Gem+/-cisplatin as first line treatment did not show any statistical differences in terms of rate of response, PFS and OS. However, our study showed that FP+cisplatin as first line and Gem based second line therapy gave a better OS rate.

Weight-based dosing regimen of peg-interferon α-2b for chronic hepatitis delta: a multicenter Romanian trial.

BACKGROUND: Antiviral therapy for chronic hepatitis D (delta) is not yet satisfactory, although it appears to be the only means to alter the progressive natural course of chronic hepatitis D virus (HDV) infection. AIM: To assess safety and efficacy, evaluated by virological, biochemical and histological end-of-treatment (EOT) and end-of-follow-up (EOF) response to peg-interferon α-2b 1.5 µg/kg body weight weekly in a Romanian cohort of naïve patients with chronic hepatitis delta. RESULTS: 49 Caucasian patients (55.1% men, 44.9% females) with a mean age of 37.95 years received study medication; per-protocol population consisted of 36 subjects. Virological EOT response was present in 33.3% and EOF response was maintained in 25% of patients. 50% of study population showed normalization of ALT level at EOT and 25% at EOF. A combined biochemical and virological response was observed in 19.4% of patients at EOT and in 16.7% at EOF. At baseline, the necroinflammation quantified by histological activity index (HAI) score was 9.72 and the mean fibrosis score was 2.03; there was a significant decrease of HAI score to 7.44 (p=0.01) at EOT, but not for fibrosis score (1.33, p=0.37). However, only 8.3% of patients at EOT and 19.4% at EOF had progressive histological disease. CONCLUSIONS: Treatment with peg-interferon α-2b succeeded in obtaining a negative HVD RNA in 25% of patients after 104 weeks of follow-up, although combined biochemical and virological response was present in only 16.7%. Necroinflammation decreased significantly in treated patients. Longer treatment periods with pegylated interferon or combination regimen peg interferon-nucleotide analogues should be tested in order to increase efficacy.

Access to peginterferon plus ribavirin therapy for hepatitis C in Romania between 2002-2009.

BACKGROUND: An overall prevalence rate of HCV infection in Romanian adult population was recently estimated to be 3.23%. The proportion of treated patients with chronic hepatitis C in our country has never been assessed. AIMS: 1) to analyze the quality and quantity of antiviral therapy delivery; 2) to determine the proportion of patients being annually and ever treated with antiviral therapy in Romania and 3) to identify barriers against treatment of HCV infected-population in Romania. RESULTS: The number of annually treated patients remained relatively stable between 2002 and 2007 (1,813 patients treated with pegylated interferon and ribavirin in 2002 and 2,446 in 2007). There was a doubled increase in reimbursed treatment in 2008 and 2009 (4,503 and respectively 4,701 treated patients) due to a special campaign organized to increase awareness and prevention of HCV transmission. The median time to therapy approval varies from county to county; overall it is 10.23 months. A total number of 25,318 patients with chronic C hepatitis were treated between 2002-2009, corresponding to a cumulative proportion of 4.1% of the prevalent cases of HCV infection treated in Romania until 1st January 2010. The main limiting factor of access to antiviral therapy for hepatitis C in Romania remains the lack of funds. CONCLUSIONS: This is the first analysis of the nationwide practice for treatment of hepatitis C in Romania. Increased public health efforts are required to improve access to antiviral therapy for hepatitis C in Romania.

Effectiveness and tolerability of pegylated Interferon alpha-2a and ribavirin combination therapy in Romanian patients with chronic hepatitis C: from clinical trials to clinical practice.

BACKGROUND AND AIM: Pegylated interferon alpha in combination with ribavirin represents nowadays the gold standard therapy in patients with chronic hepatitis C. The aim of this study was to assess early (EVR) and sustained virological response (SVR), tolerability and baseline predictive factors for SVR in patients with chronic hepatitis C treated with peginterferon alpha-2a and ribavirin combination therapy in day-to-day clinical practice. METHODS: The analysis included 174 consecutive patients with chronic hepatitis C (naive, relapsers and non-responders after standard therapy) managed in two expertise gastroenterology centers in Romania, mainly on an outpatient basis. The combination therapy was initiated between 1st of June 2002 - 30th of June 2003. RESULTS: The mean age of the study population was 47 years; 41% were men, mean BMI was 26.5 kg/sq.m. Only 7.5% of them had bridging fibrosis/cirrhosis on liver biopsy. EVR and SVR were noted in 78.7% and 51.1%, respectively. Multivariate analysis showed two independent variables associated with SVR: absence of bridging fibrosis/cirrhosis and absence of hepatic steatosis. The rate and profile of side effects associated with pegylated interferon alpha-2a and ribavirin in our clinical setting were all predictable, based on previous experience in the literature. Side effects resulted in interferon and ribavirin dose reductions in 9.2% and, respectively, 25.3%, but permanent discontinuation of the combination therapy was required in only 5.74% of patients. CONCLUSION: Combination antiviral therapy can be safely and successfully used outside clinical trials. To achieve high response rates and tolerability, similar or better than those reported in clinical trials, hepatitis C patients have to be managed in expertise centers, by experienced physicians, aiming at minimizing side effects, optimizing dosing, and enhancing compliance.

Natural history of compensated viral B and D cirrhosis.

AIM: The aim of this study was to define the natural long-term course of HDV compensated cirrhosis. METHODS: 166 consecutive patients with compensated HDV-related cirrhosis diagnosed since 1994 were followed up until the first decompensation and then until death, liver transplantation or 31st of December 2004. The survival during follow-up and the survival according to the type of first decompensation were calculated using the Kaplan Meier method. Survival curves were compared using the log-rank test. RESULTS: 56 females (33.7%) and 110 males (66.3%) with a mean age of 40.7+/-7.9 years were included in the study. The mean Child Pugh and MELD score at the first episode of hepatic decompensation was 8.6+/-2.08 and 15.19+/-5.42, respectively. The median survival was 58.3 months since the diagnosis of compensated cirrhosis and the mean time to first decompensation was 21+/-19 months. The probability of survival after the diagnosis of compensated cirrhosis was 94.3%, 82.5%, and 51.5% at 1, 2, and 5 years, respectively. Ascites was the most frequent first decompensation (80.7%), followed by jaundice (30.1%), portal hypertensive gastrointestinal bleeding (PHGIB) (28.9%), hepatic encephalopathy (HE) (12%), hepatocellular carcinoma (HCC) (12%), portal vein thrombosis (8.4%), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome. 86 patients (51.8%) presented more than one complication at initial decompensation. Survival was worse in patients with jaundice and SBP (p=0.001), followed by patients with HE (p=0.05) and patients who presented more than one initial complication (p=0.03). In the multivariate survival analysis only PHGIB as first decompensation and MELD score>15 were independent predictors of death. CONCLUSION: HDV-related cirrhosis in Romania is an aggressive disease with a median time to decompensation less than 2 years and a median survival less than 5 years. Jaundice, the main clinical consequences of portal hypertension and HCC are the most frequent causes of decompensation and more than half the patients present two or more concomitant initial complications.

Frequency and predictive factors for overlap syndrome between autoimmune hepatitis and primary cholestatic liver disease.

OBJECTIVES: To evaluate the frequency of cholestatic pattern in patients with autoimmune hepatitis (AIH) and to identify predictive factors associated with the development of the overlap syndrome. METHODS: Eighty-two consecutive patients diagnosed with AIH at the referral centre between January 1998 and June 2002 were included in the study. The new scoring system modified by the International Autoimmune Hepatitis Group was used to classify patients as definite/probable. Overlap syndrome was considered when the patient had clinical, serological and histological characteristics of two conditions: AIH and primary biliary cirrhosis (PBC) or AIH and primary sclerosing cholangitis (PSC). RESULTS: From the 82 AIH patients (76 female and six male), 84.1% presented definite AIH (> 15 points) and 15.9% probable AIH (10 - 15 points). The frequency of the overlap syndrome was 20%: 13% with PBC and 7% with PSC. In the univariate analysis the overlap syndrome was associated with male gender (P = 0.01), age < 35 years (P < 0.0001), histopathological aspect of cholestasis (P < 0.0001), suboptimal response to treatment (P < 0.0001) and probable AIH (P < 0.0001). Age < 35 years, probable AIH and the absence of anti-nuclear antibody (ANA) have been identified as independent indicators of the overlap diagnosis by the logistic regression analysis. CONCLUSION: Patients with overlap syndrome between AIH and primary cholestatic liver disease are frequently diagnosed in clinical practice, representing 20% of AIH cases in our study. The independent predictive factors associated with the diagnosis of overlap syndrome are young age, ANA(-) profile, and probable diagnosis according with the scoring system for AIH.

Argon plasma coagulation for radiation proctitis.

Radiation proctitis is a well-recognized complication following radiotherapy for pelvic malignancy. This study was designed to compare the efficacy and complications of argon plasma coagulation (APC) using the power setting of 50 W vs. 60 W in a group of patients with radiation proctitis. Forty-two patients were randomized to undergo APC using the electrical power setting of 60 W (23 patients, group A) or 50 W (19 patients, group B). Patients were asked to estimate the severity of major symptoms before and after APC using a scoring system graded 0-4. The score of major symptoms before and after APC, mean duration of the procedure, number of sessions, side effects/complications were noted. Statistical analysis was performed using Fisher's Exact Test and the 2-tailed p value less than 0.05 was considered statistically significant. A significant improvement of major symptoms was noted in all patients treated with APC, irrespective of the wattage we used, apart from the presence and severity of tenesmus. The mean number of treatment sessions to achieve control of bleeding was 1.34 for group A and 1.9 for group B and the mean time of treatment sessions was significantly shorter for group A (15 min vs. 17 min for group B). No significant differences in early side effects and long term complications between the two groups were evidenced. We can conclude that there is no statistical significance concerning efficacy and side effects of APC application between the 60W and 50W power setting, but the number of sessions and duration of the procedure tend to differ significantly. Rectal stenoses have been described only in patients treated with higher power settings.