Does the antiviral therapy of patients with chronic hepatitis exert nephrotoxic effects?

INTRODUCTION: HBV and HCV chronic hepatitis can be accompanied by secondary renal disease. In addition, these patients receive antiviral drugs with potential nephrotoxicity. It is known that interferon (IFN) therapy in HCV-infected kidney transplant recipients is followed by rejection of the transplant in 50% of the cases. Ribavirin is contraindicated in hemodialyzed patients and in patients with a GFR <50 ml/min/1.73 m(2). IFN therapy requires dosage reduction and close monitoring in patients with a GFR <50 ml/min/1.73 m(2) and in patients with end stage renal disease. The aim of our study was to assess the nephrotoxicity of antiviral drugs in patients with chronic hepatitis by measuring three renal biomarkers: urinary albumin, N-acetyl-ß-D-glucosaminidase (NAG) and α 1-microglobulin, as well as glomerular filtration rate (GFR-MDRD4) before and at 6 months of therapy. METHODS: Fifty-five patients (28 male and 27 female, with a mean age of 47.85 ± 12.03 years) with chronic hepatitis (40 patients with HCV, 13 patients with HBV, 1 patient with HBV+HCV, and 1 patient with HBV+HDV) were enrolled into the study. Different antiviral drug associations were used on a case-by-case basis. The 40 patients with HCV chronic hepatitis received either Peg-IFN-α 2a+Ribavirin (37 patients) or Peg-IFN-α 2b+Ribavirin (3 patients). The 13 patients with HBV chronic hepatitis received Peg-IFN-α 2a (9 patients), Lamivudine (2 patients), Entecavir (1 patient), or Adefovir (1 patient). The patient with HBV+HCV chronic hepatitis received Peg-IFN-α 2a+Ribavirin. The patient with HBV+HDV chronic hepatitis received IFN-α 2a. Urinary albumin (ELISA), NAG (colorimetrical method), α 1-microglobulin (ELISA), and serum creatinine were measured before and at 6 months of antiviral therapy. Urinary markers were expressed as either mg/gCr (for albumin and α 1-microglobulin) or U/gCr (for NAG). Statistical analysis (Pearson's correlation coefficient, paired t-test and χ(2)-test) was performed. RESULTS: At 6 months of therapy urinary albumin/gCr did not increase significantly: 16.58 ± 23.39 vs. 15.85 ± 24.96 mg/gCr before therapy, p = 0.87. Urinary NAG/gCr did not increase significantly: 4.21 ± 3.37 vs. 3.83 ± 3.2 U/gCr before therapy, p = 0.53. Urinary α 1-microglobulin/gCr was almost unchanged: 4.38 ± 4.47 vs. 4.38 ± 3.57 mg/gCr before therapy, p = 0.99. The GFR did not decline significantly: 92.41 ± 22.21 vs. 94.59 ± 36.1 ml/min/1.73 m(2) before therapy, p = 0.7. Ten patients (18.18%) were albuminuric before therapy, and 14 patients (25.45%) were albuminuric at 6 months of therapy, a non-significant increase (p = 0.35). We found a correlation between urinary albumin/gCr and NAG/gCr and between urinary albumin/gCr and α 1-microglobulin/gCr both at baseline and at 6 months of therapy: r = 0.54, p = 0.0005; r = 0.29, p = 0.03; r = 0.51, p = 0.0005; and r = 0.4, p = 0.002, respectively. In the patient receiving Adefovir, a known nephrotoxic drug, two of the three biomarkers (urinary albumin/gCr and NAG/gCr) increased, most notably NAG/gCr. Both HCV and HBV chronic hepatitis therapy were associated with non-significant changes in renal biomarker excretion and GFR. CONCLUSIONS: With the exception of Adefovir, all of the drug associations used in this study were safe.

Pegylated-interferon alpha 2a treatment for chronic hepatitis C in patients on chronic haemodialysis.

AIM: To evaluate the response to pegylated-interferon alpha 2a in chronic hepatitis C patients on chronic haemodialysis. METHODS: Ten patients with chronic C hepatitis were enrolled in this study. All had increased aminotransferases for more than 6 mo, positive antiHCV antibodies and positive PCR HCV-RNA. We administrated Peg-Interferon alpha 2a 180 microg/wk for 48 wk. After 12 wk of treatment we evaluated the biochemical and early virological response (EVR). At the end of the treatment we evaluated the biochemical response and 24 wk after the end of the treatment we evaluated the sustained virological response (SVR). We monitored the side-effects during the treatment. RESULTS: Two patients dropped out in the first 12 wk of treatment and 2 after the first 12 wk of treatment. After 12 wk of treatment, 7 out of 8 patients had biochemical response and EVR and 1 had biochemical response but persistent viremia. We had to reduce the dose of pegylated-interferon to 135 mug/wk in 2 cases. Three out of 6 (50%) patients had SVR 24 wk after the end of the treatment. Intention-to-treat analysis showed that 3 out of 10 patients (30%) had SVR. Side-effects occurred in most of the patients (flu-like syndrome, thrombocytopenia or leucopoenia), but they did not impose the discontinuation of treatment. CONCLUSION: After 12 wk of treatment with Peg-Interferon alpha 2a (40 ku) in patients on chronic haemodialysis with chronic C hepatitis, EVR was obtained in 87.5% (7/8) of the cases. SVR was achieved in 50% of the cases (3/6 patients) that finished the 48 wk of treatment.

Mucosal Protective Compounds in the Treatment of Gastroesophageal Reflux Disease. A Position Paper Based on Evidence of the Romanian Society of Neurogastroenterology.

BACKGROUND AND AIMS: Gastroesophageal reflux disease (GERD) therapy is challenging and suppression of acid secretion or prokinetics do not cure all cases. Some drugs with protective action on the esophageal mucosa have been used alternatively or in association with proton pump inhibitors (PPIs) and/or prokinetics. The Romanian Society of Neurogastroenterology undertook an Evidence-Based analysis, from which this position paper evolved. METHODS: We performed a systematic literature search in PubMed until October 2015, using the terms: sucralfate, guaiazulene, gaiazulene, dimethicone, alginate, antacids and gastroesophageal reflux. Forty-seven papers were included and analyzed. Several statements were elaborated regarding the use of these drugs in GERD. The evidence and recommendations were discussed between the authors. RESULTS: There is evidence in the medical literature suggesting the benefit of these drugs in GERD. In patients with persistent or mild reflux symptoms antacids rapidly relieve heartburn. Alginate-antacid combination is superior both over placebo and antacids to treat mild reflux symptoms, and can be used to treat persistent reflux symptoms despite acid suppressant therapy. Sucralfate is superior over placebo in alleviating GERD symptoms and can be used as maintenance therapy. Guaiazulene-dimethicone improves the quality of life in patients with GERD. CONCLUSIONS: Drugs used to protect the esophageal mucosa against acid are useful in alleviating chronic heartburn, especially in patients with mild reflux symptoms.

Peg-Interferon Alfa 2a (40kDa) in patients on chronic haemodialysis with chronic C hepatitis. Preliminary results.

The aim of the study was to evaluate the response to Pegylated Interferon alpha2a (40 kDa) in patients on chronic haemodialysis with chronic C hepatitis. 10 patients were enrolled in this study (4 males and 6 females). All had increased aminotransferases, anti HCV antibodies and PCR HCV-RNA positive. We administrated Peg-Interferon alpha2a 180 microg/week for 48 weeks. One patient was excluded from the study because of lack of compliance. We had to stop the treatment in one patient due to complications after surgery. After 12 weeks of treatment we evaluated the biochemical and virological response. We continued with Peg-Interferon until 48 weeks. Six patients finished the treatment. After 12 weeks of treatment with Peg-Interferon alpha 2a (40 kDa) in patients on chronic haemodialysis with chronic C hepatitis, the virological response (HCV-RNA absent by PCR) was obtained in 87.5% (7/8) of the cases. All patients who finished the 48 weeks of treatment had normal transaminases (biochemical response) (6/6). We had to reduce the dose of Peg-Interferon in only 2 cases. Even if side-effects occurred in most of the patients (flu-like syndrome, thrombocytopenia or leucopenia) they did not impose the discontinuation of treatment. The sustained response will be established by determining PCR RNA-HCV 6 months after the end of the treatment.

Role of interleukin-28B polymorphism as a predictor of sustained virological response in patients with chronic hepatitis C treated with triple therapy: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Chronic hepatitis C represents an important health problem. The aim of our meta-analysis was to establish the role of reference single nucleotide (rs) 12979860 allele of interleukin-28B (IL28B) CC versus CT+TT genotype (the most researched allele of IL28B) as a predictor of sustained virological response (SVR) in patients with chronic hepatitis C treated with triple therapy. METHODS: The PubMed, MEDLINE, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases as well as abstract books from important gastroenterology and hepatology meetings were searched for all studies published until 15 July 2012 that analysed the relationship between the polymorphism of IL28B and SVR in patients with chronic hepatitis C, genotype 1, treated with pegylated interferon + ribavirin + direct antiviral agents (telaprevir or boceprevir). The following keywords were used: IL28B polymorphism, chronic hepatitis C, sustained virological response, SVR, triple therapy, telaprevir, boceprevir. RESULTS: Odds ratios (ORs) with 95 % confidence intervals were pooled from five study populations (1,641 cases) using a random-effects model. The SVR rate was significantly higher in patients with the CC genotype of IL28B than in those with non-CC genotypes (CT and TT): OR = 3.91 (95 % CI 2.11-7.28), p < 0.0001. Higher SVR rates were obtained in chronic hepatitis C patients with the CC genotype of IL28B, regardless of their therapeutic status (naïve patients: OR = 3.99 [95 % CI 1.67-9.51], p < 0.0001; and previously treated ones: OR = 2.15 [95 % CI 1.35-3.43], p = 0.001). CONCLUSION: IL28B polymorphism seems to influence the SVR rate in patients with chronic hepatitis C treated with triple therapy, but further studies are needed to clarify the mechanism and the influence of other factors on the SVR rates.

Time for individualized colonoscopy bowel-prep regimens? A randomized controlled trial comparing sodium picosulphate and magnesium citrate versus 4-liter split-dose polyethylene glycol.

BACKGROUND & AIMS: Good bowel cleansing is essential to achieving optimal endoscopic evaluation of the colon. There are many different regimens available, but none have shown consistently superior results in achieving a clean colon. We compared the efficiency of two regimens with regard to bowel cleansing and patient satisfaction. The study also aimed to identify patient-related factors that influenced the quality of the bowel cleansing. METHODS: We conducted a single-blind, multicenter, randomized controlled trial comparing sodium picosulphate and magnesium citrate versus 4-liter split-dose polyethylene glycol (PEG). Consecutive patients presenting for colonoscopy at two tertiary referral centers were invited to participate. The main outcomes were colon cleanliness and patient satisfaction with the preparation regimen. The quality of bowel cleansing was assessed by the endoscopist with the use of a 4-grade scale. Patients completed questionnaires evaluating their experience during the preparation process. Multivariate analysis was conducted in order to compare the two regimens and identify patient-related factors that influenced the main outcomes. RESULTS: One hundred eighty-one patients were randomized and 165 completed the trial (91.1%). PEG was slightly superior to sodium picosulphate with regard to bowel cleansing (p=0.01), while patient satisfaction was higher with sodium picosulphate (p=0.008). Patients with higher education and patients reporting high adherence to instructions achieved better colon cleansing using PEG. CONCLUSIONS: There seems to be no clear advantage for one bowel preparation solution over the other. However, by taking into account individual patient characteristics, opting for a particular regimen could increase the likelihood of achieving a cleaner colon.

Response to standard of care antiviral treatment in patients with HCV liver cirrhosis - a systematic review.

BACKGROUND: Patients with HCV liver cirrhosis are a category difficult to treat. The aim of this study was to establish the sustained virological response (SVR) rates in HCV patients with liver cirrhosis treated with standard of care therapy (Pegylated Interferon and Ribavirin for 48 weeks in genotypes 1 and 4 and 24 weeks in genotypes 2 and 3). METHODS: Searching the PubMed, Medline, Lilacs, Scopus, Ovid and Medscape databases we identified all the articles published until February 2011 that included only HCV cirrhotic patients. These studies evaluated the SVR after standard of care treatment: Pegylated Interferon alpha 2a (doses ranging between 135-180 µg/week) or Pegylated Interferon alpha 2b (1 or 1.5 µg/kg/week) and Ribavirin (doses ranging between 800-1200 mg/day). We used the following key words: HCV, liver cirrhosis, sustained virological response (SVR). RESULTS: The overall SVR rate was 33.3% (95%CI-confidence interval=30.6-36.2%). SVR was significantly higher in patients with genotypes 2 and 3 (422 patients) as compared to those with genotypes 1 and 4 (692 patients): 55.4% (95%CI=50.7-60.1) versus 21.7% (95%CI=18.7-25), p < 0.0001. CONCLUSION: The overall SVR rate in cirrhotic patients treated with standard of care therapy is 33.3%, but lower in cases affected by genotypes 1 and 4 (21.6%) which makes them a priority regarding the development of more potent drugs for effective treatment.

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.

Outcome of antiviral treatment in patients with chronic genotype 1 HCV hepatitis. A retrospective study in 507 patients.

BACKGROUND AND AIM: The current standard of care in chronic HCV genotype 1 hepatitis is the combination of pegylated interferon (PegIFN) with ribavirin for 48 weeks. The aim of our paper was to verify if there are significant differences regarding the sustained virologic response (SVR) in patients treated with PegIFN alfa-2a vs. those treated PegIFN alpha-2b, both in combination with ribavirin. METHOD: We performed a retrospective study on 507 patients with chronic viral C hepatitis treated with PegIFN alpha-2a 180 microg/kg/week or PegIFN alpha-2b 1.5 microg/kg/week plus ribavirin in the recommended doses according to weight, following the current treatment guidelines. We evaluated the SVR defined as PCR RNA-HCV undetectable 24 weeks after the end of treatment. RESULTS: There were no differences regarding the baseline characteristics among the subgroups of patients treated with PegIFN alpha-2a or PegIFN alpha-2b concerning the pretreatment viral load (p=0.2445), the severity of fibrosis (p=0.2403), the mean age of the patients (p=0.9597) and the women/men ratio (p=0.2087). The SVR rates in patients treated with PegIFN alpha-2a were similar to those in patients treated with PegIFN alpha-2b: 208/338 (61.5%) vs. 94/169 (55.6%) (p=0.2129). CONCLUSION: Sustained virologic response rates were similar in HCV genotype 1 patients treated with PegIFN alpha-2a and with Peg-IFN alpha-2b.

High sustained virological response rate to combination therapy in genotype 1 patients with histologically mild hepatitis C.

BACKGROUND: Patients with mild hepatitis C have a significant risk of disease progression at medium- and long-term follow-up and should be considered for antiviral therapy. AIM: To evaluate the rate of sustained viral response (SVR) and predictive factors of SVR in HCV genotype 1 patients with mild hepatitis C (fibrosis stage F0/F1) treated with combination antiviral therapy. METHODS: 260 naïve patients were followed-up during 72 weeks in three referral hepatology centers between 2004 and 2006. Univariate and multivariate logistic regression analysis was conducted. RESULTS: Early virological response was 88.1% and SVR was 74.2%. In the univariate analysis, SVR was associated with young age (p=0.001), very low (< or = 400,000 IU/mL) baseline viremia (p=0.03) and high aminotransferase levels (p=0.04) and was not associated with gender, body mass index, inflammatory activity, steatosis, ribavirin and peginterferon dose changes, premature cessation of therapy. Multivariate analysis identified the following independent predictors of SVR: age <50 years (p=0.0009), viral load < or = 400,000 IU/mL (p=0.03) and aminotransferase level >2 times normal value (p=0.02). CONCLUSIONS: Genotype 1 HCV patients with mild hepatitis have a high rate of SVR, similar to genotype non-1. Young age, very low viremia and significant hepatocytolisis are independent predictors of SVR in patients with mild hepatitis.

Efficacy and safety of peginterferon alpha-2a (40KD) in HBeAg-positive chronic hepatitis B patients.

AIM: The study was designed to evaluate the efficacy and safety of peginterferon alpha-2a in HBeAg-positive chronic hepatitis B patients, nonresponders or relapsers after previous lamivudine or standard interferon therapy. METHODS: This prospective, national, multicentric, open label, not randomized trial enrolled 43 HBeAg-positive chronic hepatitis B patients with detectable HBsAg for at least 6 months prior to screening, positive HBeAg and negative anti-HBe, serum HBV DNA levels of at least 500,000 copies/mL by PCR assay, elevated ALT up to 10 x ULN, no response or relapse after previous lamivudine or standard interferon therapy. All eligible patients received pegIFN alpha-2a 180 micrograms weekly for 48 weeks with 24 weeks treatment free follow-up. There were two main efficacy assessments: HBeAg seroconversion and viral supression below 100,000 copies/mL. RESULTS: HBeAg seroconversion rate at the end-of-treatment was 4.65% (n=2; p less than 0.05) increasing to 11.62% 24 weeks after end of therapy (n=5; p less than 0.05). The rate of viral supression at levels below 100,000 copies/mL was 23.25% (n=10; p less than 0.05) at end-of-treatment, and 16.3% (n=7; p less than 0.05) at end of follow-up. ALT normalization was obtained in 20.9% (p less than 0.05) of patients at end-of-treatment, the percentage being significantly higher - 37.2% (p less than 0.05) at the end of follow-up. CONCLUSIONS: Even in a difficult-to-treat patient population with HBeAg-positive chronic hepatitis B, peginterferon alpha 2a proved to be efficient in a defined proportion of patients. The increase in HBeAg seroconversion rate from end-of-treatment (4.65%) to the end of follow-up period (11.62%) also proves the benefits of prolonged immunological effect of pegIFN alpha 2a.

Efficacy, tolerability and predictive factors for early and sustained virologic response in patients treated with weight-based dosing regimen of PegIFN alpha-2b ribavirin in real-life healthcare setting.

BACKGROUND AND AIM: Increasing evidence to date highlights that individualized treatment regimens with pegylated interferon (PegIFN) and ribavirin represent a better approach for patients nowadays showing negative predictive factors for sustained virological response. The aims of this study were to assess the rate of early (EVR) and sustained virological response (SVR), tolerability and baseline predictive factors associated with EVR and SVR in patients with chronic hepatitis C treated with individualized weight-based dosing regimen for both PegIFN alpha-2b and ribavirin. METHODS: The observational analysis included 234 consecutive patients with chronic hepatitis C genotype 1 treated with PegIFN alpha-2b and ribavirin on an out-patient basis between January 2003-March 2006. RESULTS: The mean age of the study group was 49.5 years, and 35% were male patients; the group was slightly overweight (mean BMI=26.5 kg/sq.m). EVR was achieved in 84.6% (198/234 patients). The end-of-treatment and sustained biochemical responses were 76.3% and 66.1%, respectively. At the end of follow-up, an overall intent-to-treat SVR was achieved by 71 of 127 patients (in 55.9%). Lower baseline (< 1,000 000 IU/mL) HCV viral load was the only predictive factor associated with EVR (p=0.04); absent or mild fibrosis (F0-1) and a low histological activity (HAI < 8) were independently associated with SVR. Side effects resulted in PegIFN and ribavirin dose reductions in 9.4% and, respectively, 18.1%, but definitive discontinuation of therapy was necessary only in 8.7% of patients. CONCLUSION: PegIFN alpha-2b and ribavirin can be safe and successful when using a weight-based dosing regimen, leading to high response rates even in overweight patients.

Comparative study concerning the efficacy of Peg-IFN alpha-2a versus Peg-IFN alpha-2b on the early virological response (EVR) in patients with chronic viral C hepatitis.

BACKGROUND: Pegylated interferons (Peg-IFNs) represent, in association with Ribavirin, the first line of treatment in chronic C viral hepatitis. The AIM of our paper was to compare the efficacy of Peg-IFN alpha 2a (Pegasys) and Peg-IFN alpha 2b (PegIntron) in a group of patients from the Department of Gastroenterology in Timisoara. MATERIAL AND METHOD: 116 patients with chronic C viral hepatitis were treated. The patients were randomized in chronological order (1:1), so that 58 patients were treated with Peg-IFN alpha 2a 180 microg/kg/week + Ribavirin (group 1) and 58 were treated with Peg-IFN alpha 2b 1.5 microg/kg/week + Ribavirin (group 2). Ribavirin was administered in the recommended doses, according to weight. The mean age was: group 1 -- 49.3 years, group 2 -- 50.9 years (p=0.37). Group 1 consisted of 37 women and 21 men and group 2 of 44 women 14 men (p=0.22). In group 1, 48 patients were naïve (N1), 7 were relapsers after previous treatment (RL1) and 3 non-responders to previous treatment (NR1). In group 2, 33 patients were naive (N2), 18 relapsers (RL2) and 7 non-responders (NR2). After 12 weeks of treatment we evaluated the early virological response (EVR), defined as a drop in the viral load with 2 logs compared to the baseline viremia. RESULTS: The following EVR rates were found: in group 1 (Pegasys) - 82.2% (48/58); in group 2 (PegIntron) -- 67.2% (39/58) (p=0.08). There were also no significant statistical differences between the response rates in the subgroups: naïve patients [89.6% vs. 75.2%, p = 0.61], relapsers [57.1% vs. 66.6%, p = 0.67] and non responders [33.3% vs. 28.6%, p = 1]. CONCLUSION: Our head to head comparative study showed that there are no statistically significant differences in the EVR between the patients treated with Peg-IFN alpha 2a and Peg-IFN alpha 2b.