Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naïve chronic hepatitis B patients in the real-world setting.

The aim of this study was to determine the long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment-naïve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End-Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long-term follow-up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.

Clinical and immunological analysis of 23 adult patients with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, defective antibody production, and recurrent upper and lower airway tract infections. OBJECTIVES: To reveal the clinical heterogeneity of this condition, analyze the high frequency of respiratory and gastrointestinal complications despite satisfactory trough immunoglobulin (Ig) G levels, and determine the main difficulties in management and treatment. METHODS: We performed a retrospective analysis of 23 patients (13 male and 10 female) diagnosed with CVID between 2001 and 2008. RESULTS: The median diagnostic delay for females and males was 15 years (range, 1-32 years) and 8 years (range, 1-31 years), respectively. Restrictive, obstructive, and combined pulmonary function defects were determined in 23%, 27%, and 14% of patients, respectively. The most frequent findings on the thoracic computed tomography scan were bronchiectasis, mediastinal lymphadenopathy, fibrosis, ground-glass patterns, mosaic oligemia, peribronchial cuffing, and parenchymal nodules. Giardiasis and duodenal lymphoid hyperplasia were detected in 52% and 42% of the patients, respectively, and Helicobacter pylori in 42%. Vitamin A levels were normal, although beta-carotene and/or vitamin E levels were decreased in patients presenting malabsorption-related symptoms. Malignancy was documented in 3 patients and decreased bone mineral density in 9 patients (3 had osteoporosis and 3 had osteomalacia). CONCLUSION: CVID is a multisystemic disease that should be managed by a multidisciplinary team. Intravenous immunoglobulin therapy and antibiotics do not seem to have a suppressive effect on granulomatous or inflammatory manifestations. More comprehensive studies based not only on peripheral blood but also on immunohistological analysis are necessary to shed light on the pathogenesis of these life-threatening complications.

Living donor liver transplantation from hepatitis B core antibody positive donors.

UNLABELLED: Liver allografts from donors previously exposed to hepatitis B virus (HBV) carry the risk of transmission of HBV infection to immunosuppressed recipients. However, exclusion of donor candidates with the serologic evidence of resolved hepatitis B-HBV surface antigen (HbsAg) negative and HBV core antibody (anti-HBc) positive-is not feasible in countries endemic for HBV. AIM: Our aim was to assess the safety of living donor liver transplantation from anti-HBc positive donors. MATERIALS AND METHODS: In our institution, 152 transplants were performed between June 1999 and April 2004. Fifty-six (37%) of the living donors were anti-HBc positive. Twenty of these liver grafts were transplanted to HbsAg-negative recipients. We excluded four HBsAg negative recipients who died because of early complications after transplantation. Lamivudine (100 mg/day) was given for prophylaxis of de novo HBV infection. RESULTS: The mean follow-up time for 16 HBsAg-negative recipients was 21.7 (7-48) months. None of them experienced de novo HBV infection. CONCLUSION: The use of liver allografts from anti-HBc-positive living donors is reasonably safe in HBsAg-negative recipients under lamivudine prophylaxis.

Nutritional status and prognosis in cirrhotic patients.

BACKGROUND AND AIM: The potential prognostic value for survival of nutritional status in cirrhotics after adjusting Child-Pugh classification and Model for End-Stage Liver Disease has not been evaluated. METHODS: We used Kaplan-Meier and Cox proportional hazards regression models to identify factors associated with mortality in a cohort of 222 cirrhotics [M/F:145/77 median age 52 (18-68) years] with prospectively collected nutritional parameters as well as modified subjective global nutritional assessment, Royal Free Hospital-Subjective Global Assessment index. Follow-up was censored at the time of transplantation. Other variables were ones in Child-Pugh and Model for End-Stage Liver Disease scores, age, aetiology of cirrhosis and renal function. RESULTS: Pretransplant mortality (Kaplan-Meier) was 21% by 2 years (135 patients were transplanted). Among the nutritional parameters, only Royal Free Hospital-Subjective Global Assessment remained significantly associated with mortality in multivariable models (P = 0.0006). The final model included the following variables: urea (P = 0.0001), Royal Free Hospital-Subjective Global Assessment (P = 0.003), age (P = 0.0001), Child-Pugh grade (P = 0.009) and prothrombin time (P = 0.003). The results were similar when the Child-Pugh grade was replaced by the Model for End-Stage Liver Disease score in the model, and whether a competing risks model was used. CONCLUSIONS: Nutritional indices add significantly to both Child-Pugh grade and Model for End-Stage Liver Disease scores when assessing the patient prognosis.

Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis: a follow-up to 12 years.

BACKGROUND: It is uncertain whether ursodeoxycholic acid therapy slows down the progression of primary biliary cirrhosis, according to two meta-analyses. However, the randomized trials evaluated had only a median of 24 months of follow-up. AIM: To evaluate long-term ursodeoxycholic acid therapy in primary biliary cirrhosis. METHODS: We evaluated 209 consecutive primary biliary cirrhosis patients, 69 compliant with ursodeoxycholic acid and 140 untreated [mean follow-up 5.79 (s.d. = 4.73) and 4.87 (s.d. = 5.21) years, respectively] with onset of all complications documented. Comparison was made following adjustment for baseline differences according to Cox modelling, Mayo and Royal Free prognostic models. RESULTS: Bilirubin and alkaline phosphatase concentrations improved with ursodeoxycholic acid (at 36 months, P = 0.007 and 0.018, respectively). Unadjusted Kaplan-Meier analysis showed benefit (P = 0.028), as 44 (31%) untreated and 15 (22%) ursodeoxycholic acid patients died or had liver transplantation. However, there was no difference when adjusted by Cox modelling (P = 0.267), Mayo (P = 0.698) and Royal Free models (P = 0.559). New pruritus or fatigue or other complications were not different, either before or after adjustment for baseline characteristics. CONCLUSIONS: Long-term ursodeoxycholic acid therapy did not alter disease progression in primary biliary cirrhosis patients despite a significant improvement in serum bilirubin and alkaline phosphatase consistent with, and similar to, those seen in ursodeoxycholic acid cohorts in randomized trials.

Angiodysplasia in a duodenal diverticulum as an unusual cause of upper gastrointestinal bleeding.

The majority of duodenal diverticula are asymptomatic but may also induce major haemorrhage on rare occasions. Gastrointestinal bleeding due to angiodysplasia in a duodenal diverticulum is very rare. We present a 70-year-old woman with repeated melaena in whom the diagnosis of angiodysplasia in a diverticulum of the fourth part of the duodenum could be made by standard upper endoscopy.

Nitroimidazole-induced chronic hepatitis.

Drug-induced chronic hepatitis is a rare pathological condition. There is no reported case with chronic hepatitis secondary to nitroimidazole use. We report a patient who developed nitroimidazole-induced chronic hepatitis following acute exacerbation of hepatitis three times after nitroimidazole use.

Impact of pretransplant MELD score on posttransplant outcome in living donor liver transplantation.

It is not clear whether pretransplantation MELD (model for End-Stage Liver Disease) score can foresee posttransplant outcome. We retrospectively evaluated 80 adult patients (55 men, 25 women) who underwent living donor liver transplantation between September 1998 and March 2003. Five other patients with fulminant hepatitis were excluded. The UNOS-modified MELD scores were calculated to stratify patients into three groups: group 1) MELD score less than 15 (n = 13); group 2) MELD score 15 to 24 (n = 36); and group 3) MELD score 25 and higher (n = 26). The patients were predominantly men (n = 52, 69.3%) with overall mean age of 43.9 years (range, 17-62 years). The mean follow-up was 15.7 months (range, 1-47; median = 14 months). The mean MELD score was 22.7 (range, 9-50; median = 21). The overall 1- and 2-year patient survivals were 87% and 78.7%, respectively. The 1-year patient survivals for groups 1, 2, and 3 were 100%, 87%, and 79%; respectively. 2-year survivals, 100%, 79%, and 61%, respectively. Survivals stratified by MELD showed no statistically remarkable differences in 1-year and 2-year patient survival (P = .08). In contrast, 1-year and 2-year patient survival rates for UNOS status 2A, 2B, and 3 were 73%-50%, 95%-91%, and 91%-91%, statistically significant difference (P = .002). Finally, to date preoperative MELD score showed no significant impact on 1- and 2-year posttransplant outcomes in adult-to-adult living donor liver transplantation recipients, but we await longer-term follow-up with greater numbers of patients.

Predicting the advent of ascites and other complications in primary biliary cirrhosis: a staged model approach.

BACKGROUND: Current survival models for primary biliary cirrhosis have limited precision for medium and long-term survival. Aim To describe a prognostic model for the advent of complications in primary biliary cirrhosis as the first approach to a staged prognostic model. METHODS: From an established database of 289 consecutive primary biliary cirrhosis patients referred to Royal Free Hospital over 12 years (mean follow-up of 4.1 years), baseline characteristics at referral were evaluated by Cox-proportional hazards regression modelling. RESULTS: The following complications occurred de novo: 85 ascites/peripheral oedema, 40 oesophagogastric varices, 63 encephalopathy, 29 spontaneous bacterial peritonitis and/or septicaemia, 59 symptomatic urinary tract infections. Age, albumin, log(10)(bilirubin), presence of ascites at referral, variceal bleeding within 6 weeks before referral, detection of oesophagogastric varices at or before referral were significant at multivariate analysis with different combinations and coefficients for each complication. The model for predicting ascites and/or peripheral oedema best fitted the observed data (ROC = 0.7682, S.E. = 0.0385). CONCLUSIONS: The known prognostic factors in primary biliary cirrhosis also model the advent of complications. In view of the prognostic importance of ascites and its more robust statistical model, ascites and/or peripheral oedema could represent, following validation, the most suitable staged model in primary biliary cirrhosis to improve precision in survival modelling.

A pilot study: longer duration of posttransplant hepatitis C virus therapy may increase the sustained response rate.

BACKGROUND: Although end of treatment virological responses are similar in posttransplant patients with recurrent chronic hepatitis C virus infection and nontransplant patients, the sustained virological response rate is lower in the posttransplant setting. We investigated the efficacy of a longer duration (3 years) of therapy. METHODS: Thirteen patients with biopsy-proven recurrent hepatitis C were included in the study. In the first year of therapy, all patients were treated with a standard regimen of interferon alpha 2b 3MU 3 times in a week plus ribavirin (800 to 1000 mg/d). After the availability of pegylated interferon, patients were converted to pegylated interferon (1.5 microg/kg body weight). Hepatitis C virus RNA was evaluated at months 3, 6, 9, 12, 24, 36, and 42. If hepatitis C virus RNA was negative at month 12, the patients continued treatment for 36 months. RESULTS: Hepatitis C virus RNA was negative in six patients at 12 months, including two who became hepatitis C virus RNA negative after 3 months; two, after 6 months; and two, after 12 months of therapy. Those six continued treatment completing 3 years of treatment with a sustained virological response. Four of those six patients with sustained virological response required colony-stimulating factors during treatment. CONCLUSION: Although the hepatitis C virus RNA status of patients at 12 weeks is a good marker to predict a sustained virological response in the nontransplant setting, it is not valid in posttransplant patients. A prolonged duration of therapy for patients who are viral responders at 12 months may prevent recurrence and increase the sustained virological response rate.

Safety, tolerability, and efficacy of pegylated-interferon alfa-2a plus ribavirin in HCV-related decompensated cirrhotics.

BACKGROUND: Pretransplantation clearance of hepatitis C virus (HCV)-RNA reduces the risk of HCV recurrence after transplantation. Furthermore, a sustained virological response could reduce disease progression and slow clinical deterioration in nontransplanted patients. AIM: To evaluate the safety, tolerability and efficacy of pegylated-interferon (PEG-IFN) alfa-2a plus ribavirin therapy in HCV-related decompensated cirrhotics. METHODS: Twenty HCV-related decompensated cirrhotics (44-67 years, 12 males, six Child-Pugh score A, 14 Child-Pugh score B, all with genotype 1b) were enrolled into the study. Treatment with PEG-IFN alfa-2a (135 microg, once a week) plus ribavirin (1000-1200 mg/day) was commenced. A 48-week treatment was planned in patients who had early virological response. RESULTS: Treatment was stopped in 8 (40%) patients. The remaining 12 (60%) patients completed 48 weeks of therapy; nine (45%) of them obtained end-of-therapy virological response and six (30%) of them obtained sustained virological response. Living donor liver transplantation was performed in three (15%) patients. Eight (40%) and six (30%) patients needed to reduce PEG-IFN alfa-2a and ribavirin dosages, respectively. No patient died during the follow-up period. CONCLUSION: PEG-IFN alfa-2a plus ribavirin therapy is safe, tolerable and efficacious in selected HCV-related decompensated cirrhotics.

HBV vaccination in liver transplant recipients: not an effective strategy in the prophylaxis of HBV recurrence.

Anti-HBs immunoglobulins (HBIG) and lamivudine are main options to prevent hepatitis B virus (HBV) reinfection after liver transplantation. Although they are very effective, development of mutant viruses and high cost of treatment are main limitations for their application. Additionally there is an uncertainity for the duration of that prophylaxis regimen and its mostly applied indefinitely. Recently, post-transplant HBV vaccination is reported to be a cheaper alternative prophylaksis strategy, that enables discontinuation of HBIG. To investigate the efficacy of HBV vaccination in patients transplanted for HBV cirrhosis, we administered double course of double dose recombinant HBV vaccine (Genhavac B; containing HBV pre-S1, pre-S2, and S gene products). Vaccination has been started 1 month after HBIg discontinuation, and lamivudine (100 mg/day) was given throughout the study. The first cycle consisted of 0, 1- and 6-month schedule, and, in nonresponders, second cycle 0, 1-, 2-month schedule. Fourteen patients included into the study. Only one patient seroconverted (an anti-HBs titre of 37 IU/L) after the first cycle. No other patient responded to second cycle. HBV vaccination in the post-transplantation setting does not seems like an effective strategy in the prophylaxis of HBV recurrence.

Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross-reactivity.

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic disease characterized by the presence of antibodies directed predominantly against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). What provokes tolerance breakdown in PBC remains to be established, though there is evidence to indicate that microbes may induce anti-mitochondrial antibodies (AMA) through a mechanism of molecular mimicry. METHODS: Having found that urease beta (UREB)(22-36) antigen of Helicobacter pylori (HELPY) shares extensive (87%) similarity with PDC-E2(212-226), the major mitochondrial autoepitope, it was hypothesized that this would also lead to cross-reactivity. The UREB/PDC-E2 mimics were thus constructed and tested by ELISA in 112 PBC patients and 114 controls. RESULTS: Reactivity to PDC-E2(212-226) was found in 104 patients but to UREB(22-36) in only 2. In these two patients, the double reactivity was not cross-reactive. The lack of surface antibody accessibility to UREB(22-36), as demonstrated through three-dimensional model prediction analysis, may explain this unexpected finding. There was some speculation on whether HELPY UREB(22-36) might act as a cross-reactive CD4 T-cell epitope. All seven PBC patients, tested in a standard proliferation assay against PDC-E2(212-226), gave a positive response. All seven were unresponsive to HELPY UREB(22-36). The pattern of reactivity to HELPY antigens by immunoblot was similar between anti-PDC-E2-positive and negative PBC cases, as well as between PBC patients and controls. CONCLUSION: Contrary to common belief, extensive sequence homology (molecular mimicry) between self and microbe does not necessarily result in cross-reactivity. It is therefore likely that, when present, cross-reactivity between self and microbes is of biological importance.