Emanuel K. Manesis

The long-term outcome of interferon-α treated and untreated patients with HBeAg-negative chronic hepatitis B

Abstract Background/Aims : This study aimed to evaluate the effect of interferon- α therapy on the long-term outcome of HBeAg-negative chronic hepatitis B. Methods : A cohort of 209 interferon- α treated and 195 untreated patients with histologically documented HBeAg-negative chronic hepatitis B were closely followed for a mean of 6 (1–13.5) years. Patients with decompensated liver disease and/or hepatocellular carcinoma at presentation were excluded. Results : Survival and complication (liver decompensation and/or hepatocellular carcinoma) - free survival were significantly worse in patients with compared to those without baseline cirrhosis and in patients older compared to those younger than 45 years ( P −4 ). Sustained biochemical remission was achieved in 57 treated patients. Sustained responders had significantly better survival and complication-free survival than non-sustained responders ( P =0.027 and P =0.019, respectively) or than untreated patients ( P =0.048 and P =0.012, respectively). Multivariate analysis showed that absence of baseline cirrhosis, younger age, and sustained biochemical remission were independently associated with an improved outcome. Conclusion : In patients with HBeAg-negative chronic hepatitis B, sustained biochemical remission induced by interferon- α is associated with improved long-term outcome, even in the presence of cirrhosis and old age, both known factors associated with worse survival. Therefore, long-term biochemical remission appears to represent a satisfactory therapeutic target in this setting.

Outcome of hepatitis B e antigen–negative chronic hepatitis B on long‐term nucleos(t)ide analog therapy starting with lamivudine

We determined the clinical outcome of hepatitis e antigen (HBeAg)‐negative chronic hepatitis B patients treated with long‐term nucleos(t)ide analog therapy starting with lamivudine. We evaluated 201 such patients treated for 3.8 ± 1.4 years and 2 historical similar cohorts: 1 treated with interferon‐alfa (n = 209) and 1 untreated (n = 195). Virological or biochemical remission rate at 48 months under lamivudine was 34% or 36%, respectively, whereas adefovir was administered in 79 patients with virological–biochemical breakthroughs or no response. Of the lamivudine‐treated patients, 4 died, 1 underwent a transplantation, and another 8 developed major events, all having advanced fibrosis at baseline and all but 1 having experienced breakthroughs or no response. At 5 years, survival was 96%, and major event–free survival was 93%. The major event–free survival was significantly better in patients with than in those without virological remission under lamivudine. At the end of follow‐up, both survival and major event–free survival were independently associated with type of and response to treatment, being significantly better in patients under long‐term antiviral therapy or interferon sustained responders than in interferon non‐sustained responders or untreated cases (5‐year survival: 96% or 98% vs. 88% or 90%, respectively). In conclusion, in HBeAg‐negative chronic hepatitis B, long‐term nucleos(t)ide analog therapy starting with lamivudine significantly improves survival and reduces the risk of major complications, compared with interferon non‐sustained responders or untreated patients. In such patients with advanced fibrosis, close follow‐up for lamivudine resistance and prompt onset of additional antiviral therapy is required or the ab initio use of agent(s) with low resistance rates should be considered. (HEPATOLOGY 2005;42:121–129.)

Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study

Objective To evaluate the risk and predictors of hepatocellular carcinoma (HCC) in HBeAg-negative chronic hepatitis B patients of the large HEPNET.Greece cohort study who received long-term oral antivirals starting with lamivudine monotherapy. Design Retrospective analysis of HCC incidence in HBeAg-negative chronic hepatitis B patients from a retrospective–prospective cohort who were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for ≥12 months. Setting A nationwide network of liver centres. Patients 818 patients were included: 517 with chronic hepatitis B only; 160 with compensated cirrhosis; 56 with decompensated cirrhosis; 85 with unclassified disease severity. Interventions All patients were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy. Main outcome measures Development of HCC. Results During a median follow-up of 4.7 years, HCC developed in 49 (6.0%) patients. The 5-year cumulative incidence of HCC was higher in patients with cirrhosis than in those with chronic hepatitis B only (11.5% vs 3.2%, respectively; p<0.001). HCC developed in 0.7%, 6.7% and 11.7% of patients <50, 50–60 and >60 years old, respectively (p<0.001). Virological on-therapy remission did not significantly affect the incidence of HCC in all patients or those with cirrhosis, but it showed a trend for lower HCC incidence in patients with chronic hepatitis B only (p=0.076). In multivariate analysis, age, gender and cirrhosis were independently associated with HCC risk regardless of virological remission. Conclusions Long-term therapy with nucleos(t)ide analogue(s) starting with lamivudine monotherapy does not eliminate HCC risk in HBeAg-negative chronic hepatitis B. The risk of HCC is particularly high in patients with cirrhosis, who should remain under HCC surveillance even during effective therapy. Older age and male gender remain independent risk factors for HCC, while virological on-therapy remission does not seem to significantly reduce the overall incidence of HCC.

Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen–negative chronic hepatitis B virus infection

OBJECTIVES:In hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection, the clinical relevance of low viremia levels remains unclear. We evaluated the clinical significance of a single baseline serum HBV DNA measurement by a quantitative polymerase chain reaction (PCR) assay in this setting.METHODS:In total, 196 patients with HBeAg-negative chronic HBV infection (62 inactive carriers, 134 with chronic hepatitis B) were studied. ALT activity was normal at baseline in 25/134 HBeAg-negative chronic hepatitis B patients (18.7%), whereas it remained normal throughout follow-up in all inactive carriers.RESULTS:HBV DNA was <30,000 copies/ml in 14 (10.5%) and <100,000 copies/ml in 17 (12.9%) HBeAg-negative chronic hepatitis B patients, whereas it was <30,000 copies/ml in all inactive carriers (undetectable in 14). In particular, HBV DNA levels were <100,000 copies/ml in eight (32%) and <30,000 copies/ml in five (20%) of the 25 patients with HBeAg-negative chronic hepatitis B and normal baseline ALT values. HBV DNA levels with a cut-off at 30,000 or 100,000 copies/ml could correctly classify 92.9% or 91.3% of patients with HBeAg-negative chronic HBV infection, whereas ALT or IgM anti-HBc (IgM class antibody to HBV core antigen) index > 0.200 could correctly classify only 87.2% and 82.1% of patients, respectively. A combined HBV DNA and IgM anti-HBc index performed better by correctly classifying 94.4% of cases.CONCLUSIONS:Serum HBV DNA levels evaluated by sensitive quantitative PCR assays can be used for differentiation between HBeAg-negative chronic hepatitis B and inactive hepatitis B surface antigen carrier state, but the cut-off level should be set at approximately 30,000 copies/ml and certainly lower than the recently suggested level of 100,000 copies/ml.

Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen–negative chronic hepatitis B virus infection?

The diagnosis of hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B indicating therapeutic intervention currently requires serum hepatitis B virus (HBV) DNA ≥2,000 IU/mL. We evaluated the severity of liver histology and the presence of histological indication for treatment in patients with HBeAg‐negative chronic HBV infection focusing on those with low viremia and/or normal alanine aminotransferase (ALT). In total, 399 patients with increased ALT and detectable serum HBV DNA (chronic hepatitis B patients) and 35 cases with persistently normal ALT and HBV DNA >2,000 IU/mL (inactive carriers) were included. Histological indication for treatment (grading score ≥7 and/or stage ≥2 in Ishaks classification) was found in 91% (185/203), 82% (75/91), 75% (47/63), and 62% (26/42) of chronic hepatitis B patients with HBV DNA ≥200,000, 20,000‐199,999, 2,000‐19,999, and <2,000 IU/mL, respectively (P < 0.001). Histological indication for treatment was more frequent in chronic hepatitis B patients with persistently elevated ALT (86% or 275/321), but it was also found in 74% (58/78) of those with transiently normal ALT (P = 0.025). All inactive carriers had HBV DNA <20,000 IU/mL. Histological indication for treatment was present in 17% (6/35) of inactive carriers always due to moderate (stage 2) fibrosis without active necroinflammation. Conclusion: HBeAg‐negative chronic HBV patients with persistently or transiently increased ALT and HBV DNA ≥20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such cases with HBV DNA <20,000 and even <2,000 IU/mL. In contrast, minimal histological lesions are observed in the majority of HBeAg‐negative patients with persistently normal ALT and HBV DNA >2,000 IU/mL, who may not require immediate liver biopsy and treatment but only close follow‐up. (HEPATOLOGY 2008.)

Increased arterial stiffness and impaired endothelial function in nonalcoholic Fatty liver disease: a pilot study.

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease both in the general and pediatric population and has been associated with increased cardiovascular risk. Arterial function and early atherosclerotic changes are markers of cardiovascular disease and independent predictors of the corresponding risk. Through a global approach, we investigated the relationships between NAFLD and functional arterial changes and early atherosclerosis. METHODS A total of 23 consecutive patients (mean age 55 ± 14 years, 11 males) with biopsy evidence of NAFLD and 28 control subjects matched for age, gender, body mass index, and other cardiovascular risk factors participated in the study. RESULTS Compared to controls, NAFLD subjects had significantly higher carotid-femoral pulse wave velocity (PWV; 8.2 ± 1.3 m/s vs. 6.9 ± 1.3 m/s, P = 0.001), higher carotid intima-media thickness (IMT; 0.79 ± 0.18 mm vs. 0.67 ± 0.13 mm, P = 0.01), and reduced flow-mediated dilatation (FMD; 1.92 ± 2.11% vs. 4.8 ± 2.43%, P < 0.001). In multivariable analysis, presence of NAFLD was an independent determinant of both PWV and FMD, whereas leptin was an independent determinant of PWV (B = 0.036, P < 0.05), and adiponectin was independently associated with FMD (B = 0.104, P < 0.05). In addition, histological activity of liver disease expressed by the global Brunt Grade was associated independently with FMD (B = -1.054, P < 0.05). CONCLUSIONS NAFLD is associated with arterial stiffness and endothelial dysfunction. Given the important independent prognostic role of these arterial indexes, these findings have important implications for increased cardiovascular risk in patients with NAFLD.

Serum adipokine levels in chronic liver diseases: Association of resistin levels with fibrosis severity

Objective. Leptin and adiponectin have been implicated in the pathogenesis and progression of non-alcoholic steatohepatitis (NASH) and chronic hepatitis C (CHC), but little is known about the role of resistin in chronic liver diseases. The objective of this study was to investigate serum levels of the above three adipokines in relation to the etiology of liver disease and to determine their associations with histological severity. Material and methods. We prospectively evaluated 146 patients (HBeAg-negative chronic hepatitis B (CHB): 52, CHC: 70, NASH: 24) who consecutively underwent liver biopsy. Detailed epidemiological, anthropometric and laboratory data were recorded. Histological lesions were evaluated blindly according to the Ishak and the Brunt classifications for CHB/CHC and NASH, respectively. Results. Serum adipokine levels were similar between CHB and CHC patients, while CHB/CHC patients had significantly lower leptin levels compared with NASH patients (8.3±7.3 versus 17.6±16.6 ng/ml, p=0.012) and higher adiponectin (10.2±5.1 versus 7.5±4 µg/ml, p=0.018) and resistin levels (7.1±2.5 versus 5.7±2.8 ng/ml, p=0.016). In CHB/CHC, there was no significant association between steatosis or necroinflammation and levels of adipokines, while the presence of moderate/severe fibrosis (stages 4–6) was associated with higher leptin and adiponectin levels in male but not in female patients and with lower resistin levels irrespective of gender or other factors (adjusted odds ratio=0.788, p=0.035). Conclusions. Serum adipokine levels depend on the etiology of liver disease differing between chronic viral hepatitis and NASH, but not between CHB and CHC. In CHB/CHC, resistin levels are independently associated with fibrosis severity, whereas in the association of leptin and adiponectin levels with fibrosis, it seems to be a gender effect.

Hepatitis B surface antigen: Relation to hepatitis B replication parameters in HBeAg-negative chronic hepatitis B

BACKGROUND & AIMS Translation of HBsAg depends on transcription of the appropriate mRNAs from cccDNA, but its relation to other hepatitis B virus (HBV) replication parameters is not known, inasmuch as integrated sequences of HBV-DNA may also contribute to its serum levels, especially in HBeAg-negative chronic hepatitis B (CHB) patients. METHODS We investigated HBsAg serum levels, its hepatocellular expression, and their relationship to HBV replicative- and host-response parameters before treatment in 54 HBeAg-negative CHB patients and in 15 of them after 40.1±33.3months of virological response on oral antiviral (NUC) therapy also. Liver cccDNA and HBV-DNA quantitation, HBsAg- and HBcAg-immunostaining were performed in the same needle biopsy material, while serum HBsAg and HBV-DNA levels were measured in samples drawn on the day of liver biopsy. RESULTS In untreated patients, serum HBsAg correlated positively with HBsAg-positive hepatocytes/mm(2) (p=0.003) and weakly with serum HBV-DNA, but not with cccDNA, liver HBV-DNA, HBcAg-positive hepatocytes/mm(2), or ALT. cccDNA correlated significantly with liver HBV-DNA (p<0.00001), ALT (p=0.001), and serum HBV-DNA levels (p=0.012) but not with liver HBsAg or HBcAg. Antiviral therapy decreased serum HBsAg levels by 79.6% (p=0.012) and liver HBV-DNA by 84.4% (p=0.026) in paired comparisons and, as expected, significantly decreased serum HBV-DNA and ALT levels, but not cccDNA. CONCLUSIONS In untreated HBeAg-negative CHB, serum HBsAg levels reflect liver HBsAg, but not cccDNA or liver HBV-DNA, suggesting that they are not solely dependent on the replicative cycle of HBV. Effective NUC therapy for 3.34 years significantly lowers serum HBsAg and liver HBV-DNA, but not cccDNA.

Optic tract neuropathy complicating low-dose interferon treatment

Optic neuritis occurred in three of our patients receiving treatment with alpha interferon-2b (Intron-A; 3MU thrice weekly) for chronic hepatitis. The complication appeared within, 1, 9 1/2 and 10 months of treatment, respectively. In all cases, blurred vision was the initial complaint and subsequent electrophysiologic investigation confirmed the presence of optic tract neuropathy. The patients had no other neurologic signs. Computerized tomography and magnetic resonance image of the brain were not remarkable. Psychiatric symptoms, in the form of an interferon-associated depressive reaction, were present in two of them; in one case, it was severe enough to require immediate discontinuation of treatment. In two patients the visual symptoms resolved and the parameters of neurophysiologic testing returned to normal within 1 month after stopping interferon. In one case, however, residual optic tract impairment associated with a unilateral central scotoma and a substantial decrease of visual acuity was present 2 years later, despite a course of methylprednizolone. In this patient the interferon treatment was continued for 3 months despite the visual symptoms, and he later received two additional interferon courses because of relapses of hepatitis. We conclude that clinically evident optic tract neuropathy may complicate interferon administration. Candidates for interferon treatment may need routine examination of optic fields and visual evoked potentials, before and during administration of the drug to avoid possibly permanent visual sequelae.

Aspartate aminotransferase to platelet ratio index for fibrosis evaluation in chronic viral hepatitis

Objective We assessed the value of the recently developed aspartate aminotransferase to platelet ratio index (APRI) for predicting significant fibrosis or cirrhosis in patients with chronic hepatitis C or HBeAg-negative chronic hepatitis B. Methods In total, 489 patients (chronic hepatitis C, 284 patients; HBeAg-negative chronic hepatitis B, 205 patients) were included. APRI values of 0.50 or less and greater than 1.50 were evaluated for predicting significant fibrosis, and APRI values of 1.00 or less and greater than 2.00 for predicting cirrhosis. Liver biopsies were evaluated according to the Ishaks classification. Fibrosis was considered to be significant in cases with scores 3–6, and cirrhosis to be present in cases with fibrosis scores of 5 and 6. Results Significant fibrosis was observed in 56/148 (38%) patients with APRI≤0.50, 130/227 (57%) patients with 0.501.50 (P<10−3). Cirrhosis was observed in 47/311 (15%) patients with APRI≤1.00, 29/93 (31%) patients with 1.002.00 (P<10−3). The areas under receiver–operating characteristic curves were 0.65 and 0.70 for prediction of significant fibrosis or cirrhosis, respectively. The combination of APRI≤0.50 and APRI>1.50 classified correctly 36% of patients with or without significant fibrosis, while the combination of APRI≤1.00 and APRI>2.00 classified correctly 62% of patients with or without cirrhosis. There was no significant difference in the predictive values of APRI between patients with chronic hepatitis C and chronic hepatitis B. Conclusions APRI is significantly associated with the extent of fibrosis, but it does not classify correctly 40–65% of patients with chronic hepatitis C or HBeAg-negative chronic hepatitis B, and thus it cannot replace liver biopsy.