George V. Papatheodoridis

2-Year GLOBE Trial Results: Telbivudine Is Superior to Lamivudine in Patients With Chronic Hepatitis B

BACKGROUND & AIMS The GLOBE trial has compared the efficacy and safety of telbivudine versus lamivudine treatment over 2 years in patients with chronic hepatitis B. METHODS Hepatitis B e antigen (HBeAg)-positive (n = 921) and HBeAg-negative (n = 446) patients received telbivudine or lamivudine once daily for 104 weeks. The primary outcome, assessed in the intent-to-treat population, was therapeutic response (hepatitis B virus DNA <5 log(10) copies/mL and either HBeAg loss or normalization of alanine aminotransferase [ALT] level). RESULTS The therapeutic response to telbivudine was superior to that of lamivudine in HBeAg-positive (63% vs 48%; P < .001) and HBeAg-negative (78% vs 66%; P = .007) patients. HBeAg-positive patients given telbivudine also had better outcomes compared with lamivudine in terms of nondetectable viremia (< 300 copies/mL) at 55.6% versus 38.5% (P < .001), HBeAg loss at 35.2% versus 29.2% (P = .056), and viral resistance at 25.1% versus 39.5% (P < .001). Hepatitis B e antigen seroconversion was 29.6% versus 24.7% (P = .095) in all patients and 36% versus 27% (P = .022) in patients with baseline ALT level > or = 2 times normal. Telbivudine-treated HBeAg-negative patients showed higher rates of nondetectable viremia compared with lamivudine at 82.0% versus 56.7% (P < .001) and less resistance at 10.8% versus 25.9% (P < .001). Adverse events occurred with similar frequency, whereas grade 3/4 increases in creatine kinase levels were more common in patients given telbivudine (12.9% vs 4.1%, P < .001). Multivariate logistic regression analyses identified telbivudine treatment, among other variables, as an independent predictor of better week 104 outcomes. CONCLUSIONS Telbivudine is superior to lamivudine in treating patients with chronic hepatitis B over a 2-year period.

Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: A systematic review

BACKGROUND & AIMS Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues. METHODS We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for> or = 24 months. RESULTS Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32-108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466). CONCLUSIONS Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC.

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.

Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease

Data are limited on the safety and effectiveness of oral antivirals other than lamivudine and adefovir dipivoxil for treatment of chronic hepatitis B (CHB) in patients with decompensated liver disease. This Phase 2, double‐blind study randomized 112 patients with CHB and decompensated liver disease to receive either tenofovir disoproxil fumarate (TDF; n = 45), emtricitabine (FTC)/TDF (fixed‐dose combination; n = 45), or entecavir (ETV; n = 22). The primary endpoint was safety; more specifically, tolerability failure (adverse events resulting in permanent treatment discontinuation) and confirmed serum creatinine increase ≥0.5 mg/dL from baseline or confirmed serum phosphorus <2 mg/dL. Patients with insufficient viral suppression (e.g., confirmed HBV DNA ≥400 copies/mL at week 8 or 24) could begin open‐label FTC/TDF but were considered failures in this interim week 48 analysis for efficacy endpoints. Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV (P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% (P = 1.000), respectively. Six patients died (none considered related to study drug) and six received liver transplants (none had HBV recurrence). The adverse event and laboratory profiles were consistent with advanced liver disease and complications, with no unexpected safety signals. At week 48, HBV DNA was <400 copies/mL (69 IU/mL) in 70.5% (TDF), 87.8% (FTC/TDF), and 72.7% (ETV) of patients. Proportions with normal alanine aminotransferase were: 57% (TDF), 76% (FTC/TDF), and 55% (ETV). Hepatitis B e antigen (HBeAg) loss/seroconversion occurred in 21%/21% (TDF), 27%/13% (FTC/TDF), and 0%/0% (ETV). Child‐Turcotte‐Pugh and Modification for End‐stage Liver Disease scores improved in all groups. Conclusion: All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters. (HEPATOLOGY 2011.)

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.)

Systematic review: the model for end-stage liver disease - should it replace Child-Pugh's classification for assessing prognosis in cirrhosis?

Background:  Prognosis in cirrhotic patients has had a resurgence of interest because of liver transplantation and new therapies for complications of end‐stage cirrhosis. The model for end‐stage liver disease score is now used for allocation in liver transplantation waiting lists, replacing Child‐Turcotte‐Pugh score. However, there is debate as whether it is better in other settings of cirrhosis.

Liver grafts from anti-hepatitis B core positive donors: a systematic review.

BACKGROUND & AIMS Although hepatitis B virus (HBV) transmission after liver transplantation of grafts from HBsAg-negative, anti-HBc positive donors is well established, the growing organ shortage favours the use of such marginal grafts. We systematically evaluated the risk of HBV infection after liver transplantation with such grafts and the effect of anti-HBV prophylaxis. METHODS We performed a literature review over the last 15 years identifying 39 studies including 903 recipients of anti-HBc positive liver grafts. RESULTS Recurrent HBV infection developed in 11% of HBsAg-positive liver transplant recipients of anti-HBc positive grafts, while survival was similar (67-100%) to HBsAg-positive recipients of anti-HBc negative grafts. De novo HBV infection developed in 19% of HBsAg-negative recipients being less frequent in anti-HBc/anti-HBs positive than HBV naive cases without prophylaxis (15% vs 48%, p<0.001). Anti-HBV prophylaxis reduced de novo infection rates in both anti-HBc/anti-HBs positive (3%) and HBV naive recipients (12%). De novo infection rates were 19%, 2.6% and 2.8% in HBsAg-negative recipients under hepatitis B immunoglobulin, lamivudine and their combination, respectively. CONCLUSIONS Liver grafts from anti-HBc positive donors can be safely used, preferentially in HBsAg-positive or anti-HBc/anti-HBs positive recipients. HBsAg-negative recipients should receive prophylaxis with lamivudine, while both anti-HBc and anti-HBs positive recipients may need no prophylaxis at all.

The evolving role of leptin and adiponectin in chronic liver diseases.

Leptin and adiponectin, the main metabolic products of adipose tissue, have been implicated in a wide spectrum of human diseases. Given the frequent presence of hepatic steatosis in several chronic liver diseases, there is currently increasing interest in the role of these adipokines in the development of hepatic steatosis and also in necroinflammation and fibrosis, mostly in patients with nonalcoholic fatty liver disease or chronic hepatitis C. According to experimental data, reduced adiponectin levels and increased leptin levels associated with leptin resistance, which are usually observed in obese patients with or without metabolic syndrome, may result in fat accumulation in the liver and in the enhancement of liver inflammation and mostly fibrogenesis. Increased leptin and decreased adiponectin serum levels have been detected initially in patients with nonalcoholic steatohepatitis and more recently in patients with chronic hepatitis C compared to healthy controls in most but not all studies, while the data on the associations between these adipokine levels and the severity of hepatic steatosis or fibrosis are still rather conflicting. However, several potential confounding parameters were not evaluated in all studies. Therefore, the associations between adipokines and liver histological lesions and their effects on liver cells should be evaluated further in prospective, carefully designed studies, including larger cohorts of patients with detailed assessment of metabolic and other potential confounding factors.

Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation

Liver transplantation (LT) is the only therapeutic option for end‐stage primary sclerosing cholangitis (PSC), but PSC can recur (rPSC) in some patients after LT. The aim of our study was to evaluate the risk factors associated with rPSC. Between 1989 and 2004, 69 patients receiving transplantation for PSC (42 male, mean age 41.9 yr). Clinical and laboratory data, activity/extension and treatment of ulcerative colitis (UC), post‐LT cytomegalovirus (CMV) infection, and immunosuppression were evaluated. Determination of rPSC was made by radiological and histological findings. Exclusion criteria were ABO blood group incompatibility, hepatic artery stenosis, and biliary strictures occurring in <3 months post‐LT. A total of 48 (70%) patients had PSC and UC pre‐LT. rPSC occurred in 7 of 53 (13.5%, 2 patients with de novo UC) who were alive 1 yr after LT and/or met inclusion/exclusion criteria: median 60 (4‐120) months. No patient without post‐LT UC had rPSC: 0 of 20 vs. 7 of 26 with post‐LT UC (P = 0.027). The multivariate logistic regression analysis showed that maintenance steroids for UC (>3 months) post‐LT was the only risk factor significantly associated with rPSC (P = 0.025). In conclusion, the presence of UC post‐LT, and the need for maintenance steroids post‐LT, which is an independent factor, are associated with rPSC. These findings could help elucidate a possible mechanism of PSC pathogenesis. Liver Transpl, 2007.

Risk of hepatocellular carcinoma in chronic hepatitis B: Assessment and modification with current antiviral therapy

In the treatment of chronic hepatitis B (CHB), the ultimate goal is preventing hepatitis B virus (HBV)-associated liver disease, including hepatocellular carcinoma (HCC). Recently published studies show that in CHB patients treated with the currently recommended first-line nucleos(t)ide analogs (NAs) entecavir or tenofovir, annual HCC incidences range from 0.01% to 1.4% in non-cirrhotic patients, and from 0.9% to 5.4% in those with cirrhosis. In Asian studies including matched untreated controls, current NA therapy consistently resulted in a significantly lower HCC incidence in patients with cirrhosis, amounting to an overall HCC risk reduction of ∼30%; in non-cirrhotic patients, HCC risk reduction was overall ∼80%, but this was only observed in some studies. For patients of Caucasian origin, no appropriate comparative studies are available to date to evaluate the impact of NA treatment on HCC. Achievement of a virologic response under current NA therapy was associated with a lower HCC risk in Asian, but not Caucasian studies. Studies comparing entecavir or tenofovir with older NAs generally found no difference in HCC risk reduction between agents, except for one study which used no rescue therapy in patients developing lamivudine resistance. Overall, these data indicate that with the current, potent NAs, HCC risk can be reduced but not eliminated, probably due to risk factors that are not amenable to change by antiviral therapy, or events that may have taken place before treatment initiation. Validated pre- and on-therapy HCC risk calculators that inform the best practice for HCC surveillance and facilitate patient counseling would be of great practical value.