Wolf Peter Hofmann

Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function

Entecavir is a potent nucleoside inhibitor of the hepatitis B virus (HBV) polymerase with a high antiviral efficacy and a high genetic barrier to viral resistance. After approval in 2006, knowledge on the side effect profile in patients with advanced liver disease and impaired liver function is still limited. Here, we report on 16 patients with liver cirrhosis and chronic hepatitis B who were treated with entecavir. Five of these patients developed lactic acidosis during entecavir treatment. All patients who developed lactic acidosis had highly impaired liver function (Model for End‐Stage Liver Disease [MELD] score ≥ 20). Lactic acidosis (lactate 26‐200 mg/dL, pH 7.02‐7.40, base excess −5 mmol/L to −18 mmol/L) occurred between 4 and 240 days after treatment initiation with entecavir. Lactic acidosis was lethal in one patient but resolved in the other cases after termination/interruption of entecavir treatment. No increased lactate serum concentrations were observed during treatment with entecavir in the other 11 patients with chronic hepatitis B and liver cirrhosis who all had MELD scores below 18. The MELD score correlated with the development of lactic acidosis (P < 0.005) as well as its single parameters bilirubin, international normalized ratio, and creatinine. In contrast, Child‐Pugh Score did not correlate with the development of lactic acidosis. Our data indicate that entecavir should be applied cautiously in patients with impaired liver function. (HEPATOLOGY 2009;50:2001–2006.)

Entecavir treatment for chronic hepatitis B: Adaptation is not needed for the majority of naïve patients with a partial virological response†‡

Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)‐naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA‐naïve CHB patients, particularly in those with detectable hepatitis B virus (HBV) DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multicenter cohort study, we investigated 333 CHB patients treated with entecavir monotherapy. The NA‐naïve population consisted of 243 patients, whereas 90 were NA‐experienced. Virological response (VR) (HBV DNA <80 IU/mL) was achieved in 48%, 76%, and 90% of hepatitis B e antigen (HBeAg)‐positive and in 89%, 98%, and 99% of HBeAg‐negative NA‐naïve patients at weeks 48, 96, and 144, respectively. Thirty‐six of 175 (21%) NA‐naïve patients with at least 48 weeks of follow‐up had a detectable load at week 48 (partial virological response [PVR]). Twenty‐nine (81%) patients with PVR reached VR during prolonged ETV monotherapy, and none of them developed ETV‐resistance. Among 22 patients with HBV DNA <1,000 IU/mL at week 48, VR was achieved in 21 (95%) patients, compared with eight of 14 (57%) patients with HBV DNA ≥1,000 IU/mL. Continuous HBV DNA decline was observed in most patients without VR during follow‐up, and in three patients adherence was suboptimal according to the treating physician. ETV was safe and did not affect renal function or cause lactic acidosis. Conclusion: ETV monotherapy can be continued in NA‐naïve patients with detectable HBV DNA at week 48, particularly in those with a low viral load because long‐term ETV leads to a virological response in the vast majority of patients. (HEPATOLOGY 2011;)

Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis

Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11–32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.

A new standard of care for the treatment of chronic HCV infection

The introduction of direct acting antiviral agents (DAAs) will markedly change treatment options for individuals who have a chronic HCV infection. Within the next few months, licensing of two HCV protease inhibitors (boceprevir and telaprevir) for the treatment of patients with chronic hepatitis C as part of a triple therapy with PEG-IFN-α and ribavirin is anticipated in the USA, Europe and many other countries. Final results of pivotal phase III clinical trials in previously untreated and treatment-experienced patients with HCV genotype 1 infection were presented at the Annual Meeting of the American Association for the Study of the Liver 2010 held in Boston, MA, USA, and at the Annual Conference of the Asian Pacific Association for the Study of the Liver 2011, held in Bangkok, Thailand. This article summarizes the results of these phase III trials in consideration of accumulating data on important baseline and on-treatment predictive factors for treatment response, such as the host IL28B genotype and the rapid virologic response; the introduction of these new therapies into clinical practice is also covered. Furthermore, preliminary data on the combination of different classes of DAAs, such as HCV protease inhibitors and HCV polymerase inhibitors, without interferon α are discussed.

Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms

Ribavirin is an old broad‐spectrum antiviral that is highly effective when used in combination with interferon‐α and also as part of triple therapies containing new inhibitors of the hepatitis C virus (HCV) non‐structural (NS)3/4 protease or HCV NS5B polymerase for the treatment of patients with chronic hepatitis C. However, the molecular mechanisms by which ribavirin enhances early and sustained virological response rates during interferon‐based antiviral HCV therapy are still unknown. Several mechanisms including (i) immunomodulatory properties, (ii) inhibition of the inosine monophosphate dehydrogenase, (iii) direct inhibition of the HCV‐encoded NS5B RNA polymerase, (iv) induction of lethal mutagenesis and (v) modulation of interferon‐stimulated gene expression are currently proposed. Here, we discuss recent advances from in vitro data and their importance for the situation in patients with chronic hepatitis C. Furthermore, theoretical aspects from mathematical modelling of ribavirin action in chronic hepatitis C are reviewed.

Etiologies and Outcomes of Acute Liver Failure in Germany

BACKGROUND & AIMS Acute liver failure (ALF) is a severe form of acute liver injury that can progress to multiple organ failure. We investigated causes and outcomes of ALF. METHODS Eleven university medical centers in Germany were asked to report patients with (primary) severe acute liver injury (sALI) (international normalized ratio [INR] >1.5 but no hepatic encephalopathy) and primary ALF (INR >1.5 with overt hepatic encephalopathy) treated from 2008 to 2009. Data were analyzed from 46 patients with sALI and 109 patients with ALF. RESULTS The most frequent etiologies of primary ALF were non-acetaminophen drug-induced (32%), indeterminate (24%), and viral (21%); acetaminophen ingestion was the cause of ALF in only 9% of patients. The support of a ventilator was required by 44% of patients with ALF, vasopressors by 38%, and renal replacement by 36%. Seventy-nine patients with ALF (72%) survived until hospital discharge, 38 (35%) survived without emergency liver transplantation (ELT), and 51 received ELT (47%); 80% of patients who received ELT survived until discharge from the hospital. CONCLUSIONS In Germany, drug toxicity, indeterminate etiology, and viral hepatitis appear to be the major causes of primary ALF, which has high mortality. Patients with ALF are at great risk of progressing to multiple organ failure, but 80% of patients who receive ELT survive until discharge from the hospital.

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection†‡

The impact of amantadine on virologic response rates of interferon‐based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)‐1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa‐2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV‐1–infected patients (mean age, 46 ± 12 years) were randomized to (A) amantadine‐sulphate (400 mg/day) (n = 352) or (B) placebo (n = 352), both in combination with 180 μg peginterferon alfa‐2a once weekly and ribavirin (1000‐1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24‐week follow‐up period were assessed by qualitative reverse transcription polymerase chain reaction (RT‐PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On‐treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P = 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per‐protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). Conclusion: In this large placebo‐controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa‐2a and ribavirin in patients with chronic genotype HCV‐1 infection. (HEPATOLOGY 2008.)

Antiviral therapy of chronic hepatitis C in patients with advanced liver disease and after liver transplantation.

Chronic infection with the hepatitis C virus (HCV) represents one of the major causes for end-stage liver disease worldwide. Although liver transplantation offers an effective treatment, HCV reinfection of the transplanted graft is a critical and almost inevitable complication with major influence on graft- and patient survival. Pre-transplant antiviral therapy in advanced liver disease is limited by poor tolerance and only applicable to mildly decompensated patients but was able to show promising results in patients reaching negative viral load when undergoing transplantation. Prophylactic therapy with HCV antibodies during the anhepatic phase has not been shown to be effective in studies to date. Antiviral therapy after transplantation but before evidence of reinfection, so called pre-emptive treatment, is limited by frequent complications and a high rate of side effects. The mainstay of management represents directed antiviral therapy after evidence of recurrence of chronic Hepatitis C. With a combination therapy of pegylated interferon and ribavirin, sustained virologic response rates of 25–45% are achieved. However, tolerability is often poor, and the need of dose reduction is frequent. To date, there is no general consensus on modality, timing and dosing of antiviral treatment of HCV in patients with advanced liver disease and after liver transplantation. More randomised, controlled trials are needed. Moreover, upcoming new treatment approaches, e.g. specifically targeted antiviral therapy for hepatitis C (STAT-C) with HCV-specific polymerase and protease inhibitors, may represent a therapeutic alternative.

Hepatitis D virus-specific cytokine responses in patients with chronic hepatitis delta before and during interferon alfa-treatment.

Background: Hepatitis delta is caused by infection with the hepatitis D virus (HDV) and is considered the most severe form of viral hepatitis. Treatment options for hepatitis delta are limited, with only 25% of patients responding to interferon (IFN)‐alfa‐based therapies. The role of the adaptive immune system in controlling HDV infection during spontaneous or treatment‐induced viral clearance is not well understood.

Long‐term follow‐up of endoscopic therapy for stenosis of the biliobiliary anastomosis associated with orthotopic liver transplantation

Endoscopic treatment for stenosis of an anastomotic biliary stricture (ABS) after orthotopic liver transplantation (OLT) has been proven to be effective and safe, but the long‐term outcomes and the risk factors for recurrence are unknown. All 374 patients who underwent OLT at Frankfurt University Hospital were screened for the occurrence of ABSs. ABSs were treated via the endoscopic insertion of a plastic endoprosthesis (29.8%), balloon dilation (12.8%), or a combination of the two (57.4%). The mean follow‐up time was 151 weeks, and the mean survival time was 3.4 years. ABSs were observed in 47 patients (12.6%). The mean time from OLT to an ABS was 16.25 months (median = 3.25 months). The cumulative incidence rates for ABSs were 0.09 after 12 months, 0.10/24 m. and 0.11/36 m. In 12 cases (25.5%), ABSs were observed more than 12 months after OLT. ABSs recurred in 16 of the 47 patients (34%). The occurrence of an ABS 6 weeks or more after OLT was a significant predictor of ABS recurrence [P = 0.04, hazard ratio (HR) = 0.235]. There was a trend of hepatitis C virus (HCV) infections being predominant in patients experiencing ABS recurrence (30% for HCV etiology versus 4% for non‐HCV etiology) in comparison with patients not experiencing recurrence (36% for HCV etiology versus 30% for non‐HCV etiology, P > 0.05). The severity of the initial stricture predicted ABS recurrence (P = 0.046, HR = 2.78), but it did not influence overall survival. The long‐term resolution of ABSs was observed in 45 of the 47 patients (95.7%), and ABS recurrence was treated with another attempt (n = 16 or 34%) or 2 more attempts (n = 1) at endoscopic treatment. In conclusion, the long‐term success of the endoscopic treatment of ABSs is highly probable if recurrent strictures are again treated endoscopically. ABSs might occur late (>36 months) after OLT, and lifelong follow‐up is essential for identifying OLT patients with ABSs. Liver Transpl 19:586–593, 2013.