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

Authors


  • Potential conflict of interest: Nothing to report.

Abstract

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.)

An estimated 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B is a major cause for liver cirrhosis and its complications hepatic decompensation and hepatocellular carcinoma (HCC), resulting in 500,000 to 1.2 million hepatitis B–related deaths annually.1 Suppression of HBV DNA is a principal goal in treating chronic hepatitis B because this was shown to significantly improve liver histology and to decrease rates of hepatic complications and HCC.2, 3 Patients with chronic hepatitis B should be considered for antiviral treatment when HBV DNA levels are >2000 IU/mL, serum alanine aminotransferase levels are above the upper limit of normal, and liver histology shows at least moderate necroinflammation or fibrosis. Patients with liver cirrhosis are candidates for antiviral therapy even if alanine aminotransferase levels are normal or if HBV DNA levels are <2000 IU/mL.

Current treatment options are pegylated interferon-alfa and nucleoside or nucleotide inhibitors of the HBV polymerase/reverse transcriptase. For treating chronic hepatitis B, five polymerase inhibitors have been approved so far: the nucleoside analogues lamivudine, telbivudine, entecavir, and the nucleotide analogues adefovir dipivoxil and, most recently, tenofovir disoproxil.

Entecavir is a potent cyclopentyl guanosine nucleoside inhibitor of the HBV polymerase which was approved for the treatment of patients with both hepatitis B envelope antigen (HBeAg)-positive and HbeAg-negative chronic hepatitis B and compensated liver disease.4 Compared to lamivudine or adefovir, entecavir has a higher antiviral efficacy and superior resistance profile.4, 5 Compared with tenofovir, entecavir's antiviral efficacy and genetic barrier to resistance seem to be similar (Table 1).4–6 Current international guidelines recommend treatment with polymerase inhibitors that have a high antiviral efficacy and genetic barrier, such as entecavir and tenofovir, for all patients with highly replicative chronic hepatitis B as well as for patients with advanced liver fibrosis or cirrhosis.7, 8 Due to the limited enrollment of patients with early liver cirrhosis and exclusion of patients with advanced liver cirrhosis in the approval studies, the side effect profile of entecavir and tenofovir in patients with impaired liver function is still limited.

Table 1. Antiviral Efficacy, Resistance Profile, and Reported Cases of Lactic Acidosis of Approved Polymerase Inhibitors for the Treatment of Chronic Hepatitis B
AgentAntiviral EfficacyResistance ProfileLactic Acidosis
  • *

    Fatal lactic acidosis was observed in a patient treated with combination therapy of adefovir and entecavir.18 †Development of lactic acidosis has been reported in case reports during combination therapies in HIV-infected patients.10, 12

Adefovir+++*
Entecavir+++++*
Lamivudine++†
Telbivudine+++
Tenofovir+++++†

In patients infected with human immunodeficiency virus (HIV), the development of lactic acidosis due to mitochondrial toxicity has been reported for a subset of polymerase inhibitors.9, 10 In large clinical trials including patients with compensated liver disease, entecavir-treatment was associated only with moderate side effects like headache, diarrhea, insomnia, or arthralgia.4 Here, we report on a series of patients who developed lactic acidosis associated with the administration of entecavir in patients with chronic hepatitis B and impaired liver function. All patients who developed lactic acidosis during treatment with entecavir had a Model for End-Stage Liver Disease (MELD) score of at least 20, whereas no case of lactic acidosis was observed in patients with a MELD score below 18. Thus, entecavir should be applied cautiously in patients with impaired liver function.

Abbreviations

BE, base excess; CRP, C-reactive protein; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B envelope antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; ITBL, ischemic-type bile duct lesions; MELD, Model for End-Stage Liver Disease; NRTI, nucleoside or nucleotide reverse transcriptase inhibitors; OLT, orthotopic liver transplantation; WBC, white blood count.

Patients and Methods

Adult patients (n = 16) who were referred to our tertiary reference center between November 2007 and December 2008 with chronic hepatitis B and associated liver cirrhosis who were treated with entecavir were included. A total of 13 treatment-naïve patients received entecavir at a dose of 0.5 mg daily. Three patients with lamivudine-refractory hepatitis B were treated with 1 mg entecavir daily. Entecavir was dose-adjusted in all patients who had an impaired creatinine clearance (<50 mL/minute) according to the package insert, with the exception of one patient (patient D) in whom lactate acidosis was recognized for the first time. This patient received 0.5 mg entecavir up to a creatinine clearance of 30.2 mL/minute. This is still the approved dosing for patients with an initial dose of 1 mg entecavir according to the package insert. With the increase of lactate above the upper limit of normal in this patient, administration of entecavir was stopped immediately. Three of five patients with lactic acidosis received antibiotics for prophylaxis of spontaneous infection of ascitic fluid. Clinical and laboratory data were reviewed. Liver biopsy for histological confirmation of liver cirrhosis was performed in 15 of 16 patients. In one patient, no liver biopsy was performed due to highly impaired blood clotting. Quantitative HBV DNA, hematology, and biochemistry parameters were assessed before treatment initiation and were performed regularly during therapy. In patients with MELD scores above 15, hematology and biochemistry parameters were tested at least once weekly. In all patients with increase of lactate serum concentrations, arterial blood gas analysis was performed immediately. To exclude other reasons for lactic acidosis, sepsis workup (fever, chest x-ray, urine analysis, blood cultures, ascitic fluid analysis, abdominal ultrasound, laboratory parameters of inflammation), evaluation of cardiopulmonary function (blood pressure, heart rate, chest x-ray, arterial blood gas analysis, echocardiography), and examination concerning intestinal infarction (physical examination, computed tomography scan) were performed. Differences between subgroups were statistically compared by Mann-Whitney U test.

Results

Baseline Characteristics of Patients.

All 16 patients were between 24 and 80 years old (mean 50.25 years) including 13 Caucasians (81.3%) and three Asians (18.7%); 62% were male. All but one patient had normal renal function and received standard dose of entecavir at the beginning of treatment (0.5 and 1.0 mg/day for initial therapy and treatment after lamivudine resistance, respectively). One patient (patient C) was treated with 0.5 mg every other day because of reduced creatinine clearance (MDRD [Modification of Diet in Renal Disease study] clearance = 40 mL/minute). All patients had liver cirrhosis with MELD scores between 6 and 38. Five patients had HCC. Two patients underwent liver transplantation 1 and 5 years ago, and one of these liver transplant patients was treated with entecavir since the date of transplantation. The other transplant patient had developed rapid progressive fibrosis that resulted in cirrhosis of the liver graft due to reactivated hepatitis B and was treated with entecavir since year 5 after liver transplantation. Four of 16 patients had a strongly impaired liver function already at the beginning of entecavir treatment. With an exception of one patient with fulminant liver failure (patient B in Table 2) the liver function was only slightly worsened during the study period, as indicated by relatively stable MELD scores (mean difference between initial MELD score and follow up MELD score = 4), international normalized ratio (INR) data, and bilirubin. In particular, the MELD scores did not significantly increase during lactic acidosis compared to baseline. However, creatinine clearance decreased in three of five patients before and during the development of lactic acidosis. Encephalopathy was present in three of five patients (patients A, B, and D) with lactic acidosis with ammonium levels from 100-130 μg/dL. After entecavir discontinuation, no hepatitis flares were observed and antiviral therapy was continued with entecavir in one patient and with lamivudine or tenofovir in the other patients. For further details on each patient with lactic acidosis and a summary of patient characteristics, see Fig. 1 and Table 2.

Table 2. Characteristics of Patients Treated with Entecavir
Patient No.Age (years)Liver ConditionHBeAgHBV DNA (IU/mL)Child-PughMELD ScoreLactic AcidosisPeak Lactate mg/dLNadir pHBE (mmol/L)GPT (U/L)Bilirubin (mg/dL)INRNa+ (mmol/L)CRP mg/dLWBC/nLOutcome
  1. Parameters before treatment initiation are shown except in patient 1, who started entecavir treatment at the time of liver transplantation. Parameters which are shown for this patient were detected one week before development of lactic acidosis. The upper limit of normal lactate is 20 mg/dL. BE, base excess; HCC, hepatocellular carcinoma; ITBL, ischemic-type biliary lesions; n.d., not determined; OLT, orthotopic liver transplantation. Virologic response: undetectable HBV DNA after 24 weeks of treatment; partial virologic response: decrease of HBV DNA of at least 1log10 but detectable HBV DNA after 24 weeks of treatment.

A36OLT, ITBLNeg.<300C38Yes507.2−184050.02.21358.510.0Resolved, re-OLT Virologic response
B79Acute liver failureNeg.8,000,00029Yes2007.1−17180032.02.41391.812.5Death
C60OLT, re-cirrhosisPos.10,300C28Yes357.4−5197.32.21242.99.8Resolved, virologic response
D60Cirrhosis, HCCNeg.1,200,000B25Yes657.3−12806.01.81314.49.9Resolved
E61Cirrhosis, HCCNeg.<300B22Yes267.4−6404.11.91301.34.2Resolved, virologic response
F74CirrhosisNeg.270,000B17No20n.d.n.d.613.91.41353.211Virologic response
G25CirrhosisPos.700B14No14n.d.n.d.361.41.71400.52.8Virologic response
H43CirrhosisNeg.<300B12No15n.d.n.d.580.91.71423.06.4Virologic response
I64Cirrhosis, HCCPos.5,267,000B11No197.4−11301.31.31281.07.0Virologic response
J47CirrhosisNeg.151,000A11No11n.d.n.d.1440.81.91380.55.0Virologic response
K43CirrhosisPos.160,000A7No12n.d.n.d.441.11.11390.15.0Partial virologic response
L45Cirrhosis, HCCPos.99,000,000A7No17n.d.n.d.1501.10.91391.34.0Virologic response
M67Cirrhosis, HCCNeg.1,050A6No16n.d.n.d.210.61.11420.23.4Virologic response
N36CirrhosisNeg.19,100A6No9n.d.n.d.250.51.01370.65.0Virologic response
O24CirrhosisPos.>99,000,000A6No8n.d.n.d.400.51.11410.49.0Virologic response
P29CirrhosisNeg.2,800,000A6No14n.d.n.d.2510.51.01410.36.0Virologic response
Figure 1.

Graphs demonstrate the courses of lactic acidosis in five patients with chronic hepatitis B and impaired liver function. See Table 2 for patient characteristics. ETV, entecavir; BE, base excess. (A) Patient A underwent liver transplantation approximately 9 months before and received entecavir treatment (0.5 mg every 72 hours) since the date of liver transplantation. He developed severe ischemic bile duct lesions (ITBL). After lactic acidosis was resolved the patient was rapidly retransplanted and received entecavir again before transplantation. Vital signs were stable: blood pressure (BP) = 110/70 mmHg, pulse (P) = 70 beats/minute, temperature = 36.8°C. Medication along with entecavir: tacrolimus, pantoprazole, propranolol, cefotaxime, vitamin K, lactulose, and ursodeoxycholic acid. (B) Patient B had acute on chronic liver failure and was treated with entecavir (0.5 mg/day) due to exacerbated chronic hepatitis B. Vital signs before detection of lactic acidosis: BP = 140/70 mmHg, P = 80/minute, temperature = 37.2°C. This patient died during lactic acidosis with fulminant liver failure. Thus, other reasons for lactic acidosis were not excludable entirely in this patient. Medication along with entecavir: pantoprazole, metoprolol, vitamin K, and lactulose. (C) Patient C underwent liver transplantation 5 years before and received entecavir treatment (0.5 mg every 48 to 72 hours) since year 5 after liver transplantation due to hepatitis B reinfection. This patient developed moderate lactic acidosis twice during entecavir treatment and was then switched to lamivudine. The second course of lactic acidosis occurred after surgery for an umbilical hernia. No events of lactic acidosis were observed after switch to lamivudine therapy. Vital signs during lactic acidosis: BP = 110/70 mmHg, P = 80/minute, temperature = 36.7°C. Medication along with entecavir: rapamycin, spironolactone, torasemide, hydrochlorothiazide, low-dose prednisolone, lactulose, pantoprazole, and levofloxacin. (D) Patient D suffered from decompensated liver cirrhosis and HCC and received entecavir (0.5 mg/dL) for the treatment of highly replicative chronic hepatitis B. Vital signs before and during lactic acidosis: BP = stable between 80/50 and 100/50 mmHg, P = 60/minute, temperature = 37°C. Medication along with entecavir: pantoprazole, propranolol, vitamin k, and meropenem. After discontinuation of entecavir treatment, the patient was treated with tenofovir. (E) Patient E had decompensated liver cirrhosis and HCC. He developed moderate lactic acidosis which was rapidly reversible after termination of entecavir treatment and did not reoccur after switch to tenofovir treatment. Vital signs during acidosis: BP = 115/70 mmHg, P = 80/minute, temperature = 36.9°C. Medication along with entecavir: spironolactone, torasemide, and propranolol. The patient was initially treated with 1 mg entecavir daily due to lamivudine resistance which was reduced to 0.5 mg/day, in line with creatinine clearance.

Virological Response to Entecavir.

Eleven of 16 patients had an HBV DNA viral load of >2000 IU/mL before entecavir treatment initiation. Administration of entecavir in 10 (90.1%) of these patients led to a sharp decline of HBV viral load, whereas one patient with lamivudine-refractory hepatitis B achieved only a partial virologic response to entecavir. In the remaining five patients with HBV DNA below 2000 IU/mL at the beginning of entecavir treatment, HBV DNA declined continuously below 300 IU/mL during treatment with entecavir.

Development of Lactic Acidosis Associated with MELD Scores Above 20.

Five of 16 patients developed lactic acidosis during treatment with entecavir. In three of these five patients, the course of lactic acidosis was severe and required treatment at our intensive care unit. The three cases of severe lactic acidosis occurred after 5 and 8 days in two patients with liver cirrhosis who were infected with highly replicative HBV and after 8 months in the liver transplant patient who had ischemic bile duct lesions and low viremia. The two cases of compensated lactic acidosis occurred after 4 and 31 days of entecavir treatment. Maximal blood lactate concentrations ranged between 26 and 200 mg/dL, minimal arterial pH values between 7.02 and 7.40 and anionic gap was maximal between 20 and 28 mmol/L. Patients with severe acidosis complained of nausea, dyspnea, and weakness and showed a reduced general physical condition, an impaired consciousness, and tachypnea. In addition, two of three patients with severe acidosis suffered from paresthesia and one developed hepatic steatosis typical for mitochondrial toxicity (patient D). Lactic acidosis was lethal in one patient. In the remaining four cases, lactic acidosis resolved within 3 and 5 days after termination of entecavir application, indicated by normalization of blood pH and lactate concentrations and a significant improvement of the patients' general physical condition and vigilance. For individual courses of lactic acidosis during entecavir therapy, see Fig. 1.

MELD scores before the development of lactic acidosis were between 22 and 38 (Table 2). MELD scores as well as liver enzymes were only slightly altered except in the patient with lethal outcome during the course of lactic acidosis and after termination of entecavir treatment, indicating a relatively stable liver status during lactic acidosis. In none of the 11 patients who had MELD scores below 18 were increased serum lactate concentrations observed during entecavir treatment, and entecavir was well tolerated. A significant correlation between the MELD score and the development of lactic acidosis was observed (P = 0.002). The single components of the MELD score—bilirubin, INR, and creatinine—correlated as well with the development of lactic acidosis (P = 0.003, P = 0.003, and P = 0.008, respectively).

Child-Pugh Score Was Not Reliable to Identify Patients with a Risk of Lactic Acidosis During Entecavir Treatment.

Four of 11 patients (36%) with a MELD score below 18 who had no increases of lactate serum concentrations and two of five patients (40%) with a MELD score of more than 20 and lactic acidosis had Child-Pugh class B cirrhosis. Thus, Child-Pugh score was not reliable to discriminate patients with a risk of developing lactic acidosis during therapy with entecavir in contrast to the MELD score (Table 2).

Discussion

Entecavir is a potent nucleoside inhibitor of the hepatitis B virus (HBV) polymerase with a high antiviral activity and a high genetic barrier to resistance. After approval in 2006, knowledge on the side effect profile in patients with advanced liver disease and impaired liver function is still limited.11 Here, we report the development of lactic acidosis in five patients with chronic hepatitis B and impaired liver function who were treated with entecavir. The risk of developing lactic acidosis correlated with the MELD score with no observed lactate increases in patients with MELD scores below 18.

From HIV-infected subjects, lactic acidosis is well-characterized for a long time as a rare but severe complication of treatment with several nucleoside inhibitors of the HIV reverse transcriptase (NRTIs). Lactic acidosis is caused by NRTIs via interactions with the mitochondrial DNA polymerase γ. As a result, decreased levels of mitochondrial DNA, impaired oxidative phosphorylation, dependence on anaerobic metabolism, and extensive lactate production may occur.9 In vitro inhibition of the DNA polymerase γ was shown for lamivudine, adefovir and tenofovir, although the extent of inhibition varies widely.9 In vivo, the development of lactic acidosis during application was reported as well, although most of the reports refer to combination therapies in HIV-infected individuals and are thus difficult to interpret.10, 12 In HBV-infected patients, mitochondrial toxicity was observed to a various extent during treatment with telbivudine, lamivudine, clevudine, and during combination therapy with entecavir and adefovir13: During treatment with clevudine and telbivudine, myopathy was observed and attributed to mitochondrial toxicity.14, 15 Treatment of lamivudine resulted in Fanconi syndrome, myopathy, and rhabdomyolysis in single cases.16, 17 Most recently, a case of fatal lactic acidosis during combination therapy with adefovir and entecavir in a patient with drug-resistant hepatitis B was reported.18 During combination therapy with telbivudine and pegylated interferon-alfa, neurotoxicity was observed which might be caused by mitochondrial toxicity.13 Interestingly, an in vitro analysis claimed no mitochondrial toxicity for entecavir, as assessed by quantification of mitochondrial DNA and lactate concentrations in hepatoma cells (HepG2) during exposure to entecavir.19, 20 Moreover, in large clinical trials evaluating entecavir in patients with well-compensated liver function, no events of lactic acidosis were yet reported.4, 5, 11 Because lactate clearance is performed mainly in liver and kidneys, an impaired liver or renal function might strongly increase the risk of lactic acidosis during application of nucleos(t)ide analogues, and side effects of entecavir might differ remarkably under these circumstances.

This study reports a risk of lactic acidosis in patients with highly impaired liver function during treatment with entecavir. Important other reasons for lactic acidosis were excluded in this study as far as possible. Furthermore, lactic acidosis was resolved after discontinuation of entecavir treatment. However, in patients with advanced liver cirrhosis or acute liver failure, alternative pathways for development of lactic acidosis because of unrevealed sepsis, splanchnic hypotension, or intestinal infarction are possible; further studies are needed to prove the causative association with entecavir treatment. Because most of the patients in our study had an impaired creatinine clearance directly before the development of lactic acidosis, renal toxicity with accumulation of entecavir might occur, although dose-adjustment of entecavir was performed. A study evaluating entecavir plasma concentrations in patients with high MELD scores might help determine the adequate entecavir dose in these patients.

In our study, the MELD score was sufficient to discriminate patients with risk of lactic acidosis during entecavir treatment with no observed events in patients with a MELD score below 18. In contrast, the Child-Pugh score correlated insufficiently with a risk of lactic acidosis. This might be explained by the factors of ascites and hepatic encephalopathy within the Child-Pugh score, which do not necessarily reflect a severe intrahepatic dysfunction. Our data encourage larger studies evaluating safety of entecavir in patients with impaired liver function, a subgroup of patients which profits in particular from its high antiviral efficacy and profound resistance profile to avoid a viral breakthrough, which may be followed by severe decompensation of liver function.8

In conclusion, our data indicate that, as described previously for the treatment of HIV-infected individuals with nucleoside and nucleotide inhibitors, lactic acidosis may be observed in patients with chronic hepatitis B and impaired liver function during treatment with entecavir. Thus, we suggest cautious use of entecavir in patients with advanced liver cirrhosis.

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