Expert Insight Into: Severe Lactic Acidosis During Treatment of Chronic Hepatitis B with a Nucleoside Analog in Patients with Impaired Liver Function (Part 8 of Series)

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Clinical Insights

All approved oral nucleos(t)ide analogs for hepatitis B treatment carry a black-box warning for mitochondrial toxicity that can manifest itself as lactic acidosis. Nucleos(t)ide treatment in patients with highly impaired liver function (MELD score >18) may be associated with a risk of severe lactic acidosis.
Impaired liver or renal function may influence the risk of developing lactic acidosis because the liver and kidneys are principally responsible for lactate clearance. Additional studies will be required to determine a causative role for entecavir and other nucleos(t)ide analogs in the development of lactic acidosis in these patients.
This study demonstrates that caution should be used when administering all nucleos(t)ide analogs to patients with decompensated liver or kidney disease.¹

PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.

Suppression of hepatitis B virus (HBV) DNA in chronic hepatitis B (CHB) patients has been shown to improve liver histology and decrease rates of hepatocellular carcinoma (HCC) and other complications. The currently approved antiviral therapies for HBV are peginterferon-alfa; the nucleoside analogs lamivudine, telbivudine, and entecavir; and the nucleotide analogs adefovir and tenofovir. Side effects associated with mitochondrial toxicity have been reported in HBV-infected patients being treated with nucleos(t)ide analogs and a case of fatal lactic acidosis has been observed in a patient treated with adefovir and entecavir. Entecavir and tenofovir have improved efficacies and resistance profiles compared to adefovir and lamivudine and are recommended for treatment of patients with highly replicative HBV and for patients with advanced fibrosis or cirrhosis. Although lactic acidosis was not reported in the clinical trials that led to the approval of these drugs, they did not enroll patients with advanced cirrhosis. A recent case series examined the development of lactic acidosis in CHB patients with cirrhosis being treated with entecavir.

The study included 16 patients (13 treatment-natïve) with CHB and liver cirrhosis between 24 and 80 years old (mean 50.25 years). Patients received the standard dose of entecavir (0.5 mg/day for treatment-natïve and 1.0 mg/day for lamivudine-resistant). Patients with renal impairment (creatinine clearance <50 mL/minute) received reduced doses as recommended by the package insert, except one patient who continued to receive 0.5 mg entecavir to a creatinine clearance of 30.2 mL/minute and in whom entecavir treatment was terminated after the development of lactic acidosis. The patients' Model for End-Stage Liver Disease (MELD) scores were between 6 and 38. Five patients had HCC, two had liver transplantation, and four had strongly impaired liver function when starting entecavir. Except for one patient with fulminant liver failure, MELD scores were relatively stable during the study, including during lactic acidosis. When lactic acidosis was observed, other potential causes (sepsis, splanchnic hypotension, intestinal infarction) were excluded as far as possible.

Of 11 patients with HBV DNA >2000 IU/mL when initiating entecavir, 10 experienced a sharp drop in viral load. The remaining patient, who had lamivudine-resistant HBV, had a partial virologic response. The five patients with HBV DNA <2000 IU/mL experienced continuous declines in viral load to <300 IU/mL.

Lactic acidosis developed in five patients during entecavir treatment (Table 1). Three cases were severe. Two of those, in patients B and D, occurred after 5 and 8 days, respectively, of entecavir treatment in patients with highly replicative HBV. The third severe case (patient A) occurred after 8 months in a liver transplant patient with ischemic bile duct lesions and low viremia. The two cases of compensated lactic acidosis, in patients C and E, occurred after 31 and 4 days, respectively, of treatment. Lactic acidosis was characterized by: maximum serum lactate concentrations between 26 and 200 mg/dL, minimal arterial pH between 7.02 and 7.40, anionic gap of 20 to 28 mmol/L, and base excess of -5 to -18 mmol/L. Encephalopathy was present in three cases (patients A, B, and D). Reduced creatinine clearance was observed in three of the five patients before and during development of lactic acidosis. Symptoms in the patients with severe acidosis were: nausea, dyspnea, weakness, reduced general physical condition, impaired consciousness, tachypnea, and paresthesia (two patients). One patient (patient D) developed hepatic steatosis indicative of mitochondrial toxicity. One case of lactic acidosis (patient B) was fatal. In the remaining cases, blood pH and lactate concentrations normalized within 3 and 5 days of terminating entecavir. Resolution resulted in improved general physical condition and vigilance. No hepatitis flares were seen after termination. Therapy was continued with entecavir in 1 case, lamivudine in 1 case, and tenofovir in the others.

Table 1. Treatment History of Patients Who Developed Lactic Acidosis on Entecavir

Patient	History
A^*	Underwent liver transplantation 9 months prior to study. Received entecavir since transplant. Developed ischemic bile duct lesions. After resolution of lactic acidosis received entecavir again prior to retransplantation.
B	Had acute-on-chronic liver failure. Died during lactic acidosis with fulminant liver failure. Other reasons for lactic acidosis were not excludable.
C	Underwent liver transplantation 5 years prior to study and received entecavir since year 5 due to reactivated HBV and cirrhosis of the graft. Developed moderate lactic acidosis twice during treatment that resolved with switch to lamivudine.
D	Had decompensated cirrhosis and HCC. Lactic acidosis resolved after discontinuation of entecavir and switch to tenofovir.
E	Had decompensated cirrhosis and HCC. Lactic acidosis resolved after discontinuation of entecavir and switch to tenofovir.

^*Patient parameters shown for patient A are 1 week prior to lactic acidosis onset.

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma

The five patients who developed lactic acidosis had MELD scores between 22 and 38, whereas those who did not develop lactic acidosis had MELD scores lower than 18. The correlation between MELD scores and development of acidosis was significant (P = .002). Each component of the MELD score also significantly correlated with development of lactic acidosis (bilirubin, P = .003; international normalized ratio, P = .003; creatinine, P = .008). In contrast, four of eleven patients (36%) without lactic acidosis and two of five patients (40%) who developed acidosis had Child-Pugh class B cirrhosis. Thus, Child-Pugh scores were not predictive of the risk of developing lactic acidosis during entecavir treatment.

Although this study suggests that lactic acidosis may be observed in CHB patients with decompensated liver disease and high MELD scores treated with entecavir, determining the cause of the lactic acidosis in severely ill patients is difficult. The timing of the mitochondrial toxicity as early as 4 days after therapy may argue against a causative role for entecavir.

A recent study examining the role of entecavir in 70 decompensated cirrhosis patients treated with entecavir showed positive clinical outcomes with improved MELD scores.²

The prescribing information of all nucleos(t)ide analogs currently approved for anti-HBV therapy contains a black-box warning stating: "Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs."

References

1. Lange CM, Bojunga J, Hofmann WP, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50:2001-2006.

2. Shim JH, Lee HC, Kim KM, et al. Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol. 2010;52:176-182.

Privacy Policy

Expert Insight Into:
Severe Lactic Acidosis During Treatment of Chronic Hepatitis B with a Nucleoside Analog in Patients with Impaired Liver Function (Part 8 of Series)

Based on the Article:

Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50:2001-2006.

Medical Writer: Shawn E. Kuhmann, PhD
Expert Faculty: Tram T. Tran, MD

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Expert Insight Into: Severe Lactic Acidosis During Treatment of Chronic Hepatitis B with a Nucleoside Analog in Patients with Impaired Liver Function (Part 8 of Series)

Based on the Article: Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50:2001-2006.

Medical Writer: Shawn E. Kuhmann, PhD Expert Faculty: Tram T. Tran, MD

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Expert Insight Into:
Severe Lactic Acidosis During Treatment of Chronic Hepatitis B with a Nucleoside Analog in Patients with Impaired Liver Function (Part 8 of Series)

Based on the Article:

Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50:2001-2006.

Medical Writer: Shawn E. Kuhmann, PhD
Expert Faculty: Tram T. Tran, MD