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Chronic Hepatitis B Patients with Liver Cirrhosis Are at Risk for Lactic Acidosis after Starting Entecavir (Baraclude)

SUMMARY: One-third of chronic hepatitis B patients with advanced liver disease who were treated with the nucleoside analog entecavir (Baraclude) developed lactic acidosis, a severe increase in blood lactic acid level associated with mitochondrial toxicity, researchers found in a small study described in the December 2009 issue of Hepatology.

By Liz Highleyman

Lactic acidosis occurs when lactate acid builds ups in the bloodstream faster than it can be removed. Lactic acidosis result when blood cells receive too little oxygen.

Entecavir is one of several oral antiviral drugs approved for treatment of chronic hepatitis B virus (HBV) infection. Nucleoside analogs -- like entecavir and one class of antiretroviral drugs for HIV -- are structurally similar to the building blocks that make up strands of genetic material (DNA and RNA). As a virus attempts to copy its genetic material, if one of these drugs is added instead of a natural nucleoside to the growing chain, the replication process is halted.

Unfortunately, nucleoside analogs can interfere with the workings of human cells as well as viruses. This can lead to a variety of side effects, some of which have been linked to damage to the mitochondria, small structures in cells that produce energy. Several nucleoside analogs used for HIV -- including d4T and ddI -- have fallen out of favor for this reason.

Entecavir is generally safe and well-tolerated in HBV positive people who do not have advanced liver disease. Less is known however, about its safety in patients with liver cirrhosis -- a group that could potentially benefit greatly from treatment.

Christian Lange from J.W. Goethe University in Frankfurt and colleagues described outcomes of 16 chronic hepatitis B patients with liver cirrhosis who were treated with entecavir.

The researchers reported that 5 of these patients developed lactic acidosis -- that is, a blood lactate level of 26-200 mg/dL, pH of 7.02-7.40, base excess -5 mmol/L to -18 mmol/L -- during entecavir therapy. Lactic acidosis occurred between 4 and 240 days after entecavir initiation. Of the 5 affected individuals, 4 experienced a resolution of lactic acidosis after entecavir was discontinued, but 1 patient died.

All patients who developed lactic acidosis had highly impaired liver function, with a MELD score of 20 or higher. The remaining 11 patients, who had MELD scores below 18, experienced no increased serum lactate concentrations during treatment with entecavir.

The researchers determined that MELD scores -- as well as its component parameters: bilirubin, international normalized ratio (prothrombin time), and creatinine -- were significantly correlated with development of lactic acidosis (P < 0.005). In contrast, Child-Pugh scores (another measure of liver disease severity) were not correlated with lactic acidosis.

Based on these findings, the investigators wrote, "Our data indicate that entecavir should be applied cautiously in patients with impaired liver function."

Klinikum der J. W. Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Frankfurt am Main, Germany.


CM Lange, J Bojunga, WP Hofmann, and others. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology 50(6): 2001-2006 (Abstract). December 2009.
























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