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

Abstract

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 Ͼ2000 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 Ͻ2000 IU/mL. Current treatment options are pegylated interferonalfa 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

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

“…Since the initiation of the present study, lactic acidosis has been reported in decompensated CHB patients treated with ETV. 30 Of 16 ETV-treated patients, lactic acidosis occurred between 4 and 240 days after start of ETV treatment in five patients (all with MELD scores >20). Four patients experienced resolution of lactic acidosis after interruption or stoppage of ETV treatment, and one died.…”

Review article: long‐term safety of oral anti‐viral treatment for chronic hepatitis B

“…51 There had been sporadic reports on lactic acidosis occurring during HBV treatment. Based on published cases related to TDF 52,53 and entecavir, 15,54 renal impairment seemed to be an important contributing factor, probably due to mitochondrial toxicity if renal dosage adjustments were not promptly enforced. The reported cases on entecavir all occurred in decompensated liver disease with high model of end-stage liver disease scores, including one patient who was prescribed entecavir 1 mg daily for lamivudine resistance.…”

“…The reported cases on entecavir all occurred in decompensated liver disease with high model of end-stage liver disease scores, including one patient who was prescribed entecavir 1 mg daily for lamivudine resistance. 15 Other contributing factors include the presence of severe sepsis 54 and immunosuppressive therapy. 55 Lactic acidosis had also been reported in patients receiving telbivudine 56 and adefovir 55 therapy.…”

“…13,14 Other rarer side effects including lactic acidosis which may happen in very sick cirrhotic patients. 15 With the rising preemptive use of TDF to reduce mother-to-child transmission of HBV, 16 safety in pregnancy and breastfeeding has become an essential topic for both hepatologists and obstetricians. Given the eminent number of patients receiving NAs worldwide, even a small risk of any of these toxicities can be translated into a major medical issue.…”

Safety of long-term nucleos(t)ide treatment in chronic hepatitis B

“…These grade 3 --4 AEs were myalgias (5%), neuropathy (hypoparesthesia and hyperparesthesia, polyneuropathy) (4%), increased lipase (2%), increased serum creatinine (SCr) (< 1%), increased serum lactate or decreased serum bicarbonate (< 1%), hypophosphatemia (< 1%), muscular weakness (< 1%), pancreatitis (< 1%) and creatinine phosphokinase elevation (< 1%). They did not report cases of LA, a serious complication of ETV treatment previously reported in patients with advanced liver disease [9]. They reported an overall discontinuation rate due to AEs was extremely low (< 1%).…”