Lactic Acidosis during Entecavir Antiviral Treatment in a Patient with Hepatitis B Virus-related Decompensated Cirrhosis

The Editor,

Sir,

Hepatitis B virus (HBV)-related decompensated cirrhosis is an end-stage liver disease; antiviral therapy can improve the prognosis in these patients (1). Entecavir (ETV) is considered an ideal drug for nucleotide and nucleoside-naïve patients with decompensated cirrhosis due to its rapid and potent antiviral effects and low risk of resistance, but clinical data on the safety in these patients with severely impaired liver function are limited.

A 58-year old Chinese male was diagnosed with chronic HBV in 2009, but he had not received any treatment for HBV at that time. He presented with HBV-related decompensated cirrhosis, including ascites and splenomegaly. The initial laboratory tests showed elevated liver tests and the serum HBV DNA level was 4.15 × 10⁷ copies/mL. He was diagnosed with HBeAg-positive chronic HBV-related decompensated cirrhosis and his model for end-stage liver disease (MELD) score was 18. He was treated with 0.5 mg ETV daily and was evaluated for liver transplantation.

After one month of therapy with ETV, he had a significant reduction in serum HBV DNA (9.70 × 10³ copies/mL) and the MELD score remained stable. After receiving two months of ETV therapy, he was admitted to hospital with diarrhoea, abdominal pain, vomiting and fever. His body temperature was 37.2 °C, his pulse 120 beats per minute, respiratory rate 20 breaths per minute and blood pressure 110/70 mmHg. The physical examination revealed yellow sclera, abdominal tenderness and rebound pain, shifting dullness and active bowel sounds. The white blood cell count was 4.15 × 10⁹/L, the neutrophil ratio 85.1%, haemoglobin 104 g/L, and the platelet count 71 × 10⁹/L. The arterial pH value was 7.17, the oxygen pressure 23.3 kPa, the carbon dioxide pressure 3.2 kPa, the oxygen saturation 99%, the base excess −18.1 mmol/L, and the lactate level > 15 mmol/L. Empiric medical treatment for infection, prevention of further insult to the liver, and maintaining water, electrolyte and acid base balance was initiated, but the patient's condition rapidly deteriorated, and he eventually died 15 hours after admission. Two days later, the blood culture showed the presence of Escherichia coli.

All of the approved oral nucleotide and nucleoside analogues for HBV carry a ‘black box’ warning in their labelling regarding potential mitochondrial toxicity that can manifest itself as lactic acidosis, myopathy, neuropathy, or even hepatotoxicity (1). The MELD score has been reported in association with lactic acidosis during ETV treatment (2). However, some recent studies observed only one adverse event of lactic acidosis in an ETV treated patient, and the event was resolved without interruption of drug. It is worth noting that two of these studies included patients with a worse liver function (median MELD score 17.1 and 15.3, respectively in the study by Liaw et al (3); 16.1 ± 4.3 and 16.7 ± 4.1, respectively in the report by Hyun et al (4)). Moreover, a small study found that the risk of lactic acidosis was not increased in patients with HBV decompensated cirrhosis with high MELD score who received ETV, compared with patients with non-HBV decompensated cirrhosis (5). The report from Germany also showed that the white blood counts of the patients with MELD scores ≥ 20 were significantly higher than those with MELD scores ≤ 17 (9.28 ± 3.06/nL vs 5.87 ± 2.43/nL, t = 2.41, p < 0.05, using SPSS version 13.0). Thus the patients with high MELD scores could have some unrevealed infections.

In conclusion, even if more high-quality and well-designed studies are needed to confirm the correlation between ETV and lactic acidosis, prevention of infection in patients with HBV-related decompensated cirrhosis and severely impaired liver function should be more emphasized. Once these patients develop lactic acidosis, infection must be first excluded or controlled in a timely manner.