Lactic Acidosis During Entecavir(ETV)Treatment

Chronic hepatitis B virus (HBV) infection is the major cause of hepatic failure worldwide. Although the clinical course of HBV infection varies widely, the prognosis of decompensated liver cirrhosis is quite poor and the 5-year survival rate has been estimated to be only 14-35% without treatment. While the ultimate treatment of decompensated cirrhosis is orthotopic liver transplantation (OLT), several studies have suggested that anti-viral therapy can also improve the clinical outcomes in this group of patients.

Entecavir (ETV) is a potent cyclopentyl guanosine nucleoside inhibitor of the HBV polymerase. It has a higher anti-viral potency and a lower resistance rate compared to lamivudine (LAM), telbivudine or adefovir, when used for nucleoside/nucleotide-naïve patients. ETV has been shown to be effective in patients with both hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B, and compensated liver disease. As for patients with decompensated cirrhosis, the investigators recently reported that ETV can not only induce virological response but also improve underlying hepatic function, and thereby can reduce the need for OLT. The cumulative OLT-free survival at 1 year and 2 years was 87.1% and 83%, respectively with ETV treatment.

Despite this dramatic benefit from ETV treatment, a recent study reported that ETV may induce lactic acidosis in patients with severe hepatic and/or renal function impairment. Lange et al. reported that 5 of 16 patients with severely impaired liver function developed lactic acidosis during ETV treatment. Of note, all the five patients who developed lactic acidosis had MELD scores over 20, and no increased serum lactate concentrations were observed in other 11 patients whose MELD scores were below 18. The Child-Pugh score correlated insufficiently with a risk of lactic acidosis. This result is not contradictory to our previous study, since the investigators did not analyze the incidence of lactic acidosis and the MELD score of the studied patients was relatively low (mean value: 11.5)in our study.

Lactic acidosis has been reported occasionally in association with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). NRTIs can induce lactic acidosis via interactions with the mitochondrial DNA polymerase. Until now, most reported cases were human immunodeficiency virus (HIV)-infected subjects treated with several nucleoside inhibitors of the HIV reverse transcriptase. Risk factors include didanosine, stavudine, a combination of the two, female gender, age over 40 years, lower CD4 counts, and shorter duration of therapy (less than 12 months). As for non-HIV-infected cases, there was only one case report of fatal lactic acidosis during combination therapy with adefovir and entecavir prior to the report of Lange et al. Interestingly, in vitro inhibition of mitochondrial DNA polymerase was shown for lamivudine, adefovir and tenofovir, but not for entecavir.

Lactate levels in the blood result from the balance between production and clearance. In normal physiologic conditions, lactate is produced primarily from skeletal muscle, skin, brain, intestine and red blood cells. In severe illness, it can be produced in many other tissues including lung, leukocytes, liver, or intestine. Lactate clearance occurs principally in the liver (60%), kidney (30%), heart and skeletal muscles. For these reasons, though lactic acidosis is typically present in shock states in which oxygen delivery is insufficient to meet cellular demand, elevated blood levels can also result from chronic liver disease and renal impairment. In addition, many other conditions have been reported in association with lactic acidosis even without ongoing evidence of hypoxia or ischemia. Examples are malignancy-related metabolic shifts, systemic inflammatory response, hepatic failure, and various drugs including acetaminophen, NRTIs, metformin, propofol, thiamine deficiency, total parenteral nutrition, and even lactulose. Therefore, in critically ill patients with cirrhosis or hepatic failure, lactic acidosis can result from various causes or in combination, in addition to the NRTIs. First of all, liver failure per se is associated with decreased lactate clearance, which is further aggravated in sepsis or renal failure. The liver can also be a source of lactate production and many medications other than NRTIs can precipitate lactic acidosis. For these reasons, it is not still conclusive whether ETV treatment itself is a direct cause of lactic acidosis in critically ill patients with cirrhosis or hepatic failure, since there was no control group in the study of Lange et al. A similar scenario was observed in a study performed in HIV-infected patients, in which mitochondrial-to-nuclear DNA ratio was compared among non-HIV-infected controls, HIV-infected individuals not on NRTIs, and HIV-infected individuals on NRTIs. In this study, HIV alone affected the mitochondrial-to-nuclear DNA ratio, and therefore resulted in lactic acidosis.

Recently, Wong et al. reported the safety and efficacy of ETV in patients with severe acute exacerbation compared to LAM. In this study, ETV treatment was associated with increased short-term mortality in patients with severe acute exacerbation of chronic hepatitis B but achieved better virological response in the long run. Wong et al. assumed that the cause of increased short-term mortality in ETV-treated patients is due to not only the strong immune response but also lactic acidosis. As such, they suggested that LAM may be initiated first and routine switching to ETV after liver function has improved or the adoption of the roadmap concept are reasonable treatment strategies. However, drug resistance can be a problem in the long term because of the increase of resistance mutation for lamivudine or entecavir later in patients who have the history of exposure to lamivudine before entecavir treatment in the past or have been treated with lamivudine.

Thus, the aim of this study is to investigate whether ETV treatment increases the incidence of lactic acidosis compared to another NRTI, lamivudine, and/or no NRTI treatment, in patients with cirrhosis or hepatic failure whose MELD scores are over 18.