Is alanine aminotransferase flare-up in nucleos(t)ide analogue treatment of chronic hepatitis B a promising, rather than a devastating, sign?

Hepatitis B is the most common cause of chronic viral hepatitis in the world, and an estimated 257 million people are living with a current hepatitis B virus (HBV) infection, which is defined as being HBsAg positive. In 2015, 887,000 deaths were due to hepatitis B, mostly from complications such as cirrhosis and hepatocellular carcinoma. The initial antiviral therapy for chronic hepatitis B (CHB) was interferon, which functioned as an immune modulator to enhance the host immunity against HBV. However, its clinical efficacy was suboptimal; the rate of virological response defined as HBeAg seroconversion was 15-32%. Since the first oral nucleoside analogue (NUC) for CHB, lamivudine, was approved in 1998, it has shown a rapid virologic suppression, but long-term treatment with lamivudine has induced the development of drugresistant variants. The clinical practice guidelines suggested entecavir (ETV) and tenofovir dipivoxil fumarate (TDF) as the first line oral NUCs because these drugs showed high antiviral efficacy and high genetic barrier for drug resistance. Owing to effective oral NUCs, the long-term outcome of patients with CHB dramatically improved, and many patients escaped liver-related mortality. Nevertheless, some patients with CHB showed elevated alanine aminotransferase (ALT) levels during NUC therapy, which made clinicians concerned about aggravation of liver function and failure of antiviral treatment. In the era of interferon therapy, this phenomenon was also observed during the early stage of treatment. Flink et al. presented two types of ALT flares in patients with CHB treated with peg-interferon α-2b, in which ALT flare following a decrease in HBV DNA was associated with high treatment response, compared with ALT flare following an increase in HBV DNA (58% versus 20%). For lamivudine, acute ALT flare was related to high HBeAg loss or seroconversion. In contrast, late ALT flare during treatment implied the occurrence of drug resistance mutation and biochemical breakthrough following virological breakthrough. According to a study by Seo et al., 7 of 181 CHB patients (3%) showed early ALT flare (>10×ULN) without viral breakthrough during administration of TDF, and all of them recovered without decompensation and were able to maintain virological response. See Article on Page 154 Is alanine aminotransferase flare-up in nucleos(t)ide analogue treatment of chronic hepatitis B a promising, rather than a devastating, sign?