Interferon for Chinese patients with chronic hepatitis B e antigen-positive diseases-the controversy arises again?

Abstract

In 2014, seven drugs were registered for the treatment of chronic hepatitis B (CHB) infection. Two were immunomodulatory agents, conventional interferon(IFN)-a and pegylated IFN-a2a, and five were direct antiviral nucleos(t)ide analogs (NUCs), lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. Due to the high resistance barrier of entecavir and tenofovir as compared to the other NUCs, only these two drugs are now in practical use in most parts of the world [1]. For chronic hepatitis B e antigen (HBeAg)-positive patients, HBeAg seroconversion, defined as the loss of HBeAg with the appearance of anti-HBe, is often associated with clinical remission and a transition to inactive liver disease. Accompanying HBeAg seroconversion, there is a reduction in liver fibrosis and a lower incidence of cirrhosis and hepatocellular carcinoma. HBeAg seroconversion, whether spontaneous or treatment induced, is also associated with a higher probability of hepatitis B surface antigen (HBsAg) loss and seroconversion, which is considered to be a more permanent clinical remission of liver disease. Thus, the achievement as well as maintenance of HBeAg seroconversion, in association with low serum hepatitis B virus (HBV) DNA levels (\3–4 log IU/ml), is an important goal in the management of patients with HBeAg-positive CHB [2]. Based on evidence demonstrating HBeAg seroconversion is an important hallmark event of a durable clinical remission of liver disease, most hepatology society treatment guidelines have adopted HBeAg seroconversion with sustained suppression of HBV DNA as an end point for treatment in patients with HBeAgpositive CHB who do not have cirrhosis or decompensated liver disease [1]. Previously, the conflicting data related to the importance of HBeAg seroconversion were largely related to the existence of a group of HBeAg seroconverters with a high HBV DNA viral load. In fact, this merely represented a transition from chronic HBeAgpositive disease to chronic HBeAg-negative disease, with little impact on the natural history of CHB. This important point was emphasized by a recent study in Taiwan, which included 2,946 chronic CHB Chinese patients. It was shown that high serum HBV DNA levels at the seroclearance of HBeAg could explain the nonsignificant association between HBeAg seroclearance and HCC risk [3]. Among the various forms of treatment, 1-year treatment with pegylated IFN-a2a yielded the highest rate of HBeAg seroconversion (around 40 %); among them, one-tenth further benefited from HBsAg seroconversion. On the other hand, treatment with NUCs achieved a much lower rate of HBeAg seroconversion; hence, more prolonged therapy is required when one has started treating CHB patients with NUCs. Hence, one of the key questions is related to the durability of HBeAg seroconversion with the various forms of therapy. This will affect the physician’s decision when choosing a therapy for our chronic HBeAg-positive patients between nucleos(t)ide analogs (NUCs) or pegylated IFN. Clinically, this has always led to a painful choice between either life-long medication with NUCs with a high genetic barrier (entecavir or tenofovir disoproxil fumarate) or lasting remission with a relatively short duration but sometimes side effect-prone therapy with 48 weeks of pegylated IFN. Previously, two large-scale clinical studies in Chinese subjects demonstrated that treatment with G. K. K. Lau (&) Humanity and Health GI and Liver Centre, Hong Kong, Hong Kong SAR e-mail: gkklau@netvigator.com