A call for attention and trials on hepatitis B e antigen–negative, alanine aminotransferase–normal chronic hepatitis B virus infection

We read with interest the article by Degertekin and Lok on the indications for therapy in hepatitis B.1 We feel obliged to call for more attention and clinical trials on patients who are negative for hepatitis B e antigen (HBeAg) and have normal alanine aminotransferase (ALT) levels, who are not routinely considered as immediate candidates for antiviral therapy by current guidelines. The question is, compared to which population is their prognosis considered “favorable”? As shown by a community-based prospective study conducted in Taiwan, the relative risk of hepatocellular carcinoma could still reach as high as 9.6 among HBeAg-negative men, compared with men who are negative for hepatitis B surface antigen (HBsAg).2 It is accepted that HBeAg is indicative of active viral replication, and thus is a surrogate marker for hepatitis B virus (HBV) DNA. However, their correlation depends on how we interpret the statistics. If we look at the absolute proportion in another report by Chen et al.3 and have the cutoff level lowered to 104 copies/mL as indicated by Yuen et al.,4 it was 34.9% among HBeAg-negative participants. Increasing evidence has shown that HBV DNA is predictive of long-term consequences of HBV infection, independent of HBeAg status and ALT level.3-8 In this sense, the prognosis of HBeAg-negative, ALT-normal patients does not seem favorable, at least for those with high levels of HBV DNA, because the prime culprit that leads to morbidity and mortality, the virus, has always been there in abundance. Considering this population was in the majority among HBsAg carriers in the REVEAL-HBV Study3 and the HBsAg carrier rate among the general population of China is 9.09%,9 they should not be overlooked as long as they are still at high risk for disease progression. It seems to be a paradox that largely due to a lack of studies, which is evident by our literature search, that directly provide evidence for or against antiviral therapy in this population, such patients do not routinely get treatment because no guidelines recommend so, which, in turn, results in even less possibility to gather sufficient evidence, whether positive or not. Quite a few practitioners may mistake “no evidence” as “evidence of no” by just telling their patients there is no need to initiate treatment while neglecting to inform them of the possible effect of available medications on prognosis improvement. Don’t these patients, particularly those who are highly concerned about their own life and capable of affording treatment cost, deserve the right to have full access to complete information and the ability to decide for themselves whether to receive treatment after weighing possible benefits against the risks? Given the fact that current antivirals have been efficient in suppressing virus replication and their adverse effects are relatively minimal, treatment should never be excluded from consideration even if it is tentative. Chances exist that their response to treatment, i.e., HBV DNA reduction and HBsAg clearance, may be even better. Therefore, we call for intensive attention and large-scale, randomized controlled trials with long-term follow-up in HBeAg-negative, ALT-normal patients, to investigate the impact of antivirals on surrogate serum biomarkers as well as the risk of advanced liver diseases, and to provide insight into the indications and endpoints of antiviral therapy.