Hepatitis B virus in children: More therapeutic options—but unknown and known unknowns still present
Authors: Nedim Hadžić, Sanjay Bansal
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article on Page 377 In the current issue, Jonas et al.1 present the results of their multicenter study on the use of entecavir for chronic hepatitis B virus (HBV) infection in 180 children between 2 and 18 years of age. This well‐designed, industry‐sponsored, placebo‐controlled study reports that oral entecavir treatment is superior to placebo in nucleoside‐naïve patients (24.2% [29 of 120 entecavir‐treated children] vs. 3.3% [2 of 60 placebo‐treated children]; P = 0.0008) for inducing the primary endpoint—hepatitis B envelope antigen/hepatitis B envelope antibody (HBeAg/anti‐HBe) seroconversion and undetectable HBV DNA <50 IU/mL at week 48. The investigators have also observed a difference in the secondary endpoints, including the normalization of alanine aminotransferase (67.5% [81 of 120 patients] vs. 23.3% [14 of 60 patients]; P < 0.0001) and HBeAg antibody seroconversion with no HBV DNA loss (24.2% [29 of 120 patients] vs. 10.0% [6 of 60 patients]; P = 0.021). Regulatory agencies promptly responded by granting a licence for the use of entecavir in children ages 2‐18 years several months ago, some 10 years after its approval for use in adult HBV patients. Management of chronic HBV infection involves all age groups and represents a paradigm for a complex long‐term public health intervention. With the rare exception of fulminant HBV infection leading to acute liver failure, chronic HBV infection usually does not represent a major clinical problem for pediatric hepatologists. However, life‐threatening long‐term complications, such as cirrhosis and hepatocellular carcinoma, typically occurring in middle age and later, when therapeutic options become more limited and potentially less efficient, justify a proactive therapeutic approach earlier—possibly in childhood. Unfortunately, present treatment options available for both adults and children are not satisfactory, given that they achieve anti‐HBe seroconversion in only approximately 20%‐25% of treated patients.2 Following the recent successful development of effective tailor‐made treatments for chronic hepatitis C, which has dominated end‐stage liver disease and transplantation lists for the last 20 years, it is now the turn for the hepatology research community and industry to focus their interests and resources in the quest for better HBV treatment. The relation between HBV and the host immune system is quite complex, possibly comparable only to infection with human immunodeficiency virus. The majority of children with HBV are in a so‐called "immune tolerant" phase, characterized by normal transaminases, high HBV viremia, minimal histological changes, and considerable resistance to available antiviral treatments. Therefore, present pediatric management guidelines suggest treating only children in the "immune active" phase with abnormal transaminases and more advanced histological changes.2 More effective strategies to control HBV infection would require a disruption of the "immune tolerant" status of the host, with the expansion of the population of host HBV‐specific T cells3 with the potential to eliminate HBV covalently closed circular DNA (cccDNA), believed to be critical for the perpetuation of the infection. Two small pediatric studies took a different approach by using an initial 8‐week lamivudine treatment followed by the combination of interferon‐alpha and lamivudine for 44 weeks in "immune tolerant" children; they reported comparable anti‐HBe and hepatitis B surface antibody seroconversion rates at 22% and 17%,4 and 39% and 21%,5 respectively. At a 5‐year follow‐up, the former study observed the rates increasing to 30% and 22% (unpublished data). One of the problems in interpreting HBV treatment studies are different outcome measures: undetectable levels of HBV DNA, HBeAg/anti‐HBe seroconversion or hepatitis B surface seroconversion/loss of hepatitis B surface antigen (HBsAg)? Recently, high serum HBsAg levels have been shown to be supportive of "immune tolerance" and inversely correlated with liver fibrosis.6 In the present study, a loss of HBsAg was exceptional in both entecavir‐ and placebo‐treated groups.1 Only 7 of 120 (5.8%) children achieved HBsAg loss after 96 weeks of entecavir treatment, but, of those, the majority belonged to the youngest age group (2‐6 years), achieving a remarkable rate of 22% (6 of 27). This intriguing observation could potentially be explained by recognized age‐related differences in immune reactivity of the host against HBV,7 which clearly requires further study. The present study reports an overall lower rate of viral suppression (49%) than in adults (67%) after 48 weeks of entecavir treatment, particularly among children with higher baseline viral load (HBV DNA ≥8 log10 IU/mL; 28%).1 However, the difference converged with prolonged treatment, given that the viral suppression rate considerably improved to 64% by week 96; this was not observed in the treated children with a lower viral load. This could indicate that the length of antiviral treatment may not necessarily need to be identical for children and adults. Furthermore, low pretreatment viremia (HBV DNA levels ≤8 log10 IU/mL) and non‐D HBV genotype have been associated with better responses to entecavir (P < 0.0001 and P = 0.021, respectively). Genotype‐related responses to entecavir have not been observed in adults, but an association between HBV genotype D and higher viremia in children was previously described.8 Viral resistance is a key aspect of pediatric HBV treatment. Patients in this crossover study have been treated between a minimum of 48 and up to 144 weeks. The probability of drug resistance was estimated to be 0.6% in the first year and 2.6% in the second year of entecavir treatment. This is several‐fold higher than in adults treated over the same period9 and remains unexplained. However, this is still considerably lower than reported corresponding HBV resistance rates for lamivudine and adefovir in children.2 Another important issue is the duration of treatment, given that there is a fine line between therapeutic viral suppression and the ongoing risk of emerging viral resistance. In the present study, HBe seroconversion was sustained in around 90% of entecavir‐treated children at week 24 post‐treatment.1 It remains unknown for how long the antivirals need to continue in order to maintain their initial virological and immune response, hoping that the ultimate goal of HBsAg loss would follow. The ideal drugs for managing HBV in children should be highly potent, with durable effects, impeccable safety, including a minimal occurrence of adverse effects, high genetic barrier to resistance, and acceptable cost. Nucleos(t)ide treatments are popular with the pharmaceutical industry because of their uncertain, often open‐ended length of therapy. Nucleoside drugs such as entecavir may be a short‐term solution, but new approaches are required for a definite control of chronic viral replication. Better strategies, aimed at stimulating host immune control of HBV, possibly through intrinsic production of interferons and other cytokines or chemokines, reducing intrahepatic viral DNA, or preventing formation of HBV cccDNA, are urgently required.10 Children should be ideal treatment candidates due to their shorter exposure to HBV, milder histological liver injury, longer expected life span, and prevention of horizontal transmission if viral clearance was achieved. Some intriguing age‐related differences in immune reactivity against HBV, including the ones noted by this study, need to be further investigated and better understood.3 Given the demonstrated safety and reasonable short‐term efficacy of entecavir in this study, it appears that pediatric hepatology has obtained a new tool, but the battle against HBV needs to continue decisively until its definite defeat.