Antiviral treatment of hepatitis B following solid organ transplantation in children

Chronic hepatitis B is characterized by twophases: an early phasewith detectable hepatitis B envelope antigen (HBeAg) and high level of viral replication, and a second later phase after seroconversion to anti-HBe and comparably low levels of viral strains in the serum. The HBeAg-positive phase harbours between 10 and 10 virions/mL serum, whereas the replication level is usually reduced below 5 10 virions/mL after seroconversion (Fig. 1). Hepatitis B virus (HBV) infection acquired early in the lifetime – most of the patients are perinatally infected – is characterized by a long HBeAg-positive immune tolerant phase with normal or near-normal alanine transaminase (ALT) levels and a low rate of spontaneous HBeAg/antiHBe seroconversion. Unfortunately, seroconversion is not predictable. The annual seroconversion rate in children depends on the mode of transmission and ranges between 3 and 12%/yr. Nevertheless, although rare in immunocompetent children and adolescents, reactivation toHBeAgmay occur at any time. However, in individuals with emerging underlying disease impairing the immune system, the risk becomes considerably higher. The spontaneous loss of HBsAg is a rare event and barely reaches 0.5%/yr (1). The clinical management of chronic hepatitis B in children and adolescents regarding treatment is significantly influenced by the understanding of the natural course of the disease. At present, most individuals in this age group are vertically infected or have acquired the disease very early by horizontal transmission. Although they generally have a lowchance for anti-HBe seroconversion, chronic disease is essentially mild throughout the first and second decades of their life. However, complications can be expected in adult life, particularly among perinatally infected subjects. Considering treatment, we have to focus on the most important endpoints such as HBeAg loss and subsequent anti-HBe seroconversion, normalization ofALT levels, andpreferably clearance ofHBsAg. Currently, there are two treatment options that are only partially successful because of side-effects, poor efficacy, and viral resistance. Two agents have been intensely studied: a-interferon and the nucleoside analogue lamivudine. The problem with both drugs is the fact that the extent of inflammatory activity corresponding with ALT levels correlates with the probability of HBeAg/ anti-HBe seroconversion (2). It has been clearly demonstrated that a-interferon treatment simply accelerates the process of anti-HBe seroconversion. This is beneficial for patients with progressive liver disease and, moreover, reduces infectivity at an earlier time. However, HBeAg clearance rates are expected to be similar between treated and untreated subjects after a follow-up period of about 5–6 yr. High pre-treatment ALT levels were predictors of response. Individuals with slightly elevated or normal ALT levels reflecting a high immune tolerance against the virus have a significantly lower chance for HBeAg loss (3). This phenomenonhas clearly been confirmed in a large trial using lamivudine in HBV-infected children ((4), Table 1). The anti-HBe seroconversion rate in patients with ALT levels beyond 2 the upper limit of normal (ULN) did not differ from those with placebo which, in fact, represents the spontaneous course of the disease. Subjects with ALT levels higher than 2 ULN experienced anti-HBe seroconversion after 12 months of treatment in 31% and those with more than 5 ULN in 50%. The results of two further studies are shown in Table 1, confirming the fact that childrenwith normalALT levels have a very poor likelihood to clear HBeAg (5, 6). Unfortunately, the HBV polymerase gene mutation YMDD, which is constantly associated with resistance against lamivudine, emerged in 19% of treated subjects after one yr. This finding is well known from studies in adult patients. Lamivudine has been approved for treatment of chronic hepatitis B in children in the USA but not in Europe. Nevertheless, because of the large Pediatr Transplantation 2006: 10: 271–275. DOI: 10.1111/j.1399-3046.2006. 00500.x Printed in Singapore. All rights reserved. Copyright r 2006 Blackwell Munksgaard