EASL Clinical Practice Guidelines

End points of treatment and definitions of response

The goal of anti-HBV therapy, in children as in adults, is to improve long-term survival and quality of life by reducing the risk of progressive liver disease, cirrhosis, and HCC.

For all patients, the ideal end point of treatment is sustained HBsAg clearance, as it stops disease progression and reduces the risk of HCC, although it occurs in a minority of treated subjects (A1) [[51], [57]].

When HBsAg seroclearance is not achieved, sustained off-therapy suppression of viral replication (undetectable HBV DNA levels with a sensitive real time polymerase chain reaction assay), associated with durable anti-HBe seroconversion in originally HBeAg-positive patients, is a good end point, being associated with improved prognosis, including decreased risk of HCC (A1) [44]. In the absence of off-therapy viral suppression, undetectable HBV DNA under long-term antiviral therapy (maintained virological response) is the next desirable end point (A1). Reduction of viremia levels leads to decreased liver inflammation and subsequent normalization of ALT levels, reducing the risk of disease progression [[2],[35], [36], [42], [43]].

Response to treatment can be evaluated at biochemical, serological, virological and histological levels. In the few available pediatric trials, several end points have been used to evaluate response. A consensus on the definition of response would be required to compare the different clinical trials. Current AASLD and EASL definitions can be adapted to pediatric clinical trials [[6], [8]]:

  • Biochemical response: normalization of ALT levels, which reflects reduction of histological activity index. ALT level is, however, a difficult parameter to assess because it can fluctuate widely over time and can remain elevated up to 6–12 months after HBeAg seroconversion. ALT levels, therefore, should be monitored every 3 months during the first year post-treatment (C1) and every 6 months during the second year post-treatment (C2).
  • Serological response for HBeAg is defined as HBeAg loss and seroconversion to anti-HBe (only for HBeAg-positive patients); serological response for HBsAg is defined as loss of HBsAg and development of anti-HBs antibodies (valid for all chronic hepatitis B patients).
  • Virological response (VR): undetectable levels of HBV DNA (as determined by a sensible PCR assay) after 3–6 months of treatment for NA-treated patients or HBV DNA <2000 IU/ml after 6 months and at the end of treatment for IFN-treated patients.
  • Complete response: off-treatment virological response associated with HBsAg loss sustained on long-term follow-up.
  • Sustained off-treatment virological response (SVR): VR persisting at least 12 months after cessation of treatment.
  • Maintained virological response: undetectable HBV DNA under long-term antiviral therapy.
  • Partial virological response: decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of treatment with NA.
  • Primary non-response: less than 1 log10 IU/ml decrease in HBV DNA levels from baseline after 3 months of therapy.
  • Virologic breakthrough: HBV DNA level increase of more than 1 log10 IU/ml during therapy, usually caused by poor adherence to treatment or emergence of a drug-resistant HBV mutant.
  • Histologic assessment of necroinflammatory activity has not been used as a criterion to evaluate response to treatment in pediatric studies.