Clinical trials of therapies of HBV infection have led to current drug approvals, including IFNs and nucleos(t)ide analogues. The reported results have used varying definitions of efficacy and failure based on different measures of virologic responses. In patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, trials generally report rates of HBeAg loss and HBeAg seroconversion, alanine aminotransferase (ALT) normalization, and suppression of serum HBV DNA. Trials of conventional IFN alfa6,7
and the early lamivudine studies8 –10
reported suppression of serum HBV DNA as measured by hybridization-based methods, which had detection limits of around 105
copies/mL. With the advent of more sensitive assays for quantification of serum HBV-DNA level, recent trials with both pegylated IFNs and nucleos(t)ide analogues have used a variety of definitions of serum HBV-DNA response with levels of suppression ranging from less than 500,000 copies/mL to less than 300 copies/mL.11–19
In patients with HBeAg-negative chronic hepatitis B, HBeAg seroconversion is not the end point: a combined end point of biochemical response (ALT normalization) and virologic (serum HBV-DNA suppression) response is used frequently. However, inconsistent levels of the target serum HBV-DNA level have been chosen. In addition, different results are reported in different units depending on the assay used. In clinical practice, different assays may be used, even for sequential assays for the same patient, making interpretation of results and identification of the emergence of resistance difficult.
Definitions and hence the reporting of “resistance” across clinical trials also vary. In some cases, the incidence of genotypic mutations (ie, nucleotide alterations that result in amino acid substitutions that are selected by antiviral drugs) may be reported with no reference to whether the mutations correlate with any virologic rebound (increase of levels of serum virus in a responder patient) or effect on clinical or biochemical parameters. Conversely, virologic and biochemical breakthrough may be reported with no description of associated viral mutation and pharmacologic data.
As more antiviral therapies become available for the treatment of chronic hepatitis B, the risk of emergence of resistance and cross-resistance will increase, and as more options for managing patients with antiviral drug resistance are developed, it will become important to define, understand, and be able to use and interpret the results of HBV virologic tools in the management of HBV therapy. The aim of this article is to discuss the virologic markers and tests and their optimal use both when planning and reporting clinical trials and in clinical practice. The authors met for 2 days. Four questions were discussed: what HBV markers should be used and what is their utility in clinical trials and practice? What are the definitions of treatment responses and failures and how should they be assessed virologically? How should HBV treatment be managed with virologic tools in clinical trials? How should HBV treatment be managed with virologic tools in clinical practice? A consensus was reached on each point after extensive discussion. A draft summary of the group’s conclusions was circulated and finalized with every author’s comments and suggestions. In this article, evidence-based (EB) recommendations are identified and recommendations based on the experts’ opinions (EO) are presented. The authors acknowledge that virologic testing is expensive and not readily available or affordable in many countries where hepatitis B is prevalent. Therefore, the recommendations for clinical practice should be considered best practice.