Video LectureHepatitis B Drug Resistance: Navigating the Way Forward

Anti-viral drug resistance is an important concern for the medication-compliant patient with an increasing HBV viral load. The typical sequence of events observed when resistance occurs is firstly the detection of genotypic resistance, followed by an increasing viral load, and much later by biochemical evidence of liver damage and worsening liver disease. The primary genotypic resistance is conferred by mutations found in the HBV polymerase.

Thus far, these mutations affect four pathways of antiviral resistance in chronic hepatitis B patients: the L-nucleoside pathway (rtM204V), the Acyclic phosphonate pathways (rtN266T), the Shared pathway (rtA181T/V) and the Cyclopentane pathway (rtL181M+rtM204V plus one of I169, or T184, or rtS202 or rtM250). Recently, multi-drug resistance pathways (MDR) are being identified as well.

The three major factors driving antiviral drug resistance in chronic hepatitis B include the genetic barrier to resistance, drug potency, and viral fitness of the resistant variants. The genetic barrier increases as the number of specific substitutions required for drug resistance increases. Thus, drugs like entecavir, which require at least 3 substitutions in the HBV polymerase, have a "high genetic barrier" whilst drugs like lamivudine, which requires only 1 substitution, have a "low genetic barrier". Thus, the physician should choose drugs with high potency and a high genetic barrier to resistance.

Originally presented June 17th, 2010 in Salt Lake City, Utah.

Lecture Presenter

Stephen Locarnini, BSc (Hons), Ph.D, MBBS, FRC(Path) Stephen Locarnini, BSc (Hons), Ph.D, MBBS, FRC(Path)
Director of WHO Collaborating Centre for Virus Reference and Research
Head, Molecular Research & Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia

Professor Locarnini has worked for the Victorian Infectious Diseases Reference Laboratory (VIDRL) since 1989. He was Director of Laboratory Services from 1990-1998 and then assumed the position of Head, Research & Molecular Development of VIDRL. He is also Director of the World Health Organisation Collaborating Centre for Virus Reference & Research. His current major research interests include viral hepatitis and antiviral chemotherapy with an emphasis on the basic virology of the various agents of hepatitis, the molecular pathogenesis of hepatitis, as well as prevention and public health control measures.

Objectives

After this presentation, attendees will be able to:

  • Understand the main factors associated with the development of antiviral drug resistance in hepatitis B
  • Understand how particular antiviral drugs select for particular patterns or pathways of antiviral drug resistance
  • Understand how best to prevent the emergence of antiviral drug resistance in the first place

Sponsored by:

University of Utah School of Medicine and ARUP Laboratories