Case Study #1 Dual Adefovir (ADV)
+ Lamivudine (LMV) Resistance

Dual ADV + LMV Resistance

  • 59 year old male
  • No risk factors for HBV (perinatally or in early childhood)
  • Abnormal liver biochemistry revealed active hepatocellular injury, HBsAg +ve, HBeAg –ve, HBeAb +ve
  • Liver biopsy showed stage 3-4 fibrosis
  • Treatment with ADV commenced

Dual ADV + LMV Resistance

  1. Patient commenced ADV monotherapy.Initial good antiviral response
    • Serum ALT returned to within the normal range by week 16
    • HBV DNA levels were also reduced by almost 2.5 logs
  2. No further suppression of viral replication
    • HBV DNA levels began to slowly rise
    • The gradual "creep" in HBV DNA l continued
    • Serum ALT levels also gradually increased
  3. Virological Breakthrough on ADV monotherapy
    • HBV DNA and ALT levels had returned to pre treatment values
    • ADV monotherapy was no longer effective
  4. Patient commenced LMV monotherapy
    • ALT levels normalised
    • Rapid decrease in serum HBV DNA levels
    • Switching antiviral therapy earlier may have prevented further disease progression

Dual ADV + LMV Resistance

Drug Resistance Testing:

  1. Antiviral drug resistance testing was performed following virological breakthrough
    • The primary resistance mutations to ADV rtN236T and rtA181T were detected
  2. Retrospective sequencing of HBV isolated from an earlier serum sample detected rtN236T as early as week 80

Dual ADV + LMV Resistance

  1. Following virological breakthrough on ADV the patient was switched to LMV monotherapy
    • Serum ALT levels normalised
    • HBV DNA levels were rapidly reduced
  2. Virological breakthrough on LMV mono therapy, with a significant flare in serum ALT
    • 2 log increase in HBV DNA
  3. Patient commenced combination ADV/LMV therapy

Dual ADV + LMV Resistance

Drug Resistance Testing:

  1. Antiviral drug resistance testing was performed following virological breakthrough on LMV.
    • Sequencing at this time point detected the primary LMV resistance mutations rtL180M and rtM204V.
    • The mutations rtN236T and rtA181T associated with ADV resistance previously selected, were no longer detectable by sequencing.

Dual ADV + LMV Resistance

  1. Good response to combination therapy
    • HBV DNA levels become undetectable
    • HBV DNA levels become undetectable
  2. HBV DNA levels begin to rise. Combination ADV and LMV therapy no longer effective
  3. Virological breakthrough on ADV and LMV
  4. ETV added to the treatment protocol
    • Rescue therapy effective
    • HBV DNA no longer detected by PCR

Dual ADV + LMV Resistance

Drug Resistance testing:
Antiviral drug resistance testing was performed at several time points during combination treatment

  1. Not detected by PCR, therefore unable to perform sequence analysis
  2. ADV resistance mutation rtA181V (switched from rtA181T) detected as HBV DNA level began to rise
  3. During virological breakthrough several primary resistance mutations were detected
    • rtA181T and rtN236T associated with ADV resistance
    • rtA181T associated with resistance to LMV
    • Potential multi drug resistant HBV variant selected for during combination therapy
    • Several additional novel mutations selected at this time (rtI233V + rtM250L)
  4. The addition of ETV as a rescue therapy was effective, rapidly suppressing viral replication to undetectable levels.