Treatment of Multidrug-Resistant Hepatitis B

Despite the development of new antiviral agents, drug resistance remains a major challenge in the treatment of hepatitis B.

Multidrug resistance may evolve in patients who receive sequential therapy with one antiviral agent at a time (monotherapy). In vitro studies have shown that while HBV mutations resistant to either lamivudine (Epivir-HBV) or adefovir (Hepsera) remain sensitive to the other drug, mutations that are resistant to both drugs have markedly reduced sensitivity to combination therapy with lamivudine plus adefovir.

A study presented at the recent Digestive Disease Week 2006 conference in Los Angeles found that mutations conferring resistance to more than one agent can co-exist on the same HBV genome. The researchers cloned HBV from blood samples taken from six chronic hepatitis B patients who developed dual-resistance to two antiviral drugs; 18-20 clones were sequenced from each sample.

Results

Mutations conferring resistance to both drugs were present on the same HBV genome in 163 out of 195 viral clones (84%) derived from patients with dual resistance to both lamivudine and adefovir, lamivudine and entecavir (Baraclude), or lamivudine and HBV immunoglobulin; 32 clones (16%) had mutations conferring resistance to just one drug.

Evolution of mutations was examined in detail for three patients: Patient 1 received lamivudine plus entecavir after lamivudine breakthrough. All 18 clones had the L180M and M204V/I mutations at month 0 (when the patient started entecavir). A clonal analysis first detected an entecavir resistance mutation (T184L) at month 20 (six months earlier than direct sequencing). Both drugs were discontinued at month 34. Six months later, T184L was detected in 12 out of 20 clones, while L180M and M204V/I remained detectable in 19 out of 20 clones. Patient 2 was switched to entecavir monotherapy after lamivudine breakthrough. All 20 clones had both the L180M and M204V mutations at month 0. At month 36, the entecavir resistance mutation I169T was detected in 15 clones and S202G in four clones. At month 41, S202G was present in 17 clones and I169T in four clones. Lamivudine-resistant mutations remained detectable in all 20 clones. Patient 3 developed HBV recurrence after a liver transplant despite receiving lamivudine plus HBV immunoglobulin. All 18 clones had the M204I and sG145R mutations when HBV recurrence was diagnosed. Adefovir was added and lamivudine was stopped seven months later. Adefovir breakthrough occurred after 41 months, at which time all 18 clones had the adefovir-resistance mutation N236T. Four months after reintroduction of lamivudine, all 20 clones had mutations L180M and M204V; 12 clones also had the V173L mutation. However, N236T was replaced by a different adefovir-resistance mutation, P237H.

Conclusion

The researchers concluded that mutations conferring resistance to multiple antiviral agents could be present on the same viral genome. Sequential antiviral monotherapy leads to selection of multidrug-resistant HBV, and mutations evolve during continued treatment, resulting in mutants with increased replication fitness. They suggested that combination therapy directed against HBV strains that are resistant to a single antiviral drug may not adequately suppress HBV that is resistant to two drugs, arguing for initial use of combination therapy.

6/13/06

Reference
H Yim, Hussain, S. Wong, and others. Evolution of multi-drug resistant HBV: implications on rescue therapy. Abstract 5. Digestive Disease Week 2006. May 20-25, 2006. Los Angeles, CA.