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ADEFOVIR RESISTANCE REPORT
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Reported by Jules Levin
Gilead Sciences researchers reported in oral hepatitis B session on ADV resistance after 144 weeks of therapy from 5 studies, at the DDW May 2004 conference (May 15-20, New Orleans, LA.).
After 3 years of ADV therapy the incidence of drug resistance was 3.9%. During the first year's use of ADV 0% developed ADV resistance. After 2 years use of ADV 2.0% had ADV resistance. After 1 and 2 years 3TC use, 24% and 42% developed 3TC resistance, respectively. After 3 years use of lamivudine in therapy for HBV, 53% of patients develop resistance.
During weeks 0-48 (n=629) no patients developed the ADV mutations (N236T, A181V); during weeks 49-96 (n=293), 4 patients had N236T & 2 had A181V, total of 6; during weeks 97-144 (n=167), 2 patients had N236T & 1 patient had A81V, total of 3. All patients who developed ADV resistance mutations (N236T or A181V) were on ADV monotherapy. No patients on Lamivudine and ADV developed mutations.
For the 6 patients identified with N236T, all 6 had HBV DNA rebounds and had 3.9 to 13.8 fold resistance to ADV (measured by change in IC50 to ADV from baseline). For the 3 patients with A181V, 2 patients had serum HBV DNA rebound along with 2.5 to 3.0 adefovir IC50 fold change from baseline. Both mutants were susceptible to lamivudine in vitro (IC50 about 3-fold of wild-type HBV.
The study investigator showed in their presentation the response to Lamivudine by 4 patients with N236T and 2 with A181V and all 6 patients had a viral load reduction after adding lamivudine to ADV. The patients with ADV resistance had lamivudine added to the regimen. It is not a good idea to switch as HBV selects so
quickly and in so many patients for the lamivudine resistance. In the
one patient where ADV was stopped and the patient was switched to
lamivudine, resistance to lamivudine and full rebound occurred within 6
months. ADV was added to the regimen with full suppression achieved very
quickly. The patient continues now, well over a year, on ADV + LAM. It is
recommended to add lamivudine to ongoing ADV, not switching to lamivudine.
In vitro cross-resistance testing of N236T to other Anti-HBV drugs showed resistance to ADV (7.3 IC50 fold change against wild-type HBV), tenofovir (4.6 fold change), 3TC (2.- fold change), FTC (2.6 fold change, telbivudine (2.4 fold change, entecavir (0.67 fold change). So there was no in vitro cross resistance to entecavir and apparently little or no clinical resistance expected to 3TC, FTC and telbivudine. Entecavir is a new HBV drug in phase III studies and telbivudine is also in clinical development. The clinical significance of in vitro susceptibility remains unknown until tested in patients. (X Qi et al, Gilead Sciences).
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