Adefovir Add-on Therapy after Emergence of Lamivudine Resistance Is Effective and Unlikely to Result in Resistance to Adefovir in HIV-HBV Coinfected Patients B

Sequential monotherapy with lamivudine (LAM) [Epivir-HBV] and adefovir dipivoxil (ADV) [Hepsera] for chronic hepatitis B may quickly lead to the selection of resistant HBV. By contrast, a strategy based on add-on ADV therapy after LAM resistance emergence may be more effective.

[In the current study] researchers have analyzed the incidence of ADV resistance in HIV patients who have been treated for up to 5 years with a combination of ADV and LAM after development of LAM-resistance (LAM-R).

In 2000, 35 HIV-patients were enrolled in an open label study of ADV add-on therapy after emergence of LAM-R HBV. In this follow-up study, all patients who presented residual HBV replication by PCR between year 4 and 5 of treatment were studied for the presence of HBV polymerase resistance mutations on serum samples. The HBV-RT was sequenced and compared to the sequences obtained before ADV introduction.

Among the 35 patients included in the initial cohort, 29 were still followed at year 4 and 14 had an undetectable viral load by PCR (<200 copies/mL). 15 had available samples with a viral load high enough to perform sequencing analysis.

Results

• Median duration of add-on ADV of these 15 patients was 235 weeks and the median HBVDNA was 3.55 log10 cop./mL.
• 14/15 patients had constant fluctuating low viral loads between 2.3 (LLD) and 5 log10 cop./mL with no evidence of viral breakthrough.
• 10/15 patients had the same LAM-resistant pattern as their baseline sequence rtV173L/L180M/M204V (n=2);
• rtL180M/M204V (n=8) and no noticeable change was observed in their RT sequences along time.
• 2/10 of them had ADV replaced by tenofovir (TDF) when the background HIV treatment required adjustment.
• 4/15 patients lost their LAM-R mutations.
• For 2 of them failure of compliance was documented. For the 2 remaining, analysis of their HIV and HBV viral load kinetics clearly suggested lack of compliance.
• 1/15 patient had a viral breakthrough with a HBV DNA rise over 1 log10 on two consecutive samples.
• At that time, LAM-R mutations rtV173L/L180M/M204V were still present but no ADV mutation (rtA181V/T or rtN236T) or new conserved site mutations were identified;
• ADV was replaced by tenofovir and HBV DNA started to decline.

Sequential monotherapy, after LAM–R breakthrough, could potentially increase the risk of subsequent HBV resistance selection. A strategy based on ADV add-on therapy seems very effective and is very unlikely to select for double ADV and LAM resistant variants, even in difficult to treat patients such those with HIV coinfection.

The persistence of initially present LAM-R mutations, the low variability of the RT sequence and the absence of selection of further compensatory mutation indicate a strong pressure on a replication impaired virus.

11/16/05

Reference
V Thibault and others. Long-term experience of adefovir dipivoxil add-on therapy in chronic hepatitis B patients co-infected with HIV and lamivudine-resistant HBV: Absence of adefovir resistance mutation selection. Abstract 979. Program and Abstracts of the 56^th annual meeting of the American Association for the Study of Liver Diseases. November 11-15, 2005. San Francisco, CA.