EASL 2010: Tenofovir (Viread) Demonstrates High Barrier to Resistance over 3 Years in Chronic Hepatitis B Patients

No participants taking tenofovir (Viread) to treat chronic hepatitis B developed drug resistance through 144 weeks in 2 Phase 3 studies, according to a poster presentation last week at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) in Vienna. Researchers also reported that among patients who still had detectable HBV DNA at week 72, adding emtricitabine (Emtriva) did not reduce viral load more than tenofovir alone.

Several nucleoside/nucleotide analog drugs are effective against HBV, but the virus can develop drug resistance mutations that compromise the efficacy long-term therapy. Experience with HIV indicates that this is most likely to occur when these drugs are used as monotherapy.

A. Snow-Lampart and colleagues from Gilead Sciences conducted population and clonal analyses of HBV polymerase from hepatitis B "e" antigen (HBeAg) negative chronic hepatitis B patients in the pivotal Study 102 and HBeAg positive participants in Study 103 who had persistent viremia (HBV DNA never fell below >400 copies/mL) or viral breakthrough (viral load 400 copies/mL after suppression below this level) after up to 144 weeks on tenofovir.

The investigators looked at 641 total participants (333 from Study 102 and 225 from Study 103) who were still being followed at year 3. Starting at week 72, persistently viremic patients had the option to add emtricitabine to tenofovir (the 2 drugs in the Truvada combination pill). Among the 51 patients who were eligible to add emtricitabine, 34 (67%) did so and 17 (33%) remained on tenofovir monotherapy.

Results

• 12 of 17 participants (71%) who remained on tenofovir alone achieved HBV DNA < 400 copies/mL at week 144 or their last visit, compared with 22 of 34 (65%) who added emtricitabine (not a significant difference).
• Among the 17 participants who remained viremic at their last visit (5 on tenofovir monotherapy, 12 on tenofovir/emtricitabine), 5 qualified for clonal analysis due to persistent viremia, 1 of whom was non-adherent.
• Among the remaining 4 patients, baseline viral load raged from 6.1 to 10.4 log and the median decline in HBV DNA was 6.1 log at week 144.
• In these 4 patients, clonal analysis revealed mutations in HBV polymerase/reverse transcriptase (rt) at 19 distinct positions, accounting for 3.6% to 9.1% of the total viral population.
• Only a single conserved mutation (rtF183L) was present in clones from more than 1 person.
• Among the 12 other participants with HBV viremia at week 144 or their last visit, 6 were non-adherent and 2 develop conserved mutations (rtR192H and rtG152E).
• Despite these genotypic mutations, phenotypic testing found that HBV from these patients remained sensitive to tenofovir in vitro, and mutations were not associated with viral breakthrough.

Based on these findings, the investigators concluded, "Through 144 weeks of [tenofovir] therapy, no resistance mutations to tenofovir have been identified among HBeAg negative and HBeAg positive patients in two Phase 3 studies."

Among the 51 tenofovir-treated participants with HBV viremia at week 72 or after, "addition of [emtricitabine] did not appear to impact the subsequent decline in HBV DNA as compared to patients who maintained [tenofovir] monotherapy," they continued.

Finally, they added, "Persistent viremia among adherent patients was rare (4/641, 0.6%) and not associated with virologic resistance to tenofovir as detected by population or clonal analyses."

Gilead Sciences, Inc, Durham, NC; Gilead Sciences, Inc, Foster City, CA.

4/23/10

Reference

A Snow-Lampart, B Chappell, J Sorbel, and others. Evaluation of potential virologic resistance in HBV polymerase among subjects with persistent viremia following up to 144 weeks of therapy with tenofovir DF. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).