By Liz Highleyman

Several directly-targeted antiviral agents are used to treat chronic hepatitis B. Long-term therapy is typically required, but the virus can develop resistance to individual drugs used alone, thereby compromising effectiveness over time. Some newer agents, however, have a higher barrier to resistance than earlier drugs such as lamivudine (Epivir-HBV).

Andrea Snow-Lampart from Gilead Sciences and colleagues analyzed long-term data from 2 Phase 3 clinical trials comparing 300 mg once-daily tenofovir versus 10 mg once-daily adefovir (Hepsera) in chronic hepatitis B patients. Study 102 included 375 hepatitis B "e" antigen (HBeAg) negative participants and Study 103 included 266 HBeAg positive patients. Some participants in both studies were previously untreated while some had previously used lamivudine.

After 48 weeks of randomized treatment, 93% of HBeAg negative patients and 76% of HBeAg positive patients achieved complete viral load suppression (> 400 copies/mL). At that point, eligible participants in both arms could receive open-label tenofovir with no treatment interruption. Participants who still had detectable HBV DNA at or after week 72 had the option of adding emtricitabine (Emtriva) to tenofovir (the 2 drugs in the Truvada combination pill approved for HIV treatment), but only 5% did so.

The researchers performed genotypic analysis to look for resistance-associated HBV polymerase/reverse transcriptase (pol/RT) mutations, and conducted phenotypic resistance testing using HepG2 laboratory cells infected with HBV obtained from patient serum.

All participants received a genotypic test at baseline. Those who still had detectable HBV on tenofovir monotherapy at week 144 (34 in the continuous tenofovir arm and 19 who were originally randomized to adefovir and switched to open-label tenofovir), or after adding emtricitabine (7 and 5, respectively), were tested again.

Researchers plan to continue this study for 8 years, and it is now at about the halfway point. In the recent Hepatology article, Snow-Lampart's team reported combined data from Study 102 and 103 through week 144, or about 3 years.

Results

	At week 144, no participants developed amino acid substitutions (mutations) known to be associated with resistance to tenofovir.
	The researchers identified 6 previously undescribed HBV pol/RT mutations, but none of these appeared to cause tenofovir resistance according to phenotypic testing.
	Virological breakthrough while on tenofovir monotherapy was infrequent, occurring in just 13 out of 426 patients (3%).
	Viral rebound was attributed to documented non-adherence in 11 of these patients (85%).
	Detectable HBV viral load (> 400 copies/mL) was rare through week 144, occurring in only 5 out of 641 patients (0.8%).
	Continued HBV viremia was not associated with resistance to tenofovir.

Based on these findings, the study authors concluded, "No nucleoside-naive or nucleoside-experienced patient developed HBV pol/RT mutations associated with [tenofovir] resistance after up to 144 weeks of exposure to [tenofovir] monotherapy."

In a follow-up analysis presented at the American Association for the Study of Liver Diseases (AASLD) "Liver Meeting" this past fall, Snow-Lampart and colleagues reported data from 196 weeks, or about 4 years, indicating that most patients on tenofovir still maintained viral suppression and none showed evidence of resistance mutations.

In comparison, the researchers noted, prior studies have shown that as many as 70% of patients develop resistance to lamivudine after 4 years, nearly one-third showed resistance after 5 years on adefovir, 25% of HBeAg positive and 11% of HBeAg negative patients did so after 2 years on telbivudine (Tyzeka), and just over 1% did so after 5 years on entecavir (Baraclude).

Investigator affiliations: Gilead Sciences, Durham, NC; Gilead Sciences, Foster City, CA; University of Toronto, Toronto, Ontario, Canada; Hospital Beaujon, University of Paris, Clichy, France.

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Reference
A Snow-Lampart, B Chappell, M Curtis, and others. No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology (Abstract). December 22, 2010 (Epub ahead of print).

Other Citation
A Snow-Lampart, KM Kitrinos, BJ Chappell, and others. No resistance to tenofovir disoproxil fumarate (TDF) detected following up to 192 weeks of treatment in subjects mono-infected with chronic hepatitis B virus. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 1365.