Laboratory Study Shows Hepatitis B Drug Entecavir (Baraclude) -- But Not Telbivudine (Tyzeka) -- Has Activity against Multiple Strains of HIV

By Liz Highleyman

Several antiretroviral agents -- including tenofovir (Viread), lamivudine (3TC, Epivir), and emtricitabine (Emtriva) -- are active against both HIV and hepatitis B virus (HBV), and therefore are well-suited for treating HIV-HBV coinfected patients who require treatment for both diseases.

The situation is more complex for coinfected people who need treatment for hepatitis B but do not yet require HIV therapy based on symptoms or CD4 cell count.

It is important to avoid using a dually active agent on its own to treat HBV in coinfected patients who are not on HAART, since the drug would act as monotherapy against HIV and could spur the emergence of drug resistance. For this reason, current U.S. antiretroviral treatment guidelines recommend that all HIV-HBV coinfected patients who require hepatitis B treatment -- regardless of CD4 cell count -- should use a combination antiretroviral regimen that includes 2 agents that also work against HBV.

Earlier guidelines advised that coinfected patients who did not yet need HIV therapy based on their CD4 count could be treated for hepatitis B using agents without anti-HIV activity. Entecavir (Baraclude) was thought to be such a drug, but at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI 2007) researchers presented evidence indicating that entecavir did have low-level activity against HIV and could select for resistant virus.

That left few agents active against HBV but not HIV. Telbivudine (Tyzeka) may be one such drug, according to data presented by C. Avila and colleagues from Novartis at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.

In a laboratory study, the investigators assessed 8 different wild-type (non-mutated) clinical isolates of HIV, representing different geographic locations and viral subtypes, for susceptibility to telbivudine and entecavir. They also tested the susceptibility of 2 multi-drug resistant HIV isolates. Anti-HIV activity was measured 48 hours after infection using the Monogram PhenoSense assay, a sensitive and robust HIV phenotypic resistance test.

Results

Telbivudine did not exhibit in vitro activity against any of the selected HIV clinical isolates (50% inhibitory concentration [IC50] values > 600 µM).

In contrast, entecavir exhibited antiviral activity against most of the HIV clinical isolates, at IC50 values ranging from 7.62 to 15.09 µM.

The IC50 of entecavir increased more than 8-fold in HIV isolates harboring the M184V mutation.

"This in vitro study confirmed entecavir activity against HIV," the researchers concluded. "In contrast telbivudine showed no antiviral effect against a broad range of wild-type and multidrug resistant HIV isolates at IC50 values > 600 µM, which is well above physiologically relevant concentrations" that are also known to inhibit HBV activity in vitro.

"Our result support investigating the anti-HBV efficacy and safety of telbivudine in HIV-HBV coinfected patients who do not require anti-HIV treatment, within [a] clinical trial setting," they added.

Novartis Pharma AG, Basel, Switzerlan; Novartis Institute for Biomedical Research, Cambridge, MA.

5/15/09

Reference
C Avila, S Karwowska, C Lai, and T Evans. Telbivudine Shows No Activity against 8 Different Clinical HIV Isolates and 2 Multi-Drug Resistant HIV Isolates. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

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15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
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