Experimental HBV Drug Clevudine Shows Promise at the XVI International HIV Drug Resistance Workshop in Barbados

Clevudine is an oral, once-daily pyrimidine nucleoside analog that is in development in the U.S. by Pharmasset, Inc. for the treatment of chronic hepatitis B virus (HBV) infection. Clevudine is approved for treatment of HBV in Korea, where it is marketed by Bukwang Pharmaceuticals under the brand name Levovir.

In addition to its on-treatment efficacy, clevudine has demonstrated sustained virological response (SVR) in patients with HBV, or undetectable virus 24 weeks after completing therapy.

Pharmasset plans to initiate 2 Phase III clinical trials of clevudine for registration in the U.S., Europe, and South America in the third calendar quarter of 2007.

In an in vitro study presented at the XVI International HIV Drug Resistance Workshop held in St. Michael, Barbados (June 12-15, 2007), researchers demonstrated that clevudine does not inhibit HIV.

Because clevudine has demonstrated no antiviral effect on HIV, it should not select for HIV mutations that will have cross-resistance to HIV therapies. Thus, clevudine may be useful for the treatment of HIV-HBV coinfected patients.

Treatment guidelines formerly recommended entecavir (Baraclude) as first-line therapy for HIV-HBV coinfected patients not requiring antiretroviral therapy. However, data recently presented clinical data at the Retrovirus conference this past February (abstract 136LB) showed that a small number of coinfected patients treated with entecavir monotherapy displayed a 1 log drop in HIV viral load.

Prospective analysis of patient samples showed the emergence of the M84V mutation. Compared to wild-type virus, both patient-derived and laboratory-derived virus containing the M184V mutation were resistant to entecavir in vitro. The same mutation also confers resistance to the antiretroviral drugs 3TC (Epivir) and emtricitabine (Emtriva). At a high dose, entecavir is able to inhibit 100% of infection by virus that does not carry the M184V mutation. The Q151M mutation appears to confer hypersensitivity to entecavir and partially reverses resistance due to the M184V mutation. Viruses that possess other mutations in the absence of M184V are sensitive to entecavir. Plasmids were obtained from the NIH AIDS Research & Reference Reagent Program. Patient-derived viruses containing multiple thymidine-associated mutations (TAMs) were sensitive to entecavir when the M184V mutation was absent. The Q151M mutation appears to confer hypersensitivity to entecavir in patient-derived viruses.

P4 CCR5 luc cells were pre-treated for 4 hours with an increasing amount of drug, in the presence of a fixed amount of clevudine. The cells were then infected with Nl4-3 virus for 40 hours and the beta-Gal was measured. The ribavirin/AZT combination, in the absence of clevudine, was used as a positive control for antagonism, since ribavirin is known to antagonize the activity of AZT. Results were performed in triplicate in 3 independent experiments.

Clevudine did not significantly affect the activity of the approved NRTI drugs in P4 CCR5 luc cells. A MTS assay was performed on peripheral blood mononuclear cells (PBMCs) treated 6 days with drugs. Entecavir, but not clevudine, was toxic to PBMCs. Entecavir demonstrated toxicity above 20 micromolar in P4CCR5 luc cells.

Table: Comparison of the Cytotoxicity of
Entecavir and Clevudine in Human PBMCs

Conclusions

The investigators concluded that:

• Entecavir, but not clevudine, shows significant anti-HIV activity.

• The M184V mutation induces resistance to entecavir and is partially reversed by a Q151M mutation.

• Virus containing the Q151M mutation appears to be hypersensitive to entecavir.

• Virus containing multiple TAMs in the absence of the M184V mutation remains sensitive to entecavir.

• Entecavir, but not clevudine, is toxic to human PBMCs and P4CCR5 luc cells.

• Clevudine does not significantly affect the in vitro inhibition of HIV by approved NRTI drugs.

In their conclusion, the researchers wrote that, "Clevudine does not inhibit HIV in vitro. We have confirmed that entecavir has activity against wild type HIV-1 virus and that the M184V mutation confers resistance to entecavir. In addition, we showed that certain nucleoside-resistant HIV variants remain sensitive to entecavir. Thus, clevudine may be useful for the treatment of HIV-HBV coinfected patients."

06/19/07

Reference
V Zennou, M Keilman, M J Otto, and P Furman. P Anti-HIV Activity and Resistance Profiles of Entecavir Compared to Clevudine. XVI International HIV Drug Resistance Workshop. St. Michael, The Barbados. June 12-15, 2007.

View Clevudine Poster presented at The Barbados Resistance Workshop 746.2 KB