EASL 2009: Antiviral Agents with Activity against Both HIV and Hepatitis C Virus

Standard therapy for chronic hepatitis C virus (HCV) infection consists of pegylated interferon plus ribavirin, but several novel agents under study directly target various steps of the HCV lifecycle, an approach known as "STAT-C." Some of these investigational agents work similarly to certain antiretroviral drugs for HIV, suggesting it may be possible to develop drugs that have activity against both HIV-HCV, a potential benefit for HIV-HCV coinfected patients.

EASL Study

At the recent 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) in Copenhagen, K. Klumpp and colleagues, representing 3 pharmaceutical companies, described the identification of agents with dual anti-HCV/anti-HIV activity.

HCV polymerase and HIV reverse transcriptase (RT) have both been shown to accept modified deoxynucleoside analogs as substrates when they copy their genetic material, the researchers noted as background. Since these agents differ from natural nucleosides, they can halt viral replication.

The investigators sought to identify nucleoside analogs that inhibit both the RNA polymerase of HCV and the DNA polymerase of HIV-RT, but do not interfere with natural human RNA and DNA polymerases, since such interference could produce significant side effects.

Candidate nucleoside analogs were tested for antiviral activity and cytotoxicity in various laboratory models of infected cells (Con1 HCV replicon in Huh-7 cells, HXB2 HIV-1 in MT-4 cells, and Dengue virus replication in Huh-7 cells).

Nucleoside triphosphate analogs were tested as inhibitors of viral and human RNA and DNA polymerases, including HCV NS5B, Dengue NS5, West Nile virus NS5, HIV-1 reverse transcriptase, cytomegalovirus (CMV) DNA polymerase, and human mitochondrial DNA polymerase-gamma.

Results

o   Lamivudine (3TC; Epivir): 50% inhibitory concentration (IC50) 2.5 mcM;

o   Emtricitabine (FTC; Emtriva): IC50 0.43 mcM;

o   Zidovudine (AZT; Retrovir): IC50 0.095 mcM.

These results led the researchers to conclude, "Novel nucleosides have been identified that can inhibit both HCV and HIV replication with higher potency as compared to reference compounds 3TC, FTC, AZT or R1479, while retaining selectivity against human and other viral polymerases."

As previously reported, another research team at EASL 2009 presented the latest data on the cyclophilin inhibitor Debio 025, which was previously shown to have activity against both HCV and HIV in preclinical studies, although its anti-HIV effect was not strong in early clinical trials.

Roche, Palo Alto, CA; Rigel Pharmaceuticals, South San Francisco, CA; Medivir AB, Huddinge, Sweden.

Nelfinavir

In a study reported in the March 3, 2009 advance online edition of Journal of Viral Hepatitis, Japanese researchers assessed whether the HIV protease inhibitor nelfinavir (Viracept) might also have activity against HCV.

The investigators evaluated the effects of nelfinavir on intracellular HCV replication using an HCV replicon model expressing a neomycin-selectable chimeric firefly luciferase reporter protein. Cytotoxicity and apoptosis induced by nelfinavir were assessed and synergism between nelfinavir and interferon (IFN) was calculated using CalcuSyn analysis.

They found that nelfinavir suppressed HCV replication in a dose-dependent manner at low concentrations (IC50 9.88 mcM/L). Nelfinavir did not cause cytotoxicity or apoptosis (programmed cell death) at concentrations that inhibited HCV replication. When clinical concentrations of nelfinavir (5 mcM/L) were combined with interferon, the 2 drugs exhibited synergistic inhibition of HCV replication in the replicon model.

Based on these findings, the researchers concluded, "Our results suggest that the direct effects of nelfinavir on the HCV subgenome and its synergism with interferon could improve clinical responses to interferon therapy in HCV-HIV coinfected patients."

First Department of Internal Medicine, School of Medicine, University of the Ryukyus, Okinawa, Japan.

6/2/09

References

K Klumpp, G Su, J Deval, and others. 2'-Deoxy-Nucleoside Analogs as Potent Dual Inhibitors of HCV and HIV Replication, with Selectivity against other Viral and Human Polymerases. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

S Toma, T Yamashiro, S Arakaki, and others. Inhibition of intracellular hepatitis C virus replication by nelfinavir and synergistic effect with interferon-alpha. Journal of Viral Hepatitis. March 3, 2009 [Epub ahead of print].