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Sensitivity of HHV-6 to Antiviral Agents

Data concerning the sensitivity of HHV-6 replication to antiviral agents is inconsistent. Investigators studying this subject use different laboratory-adapted strains of virus, different types of cell culture media, and different viral detection systems for measurement, which results in the generation of conflicting data. In order to obtain definitive information, using isolates of both virus variants (HHV-6A and HHV-6B) in cell culture systems that accurately provide a quantitative measurement of the inhibition of viral replication is essential. We have successfully developed and used such cell culture assay systems.

The following is a summary of our laboratory data and other published information pertaining to the susceptibility of HHV-6 to suppression by various antiviral agents.

Summary of Antiviral Agents

Ganciclovir CYTOVENE™
Ganciclovir is a drug used to treat CMV retinitis. It is available in both oral and intravenous forms. Studies have shown that HHV-6 replication is effectively suppressed by intravenous ganciclovir and the drug has been used to successfully treat life-threatening HHV-6 infections of the brain and spinal cord in bone marrow transplant recipients. Ganciclovir is the only drug that has demonstrated its ability to successfully treat brain infections by HHV-6. Treatment with intravenous ganciclovir may cause potentially serious side effects, most commonly bone marrow suppression. Oral ganciclovir is available, but it produces relatively low serum levels of the drug and is unlikely to be highly effective against established HHV-6 infections.

Valganciclovir VALCYTE™
Recently, the valine ester of ganciclovir (valganciclovir or VALCYTETM) has been developed by Roche Pharmaceuticals as an antiviral drug, and it was recently FDA approved for use in the treatment of cytomegalovirus retinitis in patients with AIDS. Valganciclovir is a prodrug of ganciclovir in that it is rapidly converted to ganciclovir by intestinal and hepatic enzymes producing plasma levels of drug that are similar or even superior to those achieved by intravenous ganciclovir. Valganciclovir is administered orally twice per day.

Beta Interferon AVONEX™ or BETASERON™
Interferons are used to treat certain types of cancer, chronic infections (e.g. Hepatitis C) and other diseases of infectious or autoimmune origin such as multiple sclerosis. Interferon also has known antiviral properties. Studies by our laboratory, in collaboration with investigators at the Pathogenesis Corporation in Seattle, Washington, have shown that strains of HHV-6 are sensitive to suppression by beta interferon. This finding is consistent with the known antiviral activity of interferon. However, our laboratory's data indicate that the current dosage regimens (for MS patients) produce serum levels of the drug capable of suppressing the replication of HHV-6 by less than 50%. This modest suppression may be important when beta interferon therapy is used in conjunction with another type of antiviral agent.

Acyclovir ZOVIRAX™

Acyclovir is used to treat herpes simplex (HSV), varicella zoster (VZV) infections. It is available in oral form. Available data indicate that HHV-6 is relatively insensitive to the inhibitory effects of acyclovir. The mean inhibitory concentration 50% (IC50) of acyclovir for HHV-6 strains is approximately 30 uM, a concentration well above the plasma levels achievable with either oral or intravenous therapy.

Acyclovir VALTREX™

Valacyclovir or VALTREX is an orally delivered drug chiefly used to treat HSV and VZV. It is a prodrug of acylovir, meaning that it is converted to active acyclovir within the body. This results in higher levels of drug in the blood stream and it is believed that this level of drug might be partially effective against HHV-6. Valcyclovir has been used to effectively decrease the incidence of HHV-6 associated disease in bone marrow transplant recipients. Thus it is effective against reactivation of HHV-6, but may not be effective in suppressing an active, chronic infection. Studies have also demonstrated that VALTREX therapy at standard dosages is associated with a low rate of adverse side effects. Thus, VALTREX treatment stands as a potential alternative for long-term therapy for HHV-6 associated diseases, especially in combination with another antiviral drugs such as beta interferon.

Foscarnet FOSCAVIR™

Foscarnet is used to treat CMV retinitis. It is available in injectable form. The literature concerning the sensitivity of HHV-6 replication to suppression by foscarnet is quite consistent in that all virus strains tested showed marked sensitivity to the drug. However, treatment with intravenous foscarnet carries with it a significant risk of toxicity, which most commonly manifests as renal dysfunction and electrolyte imbalances.

Cidofovir VISTIDETM or (S)-HPMPC
Cidofovir is used to treat CMV retinitis is patients with AIDS. Intravenous administration of cidofovir can be associated with significant renal toxicity, although it appears to be less toxic than either foscarnet or gancyclovir. Cidofovir is available for use in off-label applications, such as the treatment of HHV-6 associated disease. Two cell culture based studies have reported that cidofovir can effectively suppress the replication of HHV-6, although this observation has not been confirmed by other investigators.

Nonconventional Antiviral Agents
Several preparations of various types have been assessed for their ability to suppress the replication of HHV-6 in cell culture. The potential for these agents to be used in the clinical setting remains unclear, and little or nothing is known concerning their pharmokinetics or the plasma levels they can achieve.

One of these is AMPLIGEN, approved for use in Canada and Belgium, but not in the U.S. The Ampligen web site states that results of trials in the U.S. and Belgium "suggest that Ampligen may be an effective treatment for a certain subset of Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) patients, namely those with severe debilitation." The structure of this drug is similar to a known interferon inducer and this strongly suggests that any suppressive effect Ampligen may have on HHV-6 replication is mediated by interferon. Ampligen is a synthetic, mismatched, double-stranded RNA, and a single report of its ability to inhibit HHV-6 replication has been published.

 






 

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