Options for treating ganciclovir-resistant CMV discussed at IDSA conference

Cytomegalovirus (CMV) is an AIDS-defining condition and treatment options have changed little in recent years. This is of significant concern as CMV can become resistant to the current standard-of-care medications, ganciclovir and valganciclovir, leaving few treatment options. But there may be new therapeutic options on the horizon. In a symposium at the 44th annual meeting of the Infectious Diseases Society of America, Sunwen Chou MD summarized current knowledge about treating ganciclovir-resistant CMV, and presented information on promising new experimental treatments.

CMV standard of care

CMV (cytomegalovirus), a member of the herpes family of viruses, can be a serious infection for people who are severely immunosuppressed, such as transplant recipients or people with very advanced HIV disease (almost always when CD4 cell counts are below 30 cells/mm³). In the condition called CMV retinitis, CMV infects and damages the retina of the eye, quickly leading to blindness if untreated. CMV retinitis has become very rare in countries where HIV treatment is widely available.

Treating HIV is a key strategy for treating CMV, since CMV treatment can usually be (cautiously) stopped when CD4 counts have recovered to high enough levels. While CD4 cell counts remain low, however, treatment depends on using antivirals active against CMV. The current options are the intravenous drugs ganciclovir (Cymevene), foscarnet (Foscavir) and cidofovir (Vistide), and the oral valganciclovir (Valcyte.). Valganciclovir, an oral ‘pro-drug’ of ganciclovir (GCV), is converted to GCV in the body. Ganciclovir and valganciclovir, the preferred maintenance treatments, are therefore essentially the same from the standpoint of resistance.

Ganciclovir resistance can develop with prolonged drug exposure. GCV resistance has been seen in 11% of HIV-related CMV retinitis cases after six months, and 28% at nine months. (Similar levels are seen for foscarnet and cidofovir resistance.) Cross-resistance between drugs can develop relatively easily, with some CMV viral mutations causing resistance to all three drugs.

Alternatives to ganciclovir

Foscarnet is the usual alternative treatment if GCV fails or is unusable. Cidofovir is another alternative, but may not be usable because of severe kidney toxicity. Some clinicians have suggested using foscarnet and GCV in dual combination. A prospective study in transplant recipients did not find any benefit to using this combination as initial therapy. However, it has recently been suggested that GCV/foscarnet should be considered in HIV-related CMV that did not respond to standard treatment.

There have been a few reports of using ‘immune boosting’ drugs (immunomodulators) to treat CMV, including sirolimus, roscovitine, and leflunomide.

Several new anti-CMV medications, of a class known as anti-CMV benzimidazole ribosides, have been in development for some time. The development process has been fairly slow, probably because CMV is no longer a very widespread infection. Tomeglovir (Bayer 384766) and GlaxoSmithKline’s GW275175X, which inhibit CMV DNA processing, are in pre-clinical stages of development.

Further along is maribavir (1263W94), a ‘kinase inhibitor’ being developed by ViroPharma. Maribavir is available in oral form, has shown low toxicity thus far, has reduced CMV viral shedding 3 log₁₀ (a thousand-fold) in Phase I trials, and has continued into Phase II trials. There has been little information about how well maribavir works at controlling clinical CMV disease, but that question should be answered by a larger Phase III trial (in transplant patients). This study, the first of two pivotal trials, was announced in September and is expected to begin enrolling in Europe and North America within the next few months. Analyses so far have shown that maribavir-resistant CMV is still susceptible to ganciclovir.