CMV/HERPES THERAPIES: SCANNING THE NEWS

The story of treatments for cytomegalovirus (CMV) infection contains more than its share of chapters on intrigue and neglect. When CMV was first recognized as an AIDS opportunistic infection, no drug was yet available to treat it effectively. Slowly the AIDS community became aware of ganciclovir (see DHPG, AIDS TREATMENT NEWS #44) and then of Foscarnet (AIDS TREATMENT NEWS #71), as effective but limited therapies for CMV retinitis or colitis. Ganciclovir was begrudgingly approved last year by the FDA; but Foscarnet, which could save the eyesight of many PWAs who cannot continue with ganciclovir, remains unapproved and generally unavailable.

CMV belongs to a viral family which includes the cause of cold sores and genital lesions (herpes simplex 1 and 2, or HSV), the cause of chicken pox and shingles (varicella-zoster virus, or VZV), and one source of mononucleosis and certain lymphomas (Epstein-Barr virus, or EBV). These viruses are commonly latent in the general population, but can re-emerge as an active infection for people who are HIV-positive or who must take immunosuppressive drugs to protect transplanted organs.

Fortunately, the "herpesvirus" family is well-studied and some FDA-approved drugs, as well as several investigational agents, appear to have overlapping activity against more than one herpesvirus. Acyclovir (Zovirax), can be administered orally for mild herpes simplex flareups, or intravenously for severe episodes. Acyclovir is relatively non-toxic, and may suppress latent CMV as well as HSV, and is often prescribed in conjunction with AZT (AIDS TREATMENT NEWS #86).

Unfortunately, certain toxicities may pose limits on the duration of other drugs, or their safety in combination with AZT and other treatments. Prolonged treatment with ganciclovir often results in neutropenia (low neutrophil counts), and Foscarnet can be toxic to the kidneys. Vidarabine as well as Foscarnet has been used successfully to treat herpes simplex which will not respond to acyclovir, but vidarabine can suppress bone marrow, making it a questionable choice to replace ganciclovir for treating CMV. Since ganciclovir and Foscarnet pose different toxicities, people who cannot tolerate ganciclovir should have unqualified access to Foscarnet, in our opinion. In terms of therapeutic value against CMV, however, Foscarnet is not considered to be superior to ganciclovir.

We spoke to Shelley M. Gordon, M. D., an infectious disease specialist who said early trial results indicate that granulocyte macrophage-colony stimulating factor (GM-CSF) can counter the neutropenia of ganciclovir, allowing extended use of that treatment. Dr. Gordon also described laser treatments as a successful way to correct retinal detachment caused by CMV, although they would be a complementary treatment and not a replacement for anti-viral drug maintenance therapy. Laser therapy is available already for many other indications, but GM-CSF is accessible only through participation in clinical trials.

In September AIDS TREATMENT NEWS #87 reported the early success with GM-CSF for controlling the toxicity of AZT and alpha interferon, a combination approved to treat KS and which may also prove synergistic against HIV. Dr. Gordon mentioned that interferon has been discussed as a possible agent for treating CMV as well.

Ganciclovir is presently administered intravenously, but studies are under way testing the effectiveness of an oral formulation, as well as intraocular injections. In vitro studies suggest that DFMO (Eflornithine) has a synergistic effect with ganciclovir, implying that lower, less toxic doses might be possible in the future to control retinitis.

We spoke to Danny King, a researcher who has studied a drug called FIAC at Oclassen Pharmaceuticals in San Rafael, California. He said that FIAC is active against all the herpesviruses, as well as the hepatitis B virus. Although FIAC is a nucleoside analog like AZT and ddI, it has no effect on HIV. One early advantage seen with FIAC is its ability to be administered in an oral form. FIAC was first studied in the early 1980s at Memorial Sloan- Kettering Hospital in New York for treating severe VZV and CMV infections, and demonstrated some bone-marrow toxicity and gastrointestinal upsets.

FIAC is now entering additional phase one (toxicity) trials at four sites: the University of Alabama, the University of Washington in Seattle, the University of California in San Diego and the National Institute of Health in Bethesda. For information about local clinical trials involving FIAC, GM-CSF, and Foscarnet, interested persons can call 800/TRIALS-A.

In the interest of renewing the discussion of CMV treatments and questions of promising but neglected options, we want to bring attention to a list of possibilities for treating CMV or herpes infections which are still in laboratory or animal studies or known to us anecdotally: aphidicolin (APH); BHT (see AIDS TREATMENT NEWS #10); capsaicin; decyclovir; dextran sulfate; HPMPA and HPMPC (see AIDS TREATMENT NEWS #76); hypericin; pentosan polysulfate; SQ 32,829 and SQ 33,054; and tumor necrosis factor. Many of these were discussed at the Interscience Conference on Antimicrobial Agents and Chemotherapy last September in Houston. Some of them were discussed a year earlier at the same annual conference. At least five CMV possibilities have demonstrated in vitro activity against HIV as well as against the herpesviruses: APH, dextran sulfate, pentosan polysulfate, foscarnet, and hypericin.

The question now is how long these possibilities will remain on the drawing board, and why Foscarnet, GM-CSF and FIAC are usually not available to many people who need them. Compassionate use or parallel track access does not seem too much to ask for people who stand to lose first their sight and then their lives.