Seattle Treatment Education Project: STEP Perspective - Volume 4,

Most presentations about treatment of cytomegalovirus (CMV) disease focused on ways to decrease the side effects of therapy. In herpesevirus (HSV), acyclovir (ACV) resistance remains the foremost problem in therapy. Some of the more promising options are reviewed below.

Cytomegalovirus (CMV) Standard therapy. CMV disease in HIV infection is frequent, with CMV retinitis occurring in 10 to 20 percent of people with AIDS in the U.S. Retinitis comprises up to 80 percent of CMV disease in HIV infection, with gastrointestinal involvement being the next most common manifestation. There is evidence that active CMV infection may in turn activate HIV infection, so control of CMV may in itself prevent progression of HIV disease. CMV disease occurs when HIV infection is relatively progressed, usually when CD4 counts fall below 100. Currently, standard therapy consists of either ganciclovir (GCV) or foscarnet intravenously--at high doses for three weeks then at lower doses indefinitely to prevent relapse. Both drugs are considered equally effective in treating CMV disease. The main side effect of ganciclovir is decreased white blood cell count; the primary side effect of foscarnet is decreased kidney function. A recently published study of ganciclovir vs. foscarnet in CMV disease found that those who received foscarnet survived an average of four months longer, suggesting foscarnet may have significant intrinsic anti-HIV properties (Jabs, USA, PoB3193).

The combined use of foscarnet and ganciclovir has also been studied. Although it appears to be quite effective, it does have toxicity. In one study presented, all six of the participants developed penile ulcers, and leukopenia (decreased white blood cells) was seen in four of the participants (PoB3253). New drugs on the horizon for CMV include HPMC, FIAC, FIAU, and BW256 (Katlama, France, Session 85).

Use of G-CSF.

Ganciclovir decreases the white blood cell count in 30 to 50 percent of those receiving the drug. One study reviewed the concurrent administration of a drug GM-CSF (Granulocyte-macrophage colony stimulating factor) to prevent decreases in white blood cells during the treatment of CMV retinitis with ganciclovir. Eighteen percent in the group receiving both GM-CSF and ganciclovir group, vs. 45 percent in the group receiving ganciclovir only, developed a decrease in white blood cell count. The group not receiving GM-CSF missed more days of ganciclovir therapy because of low white blood cell count, and as a consequence, this group had a higher incidence of progression of CMV retinitis compared to the group receiving both drugs. Since the study began, it has been found that GM-CSF stimulates HIV replication in the laboratory. The current standard of care for treatment-related low white blood cell count is use of a closely related drug, G-CSF (granulocyte colony stimulating factor) which has not been found to stimulate HIV. In this particular study, however, GM-CSF was not associated with increased HIV replication in the patients under study (Hardy, USA, MoA0005).

Immune therapy.

A study of CMV neutralizing antibody levels in patients with retinitis showed that those patients whose retinitis progressed slowly had significantly higher neutralizing antibody levels than patients with repidly progressing retinitis. All patients were treated with foscarnet. This may have implications for treatment of patients with antibody therapy in progressive or relapsing CMV disease (Davies, USA, WeB1053).

Data was presented from a study using anti-CMV human immunoglobulins to prevent CMV disease in individuals with AIDS. This study, which is still in progress, is administering 0.25 mg of anti-CMV human immunoglobulins intramuscularly every four weeks. So far they have seen no illnesses caused by reactivation of CMV. Additionally, they have seen increases in CD3 and CD4 lymphocytes, increases in the ratio of CD4/CD8, activation of natural killer cells, and significant increases in the blood level of anti-CMV immunoglobulins (PoB3267).

Maintenance therapy.

A different approach to maintenance therapy, alternating ganciclovir and foscarnet therapy every other day, was presented. The aim of this open- label trial was to determine if this mode of therapy would decrease side effects of either drug. One of 10 patients on this regimen discontinued the trial because of decreased kidney function. Although this group was not randomized and no control arm was used, this data suggests a possible alternative to maintenance therapy for patients who are intolerant of standard maintenance regimens (Malte, Germany, WeB1054).

The most attractive treatment options on the horizon remain the development of drugs that can be taken by mouth for CMV disease. Oral forms of ganciclovir and foscarnet are under investigation.

Adrenal CMV.

Data was present from a study of adrenal insufficiency.

CMV infection of the adrenal glands is seen in 15 to 80 percent of people with AIDS, but is often not detected until after death. In this study, the investigators evaluated individuals with fatigue, weakness, and loss of appetite, which are the cardinal symptoms of adrenal insufficiency. They found 14 individuals with insufficient adrenal production of cortisol. All of these people also had other signs of CMV disease, such as CMV retinitis. After initiating treatment with 37.5 mg of hydrocortisone a day, weakness, fatigue, and appetite improved dramatically in all individuals. Adrenal insufficiency can be easily detected through laboratory tests and should be considered in individuals with these symptoms, especially if CMV disease is present (PoB3836).

Herpesvirus (HSV) Acyclovir resistance. Most of the presentations regarding HSV disease in HIV infection centered on new drugs for the treatment of acyclovir - resistant HSV. Patients with chronic HSV infections are at risk for developing acyclovir-resistant HSV, especially if their HIV disease is advanced, if they have taken repeated cycles of acyclovir for recurrent HSV disease. To be effective, acyclovir needs to be activated by the enzyme thymidine kinase, produced by HSV. The main mode of acyclovir resistance is mutation of HSV to produce low levels of thymidine kinase, thus preventing activation of acyclovir. Acyclovir-resistant HSV lesions are sometimes apparent simply by physical exam: these lesions are usually around the buttocks (but may be anywhere on the body), are much larger and deeper than acyclovir-sensitive HSV lesions, and are exquisitely painful. The severe effect on these patients has stimulated a search for effective therapies.

New agents for acyclovir viral resistance. Because of their chemical structures, the drugs FIAC, FIAU and FMAU, which have all been candidate alternative therapies in the past, are not effective against acyclovir- resistant HSV due to cross-resistance. The alternate treatment of choice is currently systemic administration of foscarnet, which acts through a different mechanism on HSV (other than the thymidine kinase enzyme), and does not exhibit cross-resistance. Also in this group of alternate therapies are Trifluridine (TFT) and Vidarabine (ARA-A). TFT holds promise as a topical therapy for acyclovir-resistant HSV as shown in preliminary open- label trials (Pottage, USA, PoB3238). In one small open-label trial, TFT topical cream completely healed six of 12 patients' acyclovir-resistant HSV lesions (Kessler, USA, Session 85).

Other new agents.

A report was presented on a drug called 256U87. It is an acyclovir pro- drug, meaning that it is converted to acyclovir inside the body. It is well absorbed and rapidly converted to acyclovir, resulting in acyclovir bioavailability equal to three to four fold greater than oral acyclovir. Side effects were minimal and included nausea, diarrhea, and abdominal pain (PoB3885). It is being studied in phase II/III trials. The AIDS Cinical Trials Unit here in Seattle is conducting one of the studies. There are also trials underway studying the use of 256U87 as an agent for CMV prevention.

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