AIDS TREATMENT NEWS No. 108 - August 3, 1990
Michelle Roland

This article will cover the information presented at the Conference on the use of ganciclovir by itself and in combination with the experimental drugs ddI and GM-CSF. In addition, we will discuss the unapproved drugs foscarnet (which is furthest along the U.S. regulatory pipeline), oral ganciclovir, and TI-23 (anti-CMV monoclonal antibodies). Preliminary results of a study on high dose intravenous acyclovir, which is FDA approved for herpes infections, will also be summarized. Finally, we will suggest some research directions which should be pursued immediately to maximize the effectiveness and minimize the toxicity of currently and soon to be available treatments for CMV retinitis. (Note: for our last CMV update, see AIDS TREATMENT NEWS #96, February 2, 1990.)

Intravenous Ganciclovir

Patients and health care workers familiar with ganciclovir know that, although ganciclovir is quite effective in initially stopping the progression of CMV retinitis, its long term effectiveness is often limited, either by time, or by its serious side effects. Data presented at the Conference shows that CMV cultured from some patients develops resistance to ganciclovir after three months of treatment, offering at least a partial explanation for the time-limited effectiveness of this treatment in many people with CMV infections. The amount of time for which this drug is effective varies among patients. In a large study of over 700 patients, almost half had experienced progression of their retinitis in a mean of approximately 97 days (with a range of 4 to 220 days); the other 56% had not experienced any progression at the time the data was presented. (References to this and other studies are listed at the end of this article.)

Although ganciclovir's effectiveness is often time-limited, it is the only drug currently available in the United States for use by people with CMV infections; it is important to learn how to use it as safely, effectively and conveniently as possible until better treatments are available, either by combining it with other drugs and/or by altering the frequency of its administration.

Ganciclovir with GM-CSF

Ganciclovir's most serious side effect is its depression of the development of a type of white blood cells called neutrophils. These cells are important in fighting off bacterial infections. Many scientists and activists have believed that a drug called GM-CSF (granulocyte macrophage colony stimulating factor), which stimulates the growth of some types of white blood cells in the bone marrow, might counter the neutropenia (depressed neutrophil count) experienced by many people using ganciclovir.

Preliminary results from a small study comparing one patients treated with GM-CSF with others who received only ganciclovir suggest that neutropenia severe enough to require discontinuation of ganciclovir may be reduced with the use of GM-CSF, although the differences between the two groups were not outstanding.

What is the clinical significance of the small decreased incidence of severe neutropenia? It is believed by many that temporary or permanent discontinuation of ganciclovir contributes to progression of CMV retinitis. Although the difference in percentage of patients in the two groups who experienced progression of their retinitis was not statistically significant, the mean time to progression was 102 vs 156 days. There were also fewer bacterial infections in those patients who received GM- CSF (47%) than in those who did not (62%).

The preliminary results of this study appear to many to be encouraging. There were some side effects, including more muscle aches in the GM-CSF group, and an increase in the number of another type of white blood cell called eosinophils. However, the overall trend seemed to indicate that GM-CSF may help reduce some of the adverse effects of ganciclovir and should be available to patients who wish to use it. GM-CSF has long been one of the drugs that treatment activists have advocated for immediate expanded access before FDA approval.

Ganciclovir with ddI

Because ganciclovir and AZT have similar toxicities with respect to bone marrow suppression and a decrease in the white blood cell count, it was believed until recently by most doctors and researchers that the two drugs should not be used together. As the standard dose of AZT is lowered, more physicians are recommending that patients may continue to take low doses of AZT with ganciclovir, as long as their blood counts are monitored frequently. With the widened availability of ddI, and the knowledge that ddI does not depress white blood cell counts when used alone, there is much hope that ganciclovir and ddI can be used together safely. This combination would provide patients with anti-retroviral therapy in addition to their anti-CMV treatment.

Preliminary results from an extremely small ongoing study (five people) support the hope that ddI and ganciclovir can be taken together without any additional toxicities. All of these patients had taken AZT previously and four of them had had to discontinue the AZT because of neutropenia. No one developed decreased blood cell counts in the short time of the study (2-7 weeks). The initial findings are far from conclusive, but do support the belief that ddI may well be a better anti-retroviral than AZT for people who need to use ganciclovir.

Ganciclovir Three Times Per Week?

Ganciclovir is currently administered twice a day for 14 days (induction phase), followed by once a day, five days a week administration as maintenance therapy. An Australian study tested the use of ganciclovir three times per week in the maintenance phase, at approximately twice the dose used in the five days per week schedule. Although this study did not have a control group with which to compare its results, it did find rates of progression of CMV retinitis similar to those reported in many other studies. 40% of the patients had experienced progression of their retinitis at a mean of 4.1 months; 38% continued to have inactive retinitis on maintenance therapy at a mean of 6.1 months in the study. (As mentioned above, the large ganciclovir study presented at the Conference reported 44% progression at a mean of 97 days.)

Again, this study is not conclusive, but it does suggest that ganciclovir may be used effectively less frequently than it is being used now. Given the inconvenience of the intravenous therapy, if this data were to be confirmed, it would be very good news. We believe that this type of information is of critical importance to people with AIDS and CMV infections and should be seriously pursued by other researchers.

Ganciclovir for CMV Colitis

Very few studies have been conducted with treatments for CMV infections other than retinitis. A single placebo-controlled study of ganciclovir in colitis showed some improvement in weight loss and significant improvement in progression to CMV retinitis and laboratory assessment of infection as compared to the placebo group. Unfortunately, although the incidence of diarrhea and abdominal pain decreased in the ganciclovir group, the group receiving placebo experienced the same degree of improvement in these symptoms, suggesting that the drug was not responsible for the improvements.

Ganciclovir appears to be useful in at least some aspects of the treatment of CMV colitis; however no studies have been done to answer such questions as whether treatment should be continued indefinitely or just until symptoms resolve. Different doctors and researchers have different opinions about ganciclovir maintenance therapy in CMV colitis. Further investigation in this area is certainly warranted.

Foscarnet

Given the limits of ganciclovir, the development of other treatments for CMV infections is essential. Furthest along the developmental and regulatory pipeline is foscarnet. Although this drug also has serious limitations (can be toxic to the kidneys; also requires daily intravenous infusion), it is essential that more than one drug be available to treat this viral infection. Data from the Conference continues to suggest that foscarnet is effective in stopping CMV retinitis for a limited time and delaying its future progression. The relapse rates appear to be similar to those found with ganciclovir. In addition, one study found a consistent decrease in p24 antigen levels (in those who were initially p24 antigen positive); these researchers concluded that due to it's potent anti-HIV and anti-CMV activities, foscarnet may prove to be the treatment of choice in CMV retinitis.

Foscarnet is not without its problems, however, and not all scientists believe that it will prove to be superior to ganciclovir. In addition to the already identified side effect of reversible kidney toxicity, reversible penile lesions have also been identified in a number of people taking foscarnet. These lesions often require cessation of therapy to heal. Also, one study found dose limiting neurotoxicity in 2 of 16 patients at a seemingly more effective but higher dose of foscarnet. Finally, another study demonstrated that, although calcium levels in the blood were not altered, the two hormones involved in keeping calcium levels steady in the body were elevated in people taking foscarnet. The clinical implication of this observation is not known at this time.

Comment

A note about the design of clinical trials for CMV retinitis: Researchers do not like to design clinical trials without a control group which receives either a placebo, no treatment, a different treatment, or a different dosage of the same treatment. In designing clinical trials for CMV, some researchers have invented a new category which they call "non-sight threatening CMV retinitis" based on the location of the CMV lesions on the retina. They created this category of patients so they could justify withholding treatment from one group to compare against a treatment group. In their abstract, these researchers write, "Data previously presented demonstrated that [immediate treatment] was more effective than delay in postponing progression of CMV retinitis." Any clinician treating patients with CMV retinitis could have told them that. It is essential that this dangerous distinction between non-sight threatening and sight threatening retinitis not be used in any future clinical trials of agents against CMV retinitis.

Ganciclovir vs Foscarnet...or Better Yet, Together?

It is believed by many researchers that foscarnet and ganciclovir are approximately equally effective. A comparison study of the two drugs under way in England has found that the initial response of CMV retinitis may be a bit slower with foscarnet than with ganciclovir. Although the mean time to reactivation of the retinitis was about 4 months in both groups, the British researcher stated that there may be a trend to later and fewer reactivations with ganciclovir than with foscarnet. Importantly, regardless of small differences in efficacy, most patients on both treatments required an interruption or change in their medication at some point during treatment; many of those who did switch therapies responded to the second drug.

As expected, both drugs have their limitations. However, because of their different toxicities, they may be more effective if used concurrently or in alternation than when used alone. Clinicians and researchers familiar with the two drugs find that people respond differently to each, but that what is most important is having an alternative treatment available if the first one does not work.

Comment

What should be the next step in testing ganciclovir and foscarnet? Researchers associated with the AIDS Clinical Trials Group (ACTG), the government sponsored research group, are currently designing a comparative study of ganciclovir and foscarnet, to determine which one is a better treatment. But as we already know (and the English study supports), neither of these treatments is ultimately satisfactory on its own. People often either experience a relapse of their retinitis or have to discontinue treatment due to serious side effects. What seems clear is that, given the reality at this time of two imperfect drugs, the most important information we need now is how best to use them together. This is the same question that is starting to be asked about the use of the anti-retroviral drugs AZT, ddC and ddI.

Instead of asking which one works better, we need to ask if it would be more efficacious and less toxic to use the two drugs concurrently or in alternation. (We have heard a report that one or more doctors may be using them concurrently now.) If used concurrently, how much of each drug should be combined? If used in alternation, when should they be switched? Business as usual in this case would be to compare the two drugs alone; business as usual is a luxury that people with AIDS cannot afford, particularly in this case. We believe that the next step should be to design a trial which intelligently examines options for using these two drugs together.

Note that activists have been pressuring foscarnet's manufacturer, Astra Pharmaceuticals, to release the drug broadly on compassionate use for about two years. In the United States, foscarnet is still only available to those patients who qualify for, and have access to, a clinical trial.

Other Treatment Possibilities: High Dose Intravenous Acyclovir

A very small study suggested that high dose intravenous acyclovir, taken with AZT, may be an acceptable alternative treatment for people who are intolerant of or have failed ganciclovir or for those patients who cannot tolerate both AZT and ganciclovir together but wish to continue taking AZT.

Patients were initially treated with ganciclovir and switched to intravenous acyclovir plus AZT for maintenance. The published abstract of this study states that 2 of the initial eight patients treated experienced progression of retinitis at weeks seven and eight after the completion of the ganciclovir induction. This study is ongoing and is too small at this time to allow us to draw any reliable conclusions.

TI-23 (CMV Monoclonal Antibody)

Results from a small, dose ranging study of intravenous TI-23, a monoclonal antibody against CMV, suggested that this approach may be a safe alternative to other anti-CMV drugs currently available or being studied. Since this drug is a foreign protein, it was important to make sure that the body would not create antibodies against the drug as a normal immune response. No such antibodies were detected and there were no objective side effects observed in the CMV positive, asymptomatic patients who were studied.

This study was not designed to determine if the drug is effective; the second phase of the study, which is currently ongoing in symptomatic patients with CMV infection, was reported to be showing encouraging early results.

Oral Ganciclovir

Alternatives to intravenous treatment for CMV infections are greatly desirable; preliminary data was presented at the Conference on an oral form of ganciclovir. Although this study was designed to determine safety rather than effectiveness, some preliminary observations can be made. At the doses studied so far in this initial dose-ranging study (designed to find the maximum tolerated dose), all 11 of the patients had experienced a relapse of their CMV retinitis in a median time of 62 days (range of 3 to 131 days). There were no problems observed with toxicity, although resistant strains of CMV were isolated in two of the patients.

With the formulation of the drug which was tested, only 6-8% of the drug was found to be active in the blood stream. It is possible that if better formulations of the drug can be developed, effectiveness will be improved.

Other Possibilities

Other oral drugs, such as FIAC and HPMPC, are also in development but no data was presented on them at the Conference (See ATN 94 for information about FIAC and ATN 76 and 96 for information on HPMPC.)

References:

Ganciclovir and GM-CSF: F. B. 92 Ganciclovir and ddI S. B. 474 Ganciclovir 3 times per week: Th.B. 433 Ganciclovir in colitis: F. B. 94 Foscarnet: Th.B. 434, Th.B. 435, Th.B. 436, Th.B. 437, Th.B. 438*, Th.B. 439, Th.B. 440, F. B. 96 *non-sight threatening Foscarnet vs Ganciclovir: F. B. 95 Intravenous Acyclovir: Th.B. 441, TI-23, Th.B. 442 Oral Ganciclovir: F. B. 9

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ATN10804

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