AIDS TREATMENT NEWS #138, November 1, 1991
John S. James

The October 21 PHS press release quoted the study's chairman, Douglas Jabs, M. D., associate professor of ophthalmology at The Johns Hopkins School of Medicine, as noting that, "These results suggest that, for many patients with AIDS and CMV retinitis, foscarnet may be a better initial treatment than ganciclovir." The press release also noted that those who entered the study with decreased kidney function lived longer if assigned to ganciclovir. (Kidney toxicity is the most serious side effect of foscarnet.)

On October 28 we interviewed Mark Jacobson, M. D., of San Francisco General Hospital, an expert in CMV retinitis who has much experience with both drugs; we had planned the interview even before the new study results were known, in order to ask about foscarnet, since it was recently approved by the FDA for marketing in the U. S. Dr. Jacobson made the following points:

* The drugs were completely equivalent in controlling CMV retinitis. But beyond that, it is difficult to come up with a take-home message from the study. The observation that made the news is that those assigned to foscarnet lived an average of 50 percent longer than those assigned to ganciclovir. This observation seems to be real, not a random fluke; the data from the study is consistent and credible.

* But it is hard to interpret what the data means, because the trial was not designed to compare survival -- only to compare the two treatments of CMV retinitis. A survival study would need to control or randomly assign the antiretroviral therapy and prophylaxis for opportunistic infections. There were major differences between the groups in the treatment which patients received; for example, more people in the foscarnet group than in the ganciclovir group used AZT. [Note: this difference is not surprising, since AZT and ganciclovir have similar toxicities and therefore it is hard to use them together.]

* What cannot be answered from this study is whether the survival difference was due to the antiretroviral effect of foscarnet (the drug is known to have some degree of anti-HIV effect), or due to the suboptimal antiretroviral therapy of patients receiving ganciclovir, who often cannot use AZT.

* Few of the patients in this study used ddI (which could probably be combined with ganciclovir better than AZT could be). And almost none received G-CSF or GM-CSF, which would allow many patients to combine ganciclovir and AZT. While the data has not yet been fully analyzed, these figures suggest that those in the ganciclovir group may have had too little anti-HIV therapy.

* What does this mean for clinical management? If all things are equal, these results would probably favor foscarnet as the first choice for treating CMV retinitis. But for many patients, all things are not equal. Most importantly, those with any kidney abnormalities had worse survival with foscarnet than with ganciclovir.

* Also, foscarnet is more expensive than ganciclovir, and more cumbersome to administer. It takes two hours daily for maintenance therapy, compared to one hour with ganciclovir; and you need an IV pump for foscarnet, but not for ganciclovir.

* If you eliminate the practical differences, patients with normal kidney function may lean toward choosing foscarnet. But when patients in this study who were taking ganciclovir were told that they could switch to foscarnet, the majority did not want to do so.

Anti-HIV effect of foscarnet:

We also asked Dr. Jacobson what was known about the anti-HIV effect of foscarnet:

* Dr. Jacobson and others published two papers showing that p24 antigen (an indication of HIV activity) went down with foscarnet treatment -- even in people who had been on AZT but still had p24 antigen. However, we know that p24 changes do not correlate well with survival. There is no question that foscarnet has biologic activity against HIV -- that is almost indisputable. But whether that is beneficial clinically is unknown. Perhaps a trial will be done to see if the drug is beneficial, now that the new survival result (from the CMV retinitis trial) has raised the issue.

Safety Concerns:

We also asked about how physicians can use foscarnet safely. We particularly asked if the package insert that comes with the drug included all the information required:

* The package insert has the information, but it's long; the physician must pay close attention and become familiar with it in order to safely give this drug. It is very important to monitor serum creatinine and and adjust doses accordingly, at least weekly during maintenance therapy, and more often during induction, in order to avoid toxicity.

* Problems are manageable if physicians are monitoring patients. But what happens if people travel or otherwise are not monitored and continue to take their drug? With foscarnet it is possible to go into renal failure over a four-day period; that is unusual, but it can happen. If patients have been on therapy for some time and are known to be stable, we (Dr. Jacobson's unit) have had some be away for as long as two weeks, but that is the outside limit with which we would be comfortable.

With ganciclovir, it is less serious to not be monitored. If the neutrophil count goes low and the patient does not get an infection, all that is necessary is to stop the drug, and the count will recover.

(We asked about hydration -- making sure patients have enough water, usually by giving intravenous fluids -- which is often emphasized by European physicians who are familiar with the drug.)

* The hydration data comes from a small French study. Patients given saline seemed to have less kidney dysfunction than controls; this study was not randomized. Hydration does make sense, and it is what people have done, although there is no controlled-study data showing that you have to do it. It is generally easy to do, since you need to give the foscarnet intravenously over two hours anyway, and the saline can be given during that time.

Other Uses of Foscarnet

(We asked Dr. Jacobson about "unlabeled" uses of foscarnet -- those not included in the official approval -- such as for treatment of CMV colitis.)

* For other CMV diseases, there is very little data, mostly anecdotal reports that it might be beneficial. Patients with gastrointestinal disease might have more problems than others with foscarnet toxicity; they might be at more risk with this drug than with ganciclovir, but there is very little data. If people have not responded to ganciclovir, then foscarnet might be worth a try for gastrointestinal CMV disease.

* For acyclovir-resistant herpes simplex, however, there is plenty of data to support use of foscarnet. A recent article (1) gives very convincing data that foscarnet works better than any other available therapy for acyclovir-resistant herpes. Foscarnet is clearly the therapy of choice for this condition.

References

1. Safrin S, Crumpacker C, Chatis P, and others. A controlled trial comparing foscarnet with vidarabine for acyclovir- resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. New England Journal of Medicine. August 22, 1991; volume 325, number 8, pages 551-555.

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