Drug-Resistant Herpes: Cidofovir Gel in Limbo. Interview with Jay Lalezari, M.D.

Cidofovir, a drug active against many herpes viruses, has been approved for over a year in intravenous formulation (VISTIDE®) for treatment of CMV retinitis in patients with AIDS. Developer Gilead Sciences has also produced a 1% cidofovir gel called Forvade (tm), to test as a topical treatment for acyclovir-resistant herpes lesions, and perhaps also for warts or other viral skin infections. A multicenter study tested Forvade for treatment of acyclovir-resistant herpes, but in May 1997 the FDA found the data insufficient and turned down the drug for marketing. The study results were published in October.1

Forvade--very important for a small number of patients--now faces an unclear future. It would be difficult to enroll another trial today, since improved antiretroviral therapy has greatly reduced the number of opportunistic infections, including cases of drug-resistant herpes.

The published study tested Forvade, vs. a weaker formulation (0.3% gel), vs. placebo, in 30 patients treated once a day for 5 days. Half of those who received drug had either complete healing or a partial response; none of those on placebo did. Herpes virus shedding stopped in 87% of those receiving treatment, vs. none of those on placebo. All measurements used--lesion healing, viral cultures, and pain relief--were consistent, and statistically significant compared to placebo. Side effects were minor, and no drug (or almost none, in patients who had the largest lesions) was absorbed into the circulation.

We interviewed Jay Lalezari, M.D., who has an HIV practice in San Francisco and is director of Quest Clinical Research. Dr. Lalezari is one of the most experienced physicians in the country in treating acyclovir-resistant herpes.

AIDS Treatment News: Why is Forvade (cidofovir gel) important?

Dr. Lalezari: This was a double-blind randomized placebo-controlled study, and all of the measured efficacy parameters including healing, pain relief, and virologic outcome point to a clear, consistent, and statistically significant benefit of this drug.

In my experience, these lesions are among the most painful, disabling, and difficult to treat complications of AIDS. For such patients the pressing issue is pain relief, and the clear benefit in this trial has been one of my most gratifying experiences in AIDS research. Although the infection has become less common, cases continue to occur, and treatment options are urgently needed.

What is surprising is how much benefit we saw with only five days of once-daily topical therapy. Cidofovir is one of the most potent antiviral drugs that has ever been developed. Its long tissue half life may also help explain why it worked as well as it did.

And there was no down side. The drug is not absorbed into the circulation, and therefore there was no systemic toxicity. There have been reports about local toxicity using a higher concentration of the gel, 3%, in treatment of warts; it has been associated with some local ulcerations. But we did not see any in this study.

ATN: What happens now?

Dr. Lalezari: Gilead is working with the FDA to determine what additional studies it wants. But the bottom line is that this condition is so infrequent that it would be extremely difficult to accrue a new study.

It took us two years to enroll 33 patients in the original study--in the era before protease inhibitors, so there was still a small but significant number of patients who had acyclovir-resistant herpes who were desperate for treatment. Therefore it was possible to enroll the study; we enrolled half the patients in this office. But to do that now would be extremely difficult--not because there are no patients, but because they are very spread out.

So I think that if the FDA insists on additional studies, it effectively kills the development of this drug. What is not clear is what are the politics behind that decision, at the FDA and in turn at Gilead.

Fortunately, Gilead has said that it will continue its compassionate use program. But no company can do that indefinitely if the drug is not being developed.

This is not a make-or-break issue for thousands of patients, but there are probably at any given time in this country ten to 50 patients with this problem.

ATN: There was a dose response in viral culture negativity, but the high dose was not better than the low dose in lesion healing or pain relief. Do you know why?

Dr. Lalezari: It appears that patients in the low-dose group took more pain medications, which tended to mask the pain response.

Tissue healing is very complex. It involves many factors, including nutritional status--not just eradicating the virus. What is important is that there was clinically significant tissue healing (50 percent or better reduction in lesion size), in half of the treated patients, vs. none of those on placebo. And there were more patients on the high-dose group who had complete lesion healing.

The results we saw were statistically significant, and were clinically meaningful, in a disease for which there are very few other treatment options.

ATN: Could the IV formulation (VISTIDE) be used topically?

Dr. Lalezari: I doubt it. You need something to keep the drug on the lesion, to allow for gradual absorption. If you just pour on the IV fluid, it runs off.

ATN: Why do you think the FDA denied permission to market the drug?

Dr. Lalezari: I do not know. There was just one study with a fairly small number of patients. But this is a very benign treatment intervention, with positive, believable results, in patients who have very limited options.

It took us two years to find all those patients. I cannot imagine having done a study much bigger. And the size should not matter as long as the results were statistically significant.

There may also be concern about the adequacy of the photographs. We took photographs of geographically complex lesions, and did the best we could. There are different focal planes, so not all the lesions are clear in all the photos.

Even if the photographs were not adequate, the virology data is clear and objective. And there is no way to argue with the fact that there was clinically significant resolution of the lesions, and reduction in pain.

These patients have advanced disease, and do not generally have a long life expectancy. All that really mattered was improving their quality of life, by eliminating the herpes virus, and reducing pain and lesion size. It made their quality of life significantly better.

I do not know what the politics are between Gilead and the FDA.

The other possible concern is potential carcinogenicity; a study in rats found an increase in mammary tumors associated with subcutaneous administration of cidofovir. This did not prevent approval of the injected drug, but if the gel were approved for acyclovir-resistant herpes, there may be concern at the FDA that it might be used much more broadly. People might start choosing it instead of acyclovir to treat less serious herpes, and the FDA may have concerns about possible long-term risk.

Drug-resistant herpes in advanced AIDS is a miserable disease. For these people, going to the bathroom can be excruciating. This drug works in drying up the lesions; in some cases there was complete healing. You do not see that in the natural history of this disease, or in the placebo group. So the drug works. And since there was no down side, I cannot imagine why it would not be approved.

It is a shame that the needs of these patients are not being given appropriate consideration.

References

1. Lalezari J, Schackter T, Feinberg J. and others. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. The Journal of Infectious Diseases. October 1997; number 176, pages 892-898.