FDA Antiviral Hearings: Community Perspectives

Dave Gilden, Gay Men's Health Crisis:

[Since we did could not attend the FDA's Antiviral Drugs Advisory Committee hearings, we asked people who did attend to comment on drafts of our report. Dave Gilden, editor of TREATMENT ISSUES, sent us the following, which we found insightful and important enough to quote in full, with his permission.]

Gilden: "My sense about the FDA is that the people there have become convinced that a four drug combination will be highly effective in suppressing HIV. Researchers like David Ho are arguing that three drugs will provide long-term viral suppression but that you need four drugs to insure that there is no pre-treatment mutant HIV able to resist the entire drug combination -- or to prevent eventual emergence of such virus.

"The FDA is therefore determined to push the necessary drugs through the approval process, whether the data on each one is complete or not. The other issue affecting the FDA deliberations is the FDA reform movement in Congress, which the FDA is countering in part by showing how decisively it can act when the situation calls for rapid drug approvals.

"Therefore, I watched the spectacle of ritonavir getting the kid glove treatment from FDA reviewers, and David Kessler pushing for full approval, while I saw Serono and human growth hormone get positively torn apart the next day. We can expect easy treatment for nevirapine and delavirdine too, even though the available data on these drugs' benefits is weak indeed. These two non-nucleoside reverse transcriptase inhibitors will then be the fourth drugs in the four-drug regimens, along with one or two nucleoside analogs [e.g., AZT plus 3TC, or ddI] and one or two protease inhibitors. Viral load testing, central to optimizing and periodically adjusting the four-drug regimens in each person, now seem to be on the FDA fast track, too. (The Hoffmann-La Roche PCR test will be considered by the Blood Products Advisory Committee on March 21.)

"Speaking of using two protease inhibitors, the upcoming ritonavir/saquinavir trial assumes tremendous importance in this four-drug scenario. I would put more money on using two protease inhibitors, especially if there is little cross-resistance, than adding a non-nucleoside reverse transcriptase inhibitor. Saquinavir is extremely potent in laboratory tests, and ritonavir may rescue its disappointing performance in the body. [Caution -- these drugs will require extreme dose adjustment when combined, and *must not* be used together until safe doses are known. Near-fatal side effects have occurred from combining protease inhibitors inappropriately. JSJ]

"In the meantime, the most treatment-savvy PWA I know is arguing that Merck's indinavir looks better than ritonavir, from the available data, and that we should not be swayed by ritonavir's full approval for advanced disease. He is not alone in this opinion. The arguments favoring indinavir are: better safety (though neither compound has much long-term data), better patient compliance with the recommended regimen (important to avoid breakthrough drug-resistant HIV), fewer evident drug-drug interactions, better CNS (central nervous system) penetration, data indicating activity in lymph nodes, and indications of greater durability of antiviral response (at least as monotherapy). Abbott also has a much worse record of working with the community, and the chances are weak of the company now trying to fill the tremendous gaps in our knowledge of how to use protease inhibitors. In particular, we need to know how well the individual brands work over the long run, when best to start protease
inhibitors (which is highl
y influenced by the durability of response issue), and what to follow these compounds with should they start to fail."

[TREATMENT ISSUES, "the Gay Men's Health Crisis newsletter of experimental AIDS therapies," is published monthly; annual subscriptions are available for a suggested contribution of $35 for individuals, $70 for physicians, institutions, or international subscriptions; a full set of back issues is available for $25. Make checks payable to GMHC, and mail to: GMHC, Treatment Education, 129 West 20th Street, 2nd floor, New York, NY 10011.]

Martin Delaney, Project Inform:

[The following are from a February 29 press release by Project Inform, supporting accelerated approval of ritonavir, but expressing caution about how the drug should be used.]

Delaney: "While this [improved survival] outcome is significant, it overlooks two other important facts from the study. It is our understanding that the majority of the deaths reported in this data occurred within the first six weeks of treatment, raising questions as to whether the outcome reflects the true longer-term effect of the drug. More importantly, we are very concerned that the data shows a rapid loss of antiviral activity, probably due to the development of drug resistance, within six months when used in this fashion. Since resistance to this drug confers resistance to most other protease inhibitors, there is good reason to fear that such a use of the drug may lead only to short-term benefit followed quickly by long-term multi-drug cross resistance to many of the key products in the field of protease inhibitors. There is evidence that the drug can work far better when used properly; giving too much weight to this data may promote use of the drug in this suboptimal fashion."

"We think it is critical that Abbott make clear to physicians and patients that great care should be employed in how these drugs are used. Simply adding them without thought to existing therapy is unlikely to produce a lasting benefit, while running a large risk of creating multi-drug cross resistant strains of virus."

A position paper available through the Project Inform hotline (800/822-7422, 10 a.m. to 4 p.m. Pacific time Monday through Saturday) describes these concerns in greater detail, and provides guidelines for the optimal use of protease inhibitors, based on what is known today. It will be published in the April 1996 issue of PI PERSPECTIVE.