AZT, ddI, and ddC Combinations at FDA Advisory Hearing

The February 28 meeting of the FDA Antiviral Drugs Advisory Committee asked whether the recently-available results of four major clinical trials should change the standard use of AZT (Retrovir(R), zidovudine), ddI (VIDEX(R), didanosine), and ddC (HIVID(R), zalcitabine) -- especially combination use of these antiretrovirals. Specifically, the FDA asked:

"(1) Do the results of ACTG Study 175 and the other studies [the Delta trials, CPCRA 007, and ACTG Study 152 -- which tested various treatment approaches with AZT, ddI, and sometimes ddC] support the safety and efficacy of didanosine as initial therapy in persons with no prior history of antiretroviral use? [Note: The current FDA-approved prescribing information for didanosine (ddI) recommends that AZT be tried first.]

"(2) Do the results of these studies provide evidence that didanosine in combination with zidovudine is clinically more effective than didanosine monotherapy? In your discussion, please include comments on treatment of persons with and without a prior history of antiretroviral use.

"(3) Do the results of ACTG Study 175 and other studies support a traditional approval of HIVID (ddC) in combination with Retrovir [AZT]." [Note: ddC is currently approved for combination use with AZT, under the FDA's accelerated approval regulations. This means that the combination has demonstrated benefit through markers of HIV disease progression such as viral load or CD4 count, but the developer, Hoffmann-La Roche, was expected to do further clinical trials to demonstrate direct clinical benefit to patients, such as increased survival or reduced incidence of opportunistic infections. The FDA asked the advisory committee to discuss and vote on whether newly available clinical-trial results have sufficiently demonstrated clinical benefit.]

These questions led to long and complicated discussions. Two analyses, one of the survival data from ACTG 175, the Delta trials, and CPCRA 007, and another based on an overview of seven studies of ddI and AZT, compiled by Jim Neaton, Ph.D., of the University of Minnesota, and others, suggested that:

* Overall both AZT+ddI and AZT+ddC were better than AZT alone in reducing the risk of death. In each of the four combination nucleoside studies considered, the reduction in risk of death (compared to AZT monotherapy) was greater with AZT+ddI than with AZT+ddC.

* The effects of ddI and AZT on survival were similar both overall and in patients who were antiretroviral naive. This analysis included ACTG 175 but did not include ACTG 152, which was presented for the first time the same day. (ACTG 152 is a pediatric trial in which children on AZT alone did worse than those on at least one of the other treatments, resulting in early closure of the AZT monotherapy arm of the trial.)

* There are not enough data to know whether or not AZT+ddI is more effective than ddI alone in reducing risk of disease progression and death.

On the FDA's questions:

* The Committee voted unanimously Yes on #1, indicating that ddI should be approved for initial treatment of HIV disease.

* The Committee voted No on #2 (meaning that there is no proof that ddI+AZT is better than ddI alone). But the Committee was uncomfortable with this vote, fearing that many patients would be denied combination treatment when it is generally believed that combination treatment is best and has become the standard of care. It also seemed "bizarre" to fail to recommend approval of AZT+ddI, when the Committee was clearly prepared to recommend approval of AZT+ddC, and when many believe that AZT+ddI is at least as good as AZT+ddC.

* On question #3, the Committee unanimously voted to recommend approval of AZT+ddC for antiretroviral-naive persons, and unanimously voted against approval for antiretroviral-experienced persons.

[Note: In support of ddI, Bristol-Myers Squibb pointed out in a February press release that it is less expensive than AZT or other antiretrovirals, and will soon be available in a new tablet which is easier for patients to use than the formulation available until now in the U.S.]

Comment

The discussion above needs to be kept in perspective. Today it is widely believed that 3TC is better than either ddI or ddC for use in combination with AZT. But there is no clinical-endpoint data on this combination yet -- only viral load and CD4 counts -- which is why 3TC was not considered at the February 28 hearing.

Also, all of the discussion outlined above dealt with averages, when really there is no such thing as the average patient. Averages may suggest which treatment to try first, when there is no better way to guess. But if viral load tests or other indications suggest that a treatment is not working well for an individual, other treatments can quickly be tried instead.

[Note: AIDS TREATMENT NEWS did not attend the February 28 hearing, and acknowledges the assistance with this article from Mark Mascolini and from Dr. Jim Neaton.]