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Being Alive

Still Looking For A Good Antiviral Drug: Treatment Options Expand (Slightly)




 

Being Alive 1992 May 5: 1

The last month has brought news of continuing, gradual expansion of the drug arsenal for treatment and prophylaxis against opportunistic infections. There is, for example, the availability of Rifabutin as prophylaxis against MAC while the FDA considers the manufacturer's application for formal approval. Some long-awaited anti-HIV drugs of a new type, most notably the tat and protease inhibitors, are moving more rapidly around the test track, but there is no evidence yet that these drugs will work as hoped.

The big news, though, concerns old drugs -- the nucleoside-analog reverse transcriptase inhibitors (a mouthful), chiefly AZT, ddI, and ddC. Though these controversial drugs are severely limited treatments at best, many thousands rely upon them as the best antiviral therapy available for now. The expansion of availability and treatment-guiding information reported this month, however modest, is welcome.

DDC APPROVAL RECOMMENDED BY FDA PANEL On April 21, the FDA's Antiviral Advisory Committee voted 8 to 3 to recommend licensing of ddC for use in combination therapy with AZT. FDA Commissioner David Kessler is not required to honor the committee's recommendation, but he usually does, and has given indications that he will do so in this case. It is likely that Hoffman-LaRoche, Inc. will be given a license to market ddC -- for combination use only -- within the next few weeks.

The wording of the prescribing information, important in obtaining insurance coverage for use of the drug, is an important detail to be worked out, as is the selling price. Hoffman-LaRoche is under pressure on the price because of the experience of underground suppliers who discovered that the drug is relatively simple and inexpensive to make.

The advisory committee's positive vote relied heavily on preliminary results from a study by Dr. Robert Schooley of the University of Colorado who showed that the ddC/AZT combination raised T-cell counts about twice as high as did AZT alone. The committee thus relied once again, as it did last year in recommending licensure of ddI, on changes in "surrogate markers" (in this case, T-cell counts) rather than the FDA's traditional requirement of demonstrated effect on clinical outcomes such as survival or development of AIDS-defining infections or tumors.

The ddC application is the first under new procedures promulgated by Commissioner Kessler to expedite approval of new drugs for life-threatening illnesses. The new guidelines allow rapid, unconditional approval for drugs which demonstrate efficacy via accepted surrogate markers. The rules also require studies of effectiveness be continued and provide for the withdrawal of licensure if clinical benefit is not confirmed or unacceptably serious or frequent toxicities occur.

So far, so good. The approval recommendation is a victory for activists who have campaigned hard for early approval of this drug and of combination therapy. We have argued for approval so as to provide compassionate options for people for whom AZT or ddI or one-drug therapy does not work. Community use of ddC and combination therapy is widespread. Approval helps make this use financially sustainable and extends the opportunity to many more.

It was disappointing, therefore, that the Advisory Committee voted earlier the same day, by an 8 to 2 margin with 2 abstentions, NOT to approve ddC for use alone, even for people who cannot tolerate or have become resistant to AZT or ddI. Of course, once ddC is approved a physician can legally prescribe it for anyone, but most insurers (including Medicare and MediCal) limit drug reimbursement to FDA-approved indications.

Opponents cited the negative results from the large trial stopped last December when ddC alone was shown to be significantly inferior to AZT alone in delaying AIDS and prolonging survival. However, the fact that, on average, ddC by itself is not as effective as AZT does NOT contradict the claim that ddC is superior for some individuals and is a much-better-than-nothing second choice for many more who cannot take or benefit from AZT.

For now, we have a limited victory which we hope to expand. And we hope approval will free some of Hoffman-LaRoche's energies for work on its tat inhibitor and other, better drugs.

DDI LOOKS A LITTLE BETTER The spring ACTG (AIDS Clinical Trials Group) meetings in Washington saw release of the first preliminary results of the large clinical trials comparing ddI to AZT. The first data made public came from the sub-trials (ACTG 116-B and 117) involving people who had taken and tolerated AZT previously. Results from the sub-trial for people who had never taken AZT will not be available until later this year.

The preliminary analysis covered 913 participants, randomized to receive either AZT (600 mg a day), higher dose ddI (750 mg a day), or lower dose ddI (500 mg a day). One third of the participants were assigned to each group. The ddI doses were adjusted for baseline weight.

To be enrolled, participants were required to have an AIDS or ARC diagnosis with less than 300 T cells or be asymptomatic and have less than 200 T cells. Everyone must have taken AZT for at least four months with no side effects serious enough to require stopping the drug.

The study population actually enrolled was 96% male, 82% white, 8% African-American, 79% gay or bisexual, with a median age of 36. The median T cell count was 94, with 49% having a count above 100. At entry, 30% had a diagnosis of AIDS, 60% had ARC diagnoses, and 10% were asymptomatic.

The lower-dose ddI group had the fewest number of new "AIDS-defining events." The one-year chance of progressing from ARC to AIDS, or to a new AIDS-defining illness for those who started with AIDS, was 28% in the ddI 500mg/day group vs. 34% in the 750 mg/day ddI group vs 40% in the AZT group. Only the 28% vs. 40% difference between lower-dose ddI and AZT was considered statistically significant. T cell counts, equal among the three groups at the beginning, averaged about 10 cells higher in the two ddI groups than in the AZT group over the first year of the study.

The advantage of ddI in delaying progression was limited to those participants with ARC or asymptomatic disease at entry. There was no significant difference in disease progression between ddI and AZT for those beginning the study with an AIDS diagnosis. Also, no differences in survival were observed between the three study arms.

In terms of toxicities, pancreatitis was more frequently reported with ddI, as expected. The one year cumulative total of reported pancreatitis side effects was 15%, 8%, and 5% for the ddI 750 mg, ddI 500, and AZT groups respectively. Two deaths during the study were attributed to pancreatitis in the ddI 750 mg/day arm. It was also no surprise that hematologic toxicities (anemia and lowered white blood cell counts) were reported more frequently in the AZT arm than in either of the ddI arms.

More surprising was that those taking ddI were no more likely to report peripheral neuropathy than those taking AZT. The overall incidence of moderate to severe neuropathy was fairly high, 15%, but was evenly distributed among all three arms of the study.

Everyone involved cautions that these results are preliminary and need more analysis (plus the results from those who had never taken either drug before and from those taking combination) before any definite conclusions can be drawn about implications for the best treatment option. Some findings raise questions. Was the apparent benefit of ddI due to the switch from one nucleoside analog to another or to an inherent superiority of ddI for at least some people? Why was the benefit limited to those with less advanced disease? Why was there no difference in survival? At the same time, it seems likely that ddI will come out as a stronger alternative or competitor to AZT than many would have believed on the basis of anecdotal reports over the last two years. Other reports, even more fragmentary and preliminary, shared during the ACTG also showed comparative benefits of ddI over AZT for significant groups of people.

Though the Antiviral Advisory Committee, in the same meeting where it considered ddC, refused for now to recommend upgrading ddI's official approval to equal status with AZT as alternative "first line" therapy (it is currently approved for those who cannot tolerate or are resistant to AZT), it will consider doing so if the results from the trials in the "AZT-naive" group are positive for ddI. The FDA was clearly relieved that these clinical results tended to confirm the decision to approve ddI last year made on the basis of surrogate markers only.

Though implications are uncertain until further analyses of these and the other major outstanding data, those taking or considering taking ddI but unsettled by the negative reports on toxicity and effectiveness which have abounded in the last two years, can rest a little easier -- so long as they remember that regular and careful monitoring for early signs of pancreatitis and neuropathy are still critically important.

MACS SURVIVAL DATA SUPPORTS AZT BENEFIT A report in the April 16 issue of the New England Journal of Medicine analyzes survival and mortality data in 2,568 men in the MACS (Multicenter AIDS Cohort Study), comparing those who began taking AZT before receiving an AIDS diagnosis to those who began taking AZT after their AIDS diagnosis. The analysis broke down the total group into subgroups based on stage of illness, determined by T-cell counts and symptoms, at the beginning of each period of follow up.

The MACS has been following a large number of men, including more than 1600 enrolled in Los Angeles, every six months since 1984. Though limited by its overwhelmingly white, well-educated, and exclusively male composition, the cohort has yielded a number of valuable reports on the "natural history" of HIV infection and related disease.

This particular analysis started with visits between October 1986 and March 1987 (about the time AZT became widely available) and compared the survival/mortality experience over the next two years.

The results showed a clear trend toward a lower probability of dying in any given time period in those who had begun AZT treatment before AIDS diagnosis compared to those who began only after such diagnosis. When the results are combined across all levels of disease stage, they are modestly statistically significant and show a 57% lower chance of dying by six months, 46% lower at 12 months, 41% lower at 18 months, and 33% lower over 24 months.

When the results are broken down by starting stage, some are statistically significant and some are not. For instance, there is no survival benefit found among the group that started with more than 350 T-cells. (This could mean that there is in reality no such benefit or it could be that a longer follow-up period is necessary to detect a difference in people starting with more than 350 T-cells.) Regardless of significance, some of the comparisons are of notable magnitude (e.g., 17% of symptomatic persons with 200-350 T-cells died within 18 months if they did not start taking AZT until after an AIDS diagnosis vs. 9% who started taking it before diagnosis) and others only modest in size (among those who started out symptomatic and with less than 200 T-cells, 43.5% of those who started "earlier" had died within 24 months vs. 48% of those who started "later.") The study also analyzed the relative contribution of AZT and PCP prophylaxis to improved survival. It reports, in essence, that AZT is the greater contributor but that PCP prophylaxis reduced the risk of death at 18 or 24 months by about 40% when compared to those who used AZT alone.

The study provides some additional data that earlier as opposed to very late use of AZT improves survival, and not merely AIDS-free time as had been earlier reported. As such, it is being described as contradictory to the findings of the controversial VA study announced earlier this year to the effect that earlier initiation of AZT therapy was associated with longer AIDS-free time but conferred no advantage in survival.

There are two major problems in interpreting the MACS study. It was observational, rather than a clinical trial. Clinical trials involving randomization tend to balance all the factors which may determine outcome across the various treatment groups. Observational studies have the advantage of perhaps more closely approximating real experience in the community but may involve "selection bias." The group that started AZT before diagnosis may be different in other important ways from the group that started later. Perhaps this group included a higher proportion of people receiving topnotch medical care in general, or more people proactive toward their infection in many health-promoting ways. In fact, when these results were reported in preliminary form last June at the International AIDS Conference, a MACS participant in the audience eloquently pointed out that he and many of his friends were included in the "early AZT" group whereas they also did many other things to fight HIV and preserve health that the MACS had never asked them about.

Secondly, the study addresses a question that is not particularly relevant any more: is it better to start AZT before an AIDS diagnosis than after? Few would disagree that, assuming one believes AZT may be useful, one should start it well before a diagnosis of full blown AIDS. The real question is: how long before? When is the optimal time to start nucleoside analog antiviral therapy? About this question there is much disagreement and the current study doesn't help much.

Nevertheless, all such studies which honestly look at the benefits and risks of long term use of AZT, ddI, and ddC and similar drugs contribute to the information base available to HIV+ people and their care providers. We fervently hope, though, that soon these problematic drugs will be superseded by better ones. Many of us think that a good portion of the money still going into the study of these drugs could more profitably be shifted in more adventuresome and creative directions.

If NIH cut back ongoing studies of AZT/ddI/ddC by half, they would have millions more for studies of promising immune system modulation and restoration strategies as well as newer antiviral drugs. They could (and should in any event) gear up the apparatus for a large simple trial so that the tat inhibitor (and future hot prospects)--assuming results from this summer's trials are promising--could be immediately tested in large numbers of people representing all affected populations, leading to approval if indicated within 18 months.



 




Information in this article was accurate in May 5, 1992. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.