AIDS TREATMENT NEWS Issue #166, January 1, 1993
Larry Tate

It is rarely possible to say exactly when data from specific trials will be made public; the timelines mentioned below can only be approximate.

The first key development in 1993 will be the long-awaited release of data from ACTG 116A, a study comparing AZT to ddI in people with fewer than four months' prior AZT use. This amounts to comparing the two drugs as first-line therapy -- and suggesting which drug patients starting anti-HIV therapy should use. By mid-January, it should be known whether ddI in this circumstance is more effective, less effective, or about the same as AZT. The study group had T-helper counts under 300, but the results might well apply to people starting treatment at all T-helper levels.

AZT has so far been the standard first-line therapy; should this study prove it to be less effective than ddI, there would be a major reassessment of how these drugs are used, affecting not only clinical practice but probably some ongoing trials as well. If the two drugs show equivalent efficacy, or if AZT is more effective than ddI, the current standard of care may not be much altered.

Also long-awaited are the results of ACTG 019, a large and very long-running trial that compared AZT to placebo in people who started with a wide range of T-helper counts -- about half of them over 500. Data on the group who started with counts over 500 should provide the clearest answer from any U.S. study on the value of AZT (and, by implication, other nucleosides) in people in early stages of infection. If AZT delays disease progression in this group, there could for the first time be an FDA-approved therapy for people with T- helper counts over 500. Data from ACTG 019 may be available as early as February, or if not, by mid-year.

The comparable and equally long-running Concorde study in Europe also looks at AZT versus placebo in people starting with a wide range of T-helper counts. Data from the Concorde study also may be available early in the year, or by mid- year.

By late spring, final data is expected from ACTG 155, a study which compared AZT to a combination of AZT and ddC in people with fewer than 200 T-helper cells. The FDA, on the basis of two smaller studies, approved ddC for combination use with AZT, but the data from ACTG 155 will be critical in confirming the value of combination therapy. If the results show an advantage for the combination, the current label indications for AZT/ddC use (which are widely considered to be somewhat tentative and confusing) may be clarified and strengthened by the FDA.

At the 1992 International AIDS Conference, three small studies reported interim data on combinations of AZT and ddI. All three have been completed or are near completion, and are likely to publish final data in the first half of the year. These studies used different doses and entry criteria and monotherapy control groups, making it difficult to compare results; however, should final data indicate an across-the- board advantage for combining AZT and ddI, there would then be at least as much data on the AZT/ddI combination as there was on the AZT/ddC combination when the FDA approved ddC. A change in clinical practice and in FDA indications might result.

(It should be noted that ACTG 175, the large trial comparing combinations of AZT/ddI and AZT/ddC to AZT and ddI as single agents, is not expected to make public any results in 1993.)

The ongoing d4T trials are not expected to announce any results this year. At least one pilot study combining d4T with ddI is planned; others may follow.

Only one nucleoside in early trials appears to be moving smoothly toward wider use. 3TC is now in late dose-ranging studies, and is expected to start large Phase II comparative studies in the spring (similar in some ways to the d4T trials now in progress). Sources have told us that this drug has so far shown clear anti-HIV activity and no serious side effects. It could be speculated that, when these Phase II trials start, there might also be a role for a 3TC expanded- access program, but it is too soon to know.

Finally, two studies comparing the combination of AZT and ddC to a three-drug combination of AZT, ddC, and alpha interferon will be continuing through the year. Late in the year, some interim data might be available from the larger of these studies, looking at people with T-helper counts between 300 and 500. Obviously, there are a number of possibilities for studies of various three-drug combinations, and results from this trial could stimulate that research.

Comment

Nucleoside analogs are often discounted by people who argue, incontestably, that there are stringent limits to what these drugs can do and that their various side effects often cause great problems to patients. Nucleosides have always been regarded as a stopgap until better treatments arrive.

That may be true, but there is a fairly clear understanding of how they work and how their side effects can sometimes be managed; three are FDA-approved and two more may be on the way to approval; and they are backed by big drug companies with the resources to develop them quickly. Although nucleosides are of limited efficacy, those limits may not turn out to be so stringent as was once thought, if up to five drugs come to be used serially and in combinations. Therefore, any new availability of nucleosides or new information on how to use them is important.

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