AEGiS-GMHC: Making Sense of 175 and Delta

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Making Sense of 175 and Delta

GMHC Treatment Issues, 9(10) - October 1995
Theo Smart

Some activists and researchers have heralded the findings of ACTG 175 and Delta as "the most important trial results ever." Much time already has been spent pouring over the studies' statistics, comparing populations, and drop-out rates in a valiant attempt to understand what these studies mean. What it all boils down to is that AZT monotherapy is not the best treatment available, whether as initial therapy or in the drug-experienced. This finding does not impress some. "Treating clinicians have known this for years," said Stacy Kreiswirth, a nurse practitioner from New York attending ICAAC, "show me something that will help my patients."

It is hard indeed to get excited about ddI and ddC, drugs that have been around for so long and that clearly do so little, as evidenced by Delta II, in which more than a quarter of the participants had died by the end of the two- year study, regardless of the treatment received. These studies' findings do little to expand people's treatment options.

Some of these studies' findings are counter-intuitive. Why didn't AZT/ddI fare better in delaying disease progression or death than ddI alone? In the experienced population this may have been due to AZT resistance, but in the naive population, one would expect to have seen at least a trend in favor of the combinations AZT/ddI and AZT/ddC. Both did have a more pronounced effect on viral load than ddI in these patients, as reported by Daniel Kuritzkes, M.D. (ICAAC abstract LB-02), but in the experienced patients AZT/ddC performed substantially worse clinically than ddI. ACTG 175 appears to call into question the clinical utility of viral load tests.

Delta II, which is still continuing, found no difference between combination and monotherapy in antiretroviral experienced people, and so contradicts the findings of ACTG 175. The participants in Delta II were at a much later stage of disease, though, so comparisons are difficult. There also could have been more resistance to AZT, which could decrease the benefit received from treatment with ddI or ddC (see page 14).

The findings of these studies may become quickly irrelevant because of new and more potent drugs being added to the therapeutic arsenal. Where will d4T or 3TC fit into the picture? Certainly, AZT/3TC is a much more potent combination, although we have little clinical information. Glaxo-Welcome has requested approval for AZT/3TC as first- line treatment. Meanwhile, test tube data suggests that virus resistant to 3TC is less susceptible to ddI and ddC. How should this effect treatment decisions? Also, clinical data on the protease inhibitors will soon become available. Treatment options are increasing, but when to employ which regimen is affected by such issues as cross-resistance, synergy and toxicity. Without the clinical data, it is impossible to know which variable is more important in making treatment decisions.

Finally, neither study provides information about the optimal time to start therapy or when to switch regimens, and there are no studies currently underway that will answer these questions soon. ACTG 175 and Delta did yield some precious, though somewhat contradictory data on clinical benefit. How to apply the lessons learned beyond the particular populations and regimens under study remains a mystery.

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