d4T Plus ddI Antiviral Results

A combination of two approved drugs showed encouraging viral suppression results in a one-year clinical trial [3rd Conference on Retroviruses and Opportunistic Infections, abstract #197]. The results are preliminary, however, as the trial is still continuing; it will not end until October 1996. Also, this trial was primarily designed to test the safety of the combination regimen, not to see how well it worked.

A total of 92 volunteers have entered the trial and were randomly assigned to one of five different dose combinations; the lowest-dose group received half the standard dose of ddI and a quarter the standard dose of d4T, while the highest-dose group combined the full dose of both drugs. Note that everyone received some of each drug. Also, since the trial is ongoing the dose assignments are still blinded, so dose-response information on antiviral activity is not yet available.

The volunteers had CD4 counts between 200 and 500, and no previous HIV therapy; note that these are persons who are more likely to show a strong response to treatment than those who were more advanced, or had extensive prior antiretroviral treatment.

Most of the volunteers had a viral load of at least 1000 at baseline; they were selected for a study of viral load changes. (Those with a very low viral load at the beginning were not included, since they could not show much of an antiviral effect even if it were there, as the viral load tests could not have recorded much decrease). Preliminary data from the ongoing study showed a median viral load decrease of about 1.2 logs (16 fold), and a median CD4 increase of about 60 to 80; these increases appear to be sustained for at least a year, but it is not possible to be sure yet, as only 14 patients in the viral-load substudy have completed the full year.

Six of the volunteers discontinued the trial due to adverse events which might have been caused by the drug; however, these events did not seem to be dose related. [The eight events which led to drug discontinuation in six people were grade 2-4 lipase elevation (3 cases), abdominal pain (2 cases), and one case each of grade 4 liver transaminase elevation, grade 3 neutropenia, and grade 3 depression.] Only one volunteer had to interrupt therapy due to peripheral neuropathy, and he was able to go back on treatment at a lower dose.

The next report from this study is likely to be at the Vancouver conference in July -- although the trial will still not be finished by then.

Note: A separate, laboratory study reported at the Retroviruses conference compared the antiviral activity of the d4T plus ddI combination with that of the two drugs individually (abstract 294). The combination showed additive antiviral effects in one test (meaning that the combination worked as well as would be expected by adding the activities of the separate drugs), and synergistic (better than additive) activity in another test, depending on the cells and viruses used.

Comment

One of the most critical research tasks now is to learn which combinations of drug tend to work well together. Small trials like this, with about ten to 20 volunteers per arm and measuring viral load for at least six months, may be the most feasible way to test combinations which have some clinical, laboratory, or theoretical rationale. The main challenge will be getting different pharmaceutical companies to work together; that was not a problem with d4T plus ddI, since both are marketed by the same company, Bristol-Myers Squibb, which funded this clinical trial.

This trial focused on the safety of the drug combination; its design is less than ideal for looking at drug activity. For example, only one viral load baseline measurement was used; and there were provisions for replacing volunteers in the study arms, instead of analyzing everyone assigned to treatment and/or everyone treated. There is a need to develop realistic consensus guidelines for small drug-activity trials -- based on the realization that physicians will use the results in making treatment decisions, and that with the great number of potential combination treatments available today, "definitive" phase III trials for most of them will never be run.