Gay Men's Health Crisis "Treatment Issues", Vol. 8, No. 5 - July 1994
Derek Link and Dave Gilden

Consideration of d4T took place under the FDA's "accelerated approval" recommendations for life-threatening conditions with no established treatment. Supporting the d4T application for marketing approval were data from studies on people who had already received AZT for long periods of time or were failing on that or other antiviral drugs. The point was to show that switching to d4T resulted in immediate increases in CD4 cells and a lowering of HIV levels in the blood. The clinical information needed to determine whether people remained healthier or alive longer on d4T is still nonexistent.

Two important studies were presented: AI455-019, the main clinical trial, which compared d4T to AZT in people who had used AZT for at least six months (as it turned out, the average was over 18 months of prior AZT); and the parallel track protocol that distributed d4T through community physicians to patients failing on or intolerant to the already approved anti-HIV drugs.

d4T produced an average CD4 count boost of approximately twenty cells among participants in AI455-019, and the average count fell back to baseline by 24 weeks. Through week 80, the end of the time period presented, average CD4 count in the d4T group remained about 40 cells higher than the control group that stayed on AZT. Whether CD4 spikes of this magnitude and duration have any lasting influence on people's health is doubtful, though.

The other large d4T study (the parallel track) failed to find a difference in survival or CD4 cell response between the two doses (20 and 40 mg twice daily). Such a dose-related difference might be expected with an active therapeutic agent.

The other main component of the data concerned d4T's antiviral activity. Although antiviral activity is no proof that a drug improves health, an anti-HIV medication would be expected to reduce HIV levels if it does any good at all.

d4T use led to an initial dramatic drop in the most widely used measure of HIV activity, p24 antigen. But p24 levels were at baseline by week 24 again, and in the end the difference between the d4T and AZT groups was not statistically significant.

At least switching to d4T reduced drug-related side effects in the AI455-019 trial: People who started on d4T saw their red and total white blood cell counts improve as the bone marrow suppression that is a common side effect of AZT disappeared. But the rate of serious neuropathy (numbing or painful nerve damage), about fifteen percent after one year, was higher than for the group kept on AZT. In sum, d4T performed remarkably like ddI when taken as a successor to AZT - minus the incidents of life-threatening pancreatitis, but more neuropathy.

After nine grueling hours, the advisory committee gave d4T a very limited endorsement. The committee voted yes to the following two questions: 1) Is there a medical need for new HIV therapies? 2) Are the surrogate responses [laboratory data] in the application "reasonably likely" to predict clinical benefit? Panel members were unable to decide which patients should take d4T, how it can be safely used and what additional studies ought to be conducted with the drug. They left these issues to the FDA staff, which will have the final say on whether d4T can go on the market.

The d4T saga is extremely disappointing in that initial safety studies indicated that at high doses (greater than four times the present maximum dose) the drug seemed more effective than other available nucleoside analogs, according to the data submitted by Bristol-Myers to the FDA. These improvements in laboratory values were sustained for at least a year without starting to slip. But two- thirds and more of the people taking these high doses eventually suffered from neuropathy, which is itself disabling.

Nonetheless, the early d4T data is tempting. Further research on the cause of drug-induced neuropathy could lead to conjunctive therapies that ameliorate neuropathy. It could also suggest ways to avoid the problem entirely by modifying the structure of d4T and similar molecules. It might be possible to reduce neuropathy without interfering with the drug's potential efficacy.

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