AIDS Treatment News #159, September 18, 1992
John S. James

* A "parallel track" trial, run by d4T developer Bristol-Myers Squibb, will soon make this drug available to persons who have failed both AZT and ddI, and therefore have no approved HIV treatment options; and

* Results of early trials, as well as the impressions of researchers and others who have worked with d4T, suggest that this drug might be somewhat better than either AZT or ddI as a single agent. If so, d4T could be a modest but important improvement in AIDS/HIV treatment. But the benefits are limited, as the drug does not totally stop disease progression. Like AZT, ddI, and ddC it can only prevent infection of new cells, but cannot reduce viral activity in chronically infected cells.

[Comment: d4T would be less important today if any truly good AIDS treatment were on the near horizon. Where we are now in HIV treatment can be illustrated by comparison with the history of other diseases. For example, it has recently been noted that treatment of the opportunistic infection MAC is where treatment of tuberculosis was several decades ago -- in that one good drug had been discovered (clarithromycin for MAC, streptomycin for TB), although clearly other drugs would be needed too. Today we are not yet at that stage in treating HIV, as we only have poor to mediocre drugs: AZT, ddI, ddC, and now (an anticipated improvement, but still in the mediocre-at-best category) d4T.

We suspect that the most likely source of a good drug today would be protease or tat inhibitors. But these are moving slowly -- mainly, it seems, because of technical difficulties in the former case, and corporate politics in the latter.]

Until better drugs are developed, the available improvements in second-rate technology (in this case, blocking of reverse transcriptase, which will not work for chronically infected cells) will be important. For this reason we have prepared an overview of d4T itself, the ongoing phase II/III trial, and the parallel-track program which is expected to begin soon.

d4T

d4T is a close chemical relative of AZT, but it does not have the azido group (three nitrogen atoms) in the molecule. In test-tube studies with AZT, and in animal studies with other retroviruses, d4T often worked less well than AZT.

But d4T may make up for this disadvantage by being processed more efficiently in human cells. Both drugs enter the cell unchanged, but are not active against HIV until they are chemically converted to a triphosphate form (with three phosphate groups added to the molecule) by enzymes within some (not all) cells. A major problem with AZT is that it tends to accumulate in the monophosphate form (with only one phosphate group attached, instead of three); in this form it is ineffective and may be harmful. d4T is converted much better to the triphosphate.

d4T has very good oral bioavailability; and unlike ddI, it does not need a buffer to protect it from stomach acidity. Like AZT, it partially crosses the blood-brain barrier. And HIV strains which have become resistant to AZT are often still susceptible to d4T -- potentially an important advantage of the latter drug.

d4T has been given to over 250 patients in early trials (not counting the almost 400 patients already enrolled in a large phase II/III trial now ongoing, who have been randomized to receive either d4T or AZT). The most important findings are:

* T-helper cell increases last longer with d4T than with AZT, often lasting for more than a year before returning to baseline. (The size of the increase is probably larger, too, but we do not have exact comparisons.)

* d4T also shows antiviral activity in humans by reducing p24 antigen.

* The main side effect is peripheral neuropathy, similar to that caused by ddI or ddC. Some patients have had elevated liver-function tests. These toxicities happened most often at higher doses than are currently being used. We have not heard of any case of pancreatitis caused by d4T.

* The maximum tolerated dose of d4T for long-term use is about 4.0 milligrams per kilogram of body weight per day; above this level, toxicities are unacceptable. The dose which will be used when the drug is approved is still not determined, but it will probably be not far from 1.0 mg/kg, four times lower than what can be tolerated -- probably no less than 0.5 and no more than more than 2.0. (A much lower dose, 0.1 mg/kg/day, has been tested and found to be too low.)

* There is not enough data yet to know whether d4T will work better than AZT or ddI in preventing AIDS progression or death. (This is what the phase II/III trial should determine.)

* d4T has not yet been tested in combination with other antiretrovirals in clinical trials. But experts suspect that a combination with AZT will probably not work, because AZT would prevent d4T from being effective; using the drugs in alternation might be OK. On the other hand, the combination of d4T and ddI looks good in laboratory tests; see V. Brankovan and others, "Strong synergistic anti-HIV activity of a purine and a pyrimidine nucleoside analog, ddI and d4T," V International Conference on AIDS, Montreal, June 4-9, 1989 [abstract # M. CP. 128]. This study found that the 50 percent effective concentrations were 5 and 32 uM respectively for d4T and ddI, but only 0.2 uM for the combination; in addition, the toxicity was not synergistic in this laboratory study. But in people, both drugs can cause peripheral neuropathy; therefore it would be risky to try them together, except in a carefully monitored scientific study.

* "Underground" d4T was available recently, but then the supply dried up, apparently because of disputes among people involved, not because of government interference. We heard good reports about this d4T, which was used by people without other treatment options. However, underground d4T is unlikely to be important in the future, because the drug is expensive to manufacture in small quantities, and the parallel track will soon make it available without charge to those who need it most. And when d4T is approved it will be available to anyone, probably for no more than the underground drug would cost, eliminating the market for an underground version, which no one would use if they could get the pharmaceutical drug instead.

* d4T is quite stable, and most of it is excreted unchanged in the urine. When cost or supply is critical, it might be possible to recycle the drug and provide treatment at a fraction of the price otherwise required.

Phase II/III Ongoing Clinical Trial

A large multicenter trial comparing d4T to AZT is now recruiting throughout the United States and in Europe. Volunteers must have T-helper counts between 50 and 500 and have received AZT for at least six months and currently be tolerating at least 500 mg of AZT daily; they must not have used d4T, ddI, or ddC at any time. There are also a number of other medical and laboratory criteria for entry into this study.

This trial has now enrolled about 400 volunteers; it is seeking a total of 700. It has 45 U. S. sites in the following cities (list is alphabetical by state and by city within state): Tucson, Berkeley, Los Angeles, Sacramento, San Francisco, Torrance, Denver, Washington D. C., Ft. Lauderdale, Miami, South Miami, Tampa, Atlanta, Chicago, Indianapolis, Kansas City, Wichita, Boston, Baltimore, Charlotte, Durham, Omaha, Albuquerque, Bronx, New York, Stony Brook, Philadelphia, Pittsburgh, San Juan (Puerto Rico), Charleston, Dallas, Houston, San Antonio, Salt Lake City, and Milwaukee.

For information about this trial, including locations and phone numbers of sites in your area, call the AIDS Clinical Trials Information Service, 800/TRIALS-A.

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