Being Alive; June 1997

The drug, known as anti-retroviral PMPA, belongs to a class of compounds known as nucleotide analogs, which block hiv from replicating. While it is similar to some of the most widely used aids drugs like AZT, PMPA targets a wider area of the virus, reducing the risk that it can develop a resistance, Gilead said.

"Based on mathematical models of how the virus replicates, you would not be able to do much better than (90%) reduction in viral load in a single week, regardless of how many therapies or the potencies of the drugs," said Dr. Howard Jaffe, senior vice president of drug development at Gilead. "But based on the animal data and the slope of the decline in the eight-day test on humans, we have every reason to believe it would continue to drive down viral levels if used over a longer term."

While many doctors have successfully lowered their patients' viral load by more than 99% using the celebrated three-drug cocktail, Gilead's findings could potentially achieve the same results with a lighter drug regimen. Jaffe said the Gilead drug would need to be taken only once a day, and preliminary results showed it was well tolerated with no significant side effects except nausea. Jaffe said Gilead also tested a vaginal gel form of the drug in animals, which was found to block the spread of the virus during sexual activity. It plans to begin similar studies in humans later this year in collaboration with the National Institutes of Health.

Protease Inhibitors

The scientific journal Nature recently published three studies which indicate that triple therapy using protease inhibitors kills hiv faster than originally thought. These studies show that the new drug combinations can successfully battle hiv not only in the blood, as has been previously shown, but also in the lymph nodes, tonsils, and other parts of the body, where the virus appears to become highly entrenched. Scientists had previously been uncertain whether triple combination would work in these protected areas, where some 90% of the virus often hides. (These studies reiterate findings presented at last January's National Conference on Retroviruses.)

Whether the new drug combinations are actually-rather than just theoretically-potent enough to eliminate every last one of the billions of viruses an infected person harbors is a question not yet answered. "It would be wrong to believe that we are close to a cure for aids," mathematician Alan S. Perelson and biologist David D. Ho write at the conclusion their paper. "However, the recent advances in treatmentdo warrant a close examination of the feasibility of eradicating [the virus] from an infected person." In theory at least, three years of treatment may be enough to eradicate hiv from the bodies of infected people.

In another article in Nature, Tae-Wook Chun and Robert F. Siliciano, of the Johns Hopkins University School of Medicine, gave credence to the theory that pockets of hiv can lie hidden in the body untouched by treatment. They studied lymphocytes that remained infected after a period of apparently successful triple therapy. The researchers found that the virus is damaged, incomplete or otherwise "incompetent" in most of those cells. However, in about one in a million of them, the virus is tucked away in the host's genetic material, hidden from the immune system, and-under the right conditions-capable of being awoken and made virulent again. "The importance of this small reservoir should not be underestimated because [certain categories of these cells] can survive for months and possibly years."

Cancer Drugs

The New York Times recently reported that more than thirty experimental cancer drugs are in the final phase of clinical trials, including two drugs against Kaposi's sarcoma, a new non-toxic drug to treat non-Hodgkin's lymphoma, a therapeutic vaccine for malignant melanoma, and medications for metastatic breast cancer and inoperable brain cancers. Unlike some existing drugs, many of the new drugs have few and mild side effects and can be prescribed in large doses and taken for many years. Moreover, unlike chemotherapies, which are chemical based, these new medications are biologic as well as more specific in their attack on cancer cells. Much in the way that protease inhibitors can lengthen the lives of people with aids without offering an absolute cure, these new cancer drugs are expected to offer cancer patients years of additional life, with much reduced side effects.

Genital Warts: An Injected Gel

A new drug being developed by Matrix Pharmaceuticals has been shown to be highly effective in treating genital warts, a common condition in people with aids. New research presented at the annual meeting of the American College of Obstetrics and Gynecology suggests that an injectable gel spiked with fluorouracil (5-FU), a blood vessel constrictor epinephrine, may clear most or all genital warts for the majority of people who have failed other therapies. This biodegradable gel was effective in eliminating all the warts in 61% of the 270 subjects and clearing more than half the warts in another 30% of patients. The gel's manufacturer expects it to receive FDA approval by the end of this year.

Oral Ganciclovir Prodrug RS-79079 Endangered

The highly promising oral prodrug of ganciclovir, RS-79070, which is now in Phase II trials (see below), may never make it out of the pipeline. Plans for future Phase III trials of RS-79079 have been suspended by Hoffmann-La Roche, apparently because of concern that there are no longer enough new cases of CMV retinitis to justify the expense of continuing development.

Current treatment of CMV requires intravenous infusion of ganciclovir twice daily through an indwelling catheter. While the oral form of ganciclovir has been approved and available for some time, it is poorly absorbed by the body into the bloodstream. It cannot be used for induction therapy (the initial high-dose treatment of CMV retinitis) and is controversial for maintenance (long-term treatment of active CMV disease after induction) and prophylaxis (prevention of CMV disease in persons who are at risk).

The prodrug RS-79079 is a chemical relative of ganciclovir. When it is taken orally and absorbed by the body, it is metabolized into ganciclovir in the bloodstream. It provides much higher blood levels of ganciclovir than the currently approved oral drug, and as high or perhaps higher levels of ganciclovir as intravenous infusion.

Because of its greater bioavailability, the oral RS-79079 could very well replace intravenous treatments or retinal implants as treatment for CMV disease. Treatment would consist of a pill taken once a day (twice a day for the first three weeks of treatment for the induction phase). The side effects of RS-79079 would be the same as IV ganciclovir.

The effectiveness of triple combination therapy with protease inhibitors have apparently reduced the incidence of CMV retinitis, leading the Hoffman-La Roche offices in Basel, Switzerland, to suspend further trials. Unfortunately, current drug-development rules require large and expensive phase III trials before RS-79079 can be marketed-even though (1) this drug serves only as a better delivery vehicle for supplying ganciclovir orally, (2) a less effective oral ganciclovir is already approved, and (3) the smaller phase II trial now recruiting will show whether or not RS-79079 is comparable to intravenous ganciclovir for induction treatment of CMV retinitis.

Ganciclovir Prodrug Clinical Trial

Individuals with newly diagnosed CMV retinitis may be eligible for this trial which compares RS-79079 with currently approved intravenous ganciclovir for CMV retinitis. After four weeks for the randomized comparison, volunteers in either group will be allowed to continue treatment with open-label RS-79079

For the first three weeks (induction phase), both groups will receive treatment twice a day-either with 5 mg/kg of intravenous ganciclovir, or 900 mg orally of RS-79079. After the induction, each group will receive the same treatment only once per day (maintenance phase). After one week on the maintenance dose, the blinded study will be over, and volunteers can continue treatment with RS-79079, the oral prodrug.

This trial has not been well known and so far has recruited only 13 of the total of 60 to 70 volunteers it needs - which may have helped precipitate the decision to suspend development of the large phase III trials.

As of May 1, a Los Angeles site was possible but not yet official. For information call the aids Clinical Trials Information Service, 800.trials-a.

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