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AIDS Treatment News
Antiviral Conference Reports
John S. James
May 19, 1995
AIDS TREATMENT NEWS Issue #223, May 19, 1995

The Eighth International Conference on Antiviral Research took place April 23-28, 1995, in Santa Fe, New Mexico. In our last issue, AIDS TREATMENT NEWS reported results on d4T, and on the Agouron protease inhibitor, which were presented at this meeting. But over two hundred other research reports were also given.

Two hundred and fifty six abstracts of conference presentations were published in the March 1995 issue of ANTIVIRAL RESEARCH, a journal published by the International Society of Antiviral Research, which sponsored the Santa Fe conference. This article summarizes some of those published abstracts. Note that they were submitted to the journal months before the conference, so they represent the state of the research at that time.

NIM 811 NIM 811 is a derivative of cyclosporin (an immune suppressive drug used in organ-transplant patients; cyclosporin has anti- HIV activity and has been proposed for treatment use, but could be dangerous because of its immune effects). NIM 811 has no immune suppressive activity, but still is active against HIV. This research team at Sandoz, the Austrian pharmaceutical company which sells cyclosporin, reported that the mechanism of action of NIM 811 is different than that of all other known anti-HIV agents; it binds with cyclophilin A, and inhibits HIV at two different stages in its life cycle.

B. Rosenwirth and others, Mode of Action of SDZ NIM 811, a Non-Immunosuppressive Cyclosporin A Analog with Activity against Human Immunodeficiency Virus Type 1 (HIV-1). Abstract #4.

Ingenol Derivatives, in Kansui Plant In laboratory tests, a compound derived from dried roots of Euphorbia Kansui Liou, inhibited HIV in extremely low concentrations, 0.1 nanomolar, which is thousands of times lower than the amount of AZT required. The concentration toxic to cells was 100,000 times the antiviral concentration. This series of compounds was also effective against virus resistant to AZT, virus resistant to non-nucleoside reverse transcriptase inhibitors, and HIV-2. It is believed that these compounds work by preventing the entry of viruses into cells. This work was done by researchers at a number of Japanese universities and companies.

M. Fugiwara and others, Ingenol Derivatives, Ingredients of Kansui, are Highly Potent Inhibitor of HIV. Abstract #6.

Burroughs-Wellcome's 1592U89 1592U89 is a potential HIV treatment now in early clinical trials. It is chemically related to carbovir, an antiviral proposed as an HIV treatment for many years; but 1592U89 is more active against HIV, more bioavailable, and has better penetration into the brain in animal tests. It is about as active against HIV as AZT, but seems to be synergistic with AZT; several mutations are required to give low-level resistance to 1529U89, and some of those mutations restore some susceptibility to AZT. In monkeys, very high doses were necessary to cause side effects in 90-day tests.

S.M. Daluge and others. 1592U89 Succinate -- A Potent, Selective Anti-HIV Carbocyclic Nucleoside. Abstract #7.

And S.S. Good and others, 1592U89 Succinate -- Preclinical Toxicological and Disposition Studies and Preliminary Clinical Pharmacokinetics. Abstract #8.

PMEA PMEA is chemically related to the anti-CMV drug cidofovir (HPMPC); but unlike HPMPC, PMEA is active against HIV, as well as against CMV and other herpes viruses. This abstract describes a placebo-controlled study in which escalating doses of a prodrug of PMEA (a drug which is changed to PMEA inside the body, since PMEA itself has poor oral bioavailability) are given to successive groups of volunteers; 24 patients have received the drug so far.

Comment: PMEA is also being developed in Holland. Some of the researchers there believe that it would be better to give PMEA by injection once per week, than to use the oral prodrug. In the U.S., there has long been an assumption that an HIV treatment which must be injected indefinitely would not be acceptable to the marketplace; therefore much delay occurs due to oral bioavailability problems. This assumption should be re-examined, especially for drugs which would only need to be injected infrequently.

P.A. Barditch-Crovo and others, A Randomized, Double-Blind, Placebo-Controlled Phase I/II Evaluation of 9-[-2- (Bispivaloyloxy-Methyl) phosphonyl-Methoxy]Adenine (bis-POM PMEA), an Orally Bioavailable Prodrug of the Anti-HIV Nucleotide, PMEA. Abstract #9. The researchers are from Johns Hopkins University, and Gilead Sciences.

Antabuse Antabuse is a prescription drug used for treating alcoholism; it makes people very sick if they drink alcohol. This abstract notes that Antabuse, as well as a number of new proprietary compounds, may have anti-HIV action through a mechanism of action which is different from other drugs -- targeting the "zinc fingers" in HIV proteins. In laboratory tests, these compounds are synergistic with approved HIV treatments. Antabuse and the other chemicals are now being tested for antiviral activity in both rodents and primates.

Comment: A few patients tried Antabuse as an AIDS treatment many years ago; it was used as a substitute for the French drug Imuthiol, which was later abandoned when a long-term trial found that those assigned to the drug did worse than those assigned to the placebo. Despite this unpromising history, Antabuse should be tested again, using viral load tests; it may have some potential benefit which was missed in the early experience. Since Antabuse is an approved, available drug, and antiviral effects (if any) can be seen quickly, within days or weeks, in humans, it is unfortunate that time should be spent on monkey trials when a small human trial would be faster and more definitive.

W.G. Rice and others. New Classes of Reagents That Attack Conserved and Chemically Reactive Zinc Fingers in Retroviral Nucleocapsid Proteins: A Strategy for Rational Drug Design. Abstract #18. The researchers are from PRI/DynCorp and the U.S. National Cancer Institute.

PETT Compounds In laboratory tests, some substances in this series of non- nucleoside RT inhibitors cause HIV resistance to develop ten times slower than other non-nucleoside compounds such as TIBO derivatives or nevirapine. And one advantage of this approach is that there are many PETT compounds to choose from.

B. Oberg and others. Anti-HIV Activities of New PETT Compounds in Cell Cultures. Abstract #19. The researchers are from Medivir AB in Sweden, the Karolinska Institute in Sweden, and Eli Lilly and Company in Indianapolis.

Foscarnet Resistance and AZT Foscarnet is an approved drug usually used for treating CMV, but it also has anti-HIV activity. This study of foscarnet resistance found that HIV which had become resistant to foscarnet was hypersusceptible to AZT and to non-nucleoside RT inhibitors, suggesting that combination therapy might be useful.

J. Mellors and others. Novel Mutations in the Reverse Transcriptase of HIV-1 Reduce Susceptibility to Phosphonoformate in Laboratory and Clinical Isolates. Abstract #20. The researchers are from several U.S. universities, and from the Military Medicine Consortium for Applied Retroviral Research.

New Combinations Vs. Drug Resistance A new series of non-nucleoside RT inhibitors (NNRTs) was found to cause different mutations than the NNRTs now known. Certain combinations of two drugs could greatly delay the development of resistant HIV. Some combinations of three NNRT drugs did even better.

Comment: About two years ago NNRT drugs were largely abandoned, although they are very effective at first, because HIV rapidly developed resistance to them. At that time it was widely believed that when HIV became resistant to one of these drugs, it would also be resistant to the others. But since then it has been learned that these drugs can have very different resistance patterns, and that by combining different drugs, resistance could be greatly delayed.

The best three-drug combinations reported in this abstract, however, used drugs which are not available; as far as we know, two of the three have never been tested in people.

J. Balzarini and others. Thiocarboxanilide Derivatives Synergistically Suppress the Breakthrough of Human Immunodeficiency Virus Type 1 (HIV-1) in CEM Cell Cultures When Used in Combination with TSAO Derivatives. Abstract #21. The authors are from research institutions in Belgium, Spain, and Sweden.

DuPont Merck Protease Inhibitor This abstract reports laboratory work with the DuPont Merck protease inhibitor DMP450.

D.L. Winslow and others. DMP450, A New Cyclic Urea Inhibitor of HIV Protease with Potent IN VITRO Antiviral Activity. Abstract #22.

New Kind of NNRT This abstract reports results with a new series of non- nucleoside RT inhibitors. The best one was active in quite small concentrations (4 to 13 nanomolar) in laboratory tests; it took about 10,000 times that concentration to be toxic to cells.

M. Fujiwara and others. Thiadiazole Derivatives as Highly Potent Inhibitor of Human Immunodeficiency Virus Type 1 (HIV- 1). Abstract #51. The authors are researchers at universities and companies in Japan.

AZT Plus ddI Combination: Better Ratio Possible? This study tested different ratios of AZT and ddI in laboratory tests. It did not look at antiviral activity, however, because it did not use live HIV; instead, it measured the biochemical activation of the drugs within cells.

Comment: This study suggests further research to see if it is possible to lower the dose of one or the other of the drugs in this combination (or in other widely used combinations) while maintaining efficacy. A simple laboratory test of different combinations against HIV could guide clinical trials, which could use viral load measurements to quickly see if it is possible to reduce the dose of one drug.

The laboratory work would not cost much, and the clinical trial could be done in a community-based research setting -- at least to check for initial antiviral activity -- without the need for industry support. The dose of one or the other drug would be lowered, in several steps, to see when the antiviral activity of the combination was affected.

S. Palmer and S. Cox. Intracellular Activation and Cytotoxicity of Combinations of 3'-Azido-3'-Deoxythymidine and 2',3'-Dideoxyinosine. Abstract #53. The research was done at the Karolinska Institute in Sweden.

[This review of the International Conference on Antiviral Research will be continued in future issues.]