Antiviral Conference Reports


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.]