AIDS TREATMENT NEWS Issue # 76, March 24, 1989
John S. James

Both ganciclovir and foscarnet, however, have important draw- backs. Therefore the AIDS community should also know about HPMPC (also called "(S)-HPMPC"), a chemical developed by Belgian research- ers, which appears in test-tube studies to be much more active then either ganciclovir or foscarnet against CMV. While HPMPC has not yet been given to humans and therefore is not an immediate treatment option, community awareness, investigation, and involvement may be necessary to make sure that it is not lost by lack of followup before clinical trials, or in the usual five-year to eight-year "drugjam" of new treatments going through clinical trials for U.S. approval.

HPMPC is also effective against some other viruses, including herpes simplex. It may be part of a new class of broad- spectrum antivirals.

A major article on HPMPC was published last December in Antimi- crobial Agents and Chemotherapy (Snoeck and others, 1988). These are the major points from that article:

* The scientists measured an "inhibitory index", the ratio of the drug concentration which inhibited cell growth by 50 percent to the concentration which inhibited the virus by 50 percent. This ratio provides an early indication of the possible usefulness of the drug. A large value suggests that there may be a wide margin between effective and toxic doses, increasing safety and also allowing physicians to increase doses when necessary without unacceptable toxicity.

In tests against CMV, the ratios for foscarnet, ganciclovir, HPMPA (a relative of HPMPC), and HPMPC were 14, 150, 200, and 1,500, respectively. (Using another strain of CMV, the ratios were 20, 200, 100, and 1,000.) These results suggest that HPMPC might have about ten times the range between effective and toxic doses as ganciclovir -- and even more when compared to foscarnet.

* HPMPC completely suppressed the growth of CMV at concentrations of 0.1 microgram per milliliter, about ten times lower than required for ganciclovir.

* Like ganciclovir, HPMPC suppressed CMV plaque formation when added two, 24, or 48 hours after infection. Both failed to do so when added after 72 hours. But the two differed in that HPMPC protected cells even after it had been removed from the culture, while ganciclovir did not.

* For those who are interested, the full chemical name of HPMPC is (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine.

It is not known exactly how it works. In one experiment, several natural nucleosides were tested to see if they could inhibit the antiviral effect of HPMPC. None of them did.

* Based on their results, the researchers suggested testing HPMPC in animals as a CMV treatment. They pointed out that appropriate "animal models" for CMV infection are available -- for example, the mouse or guinea pig.

* All funding for the above research was from institutions in Belgium. The researchers synthesized their own HPMPC, by a procedure outlined in the article. We do not know of any pharmaceutical com- pany involved in this work, although Bristol-Myers researchers have also published a paper on synthesis of HPMPC (Webb and others, 1988).

Comment

We suggest that the AIDS community follow HPMPC, and become fami- liar with its current status and future prospects. Are there any financial or other obstacles to further research, which community awareness could help to overcome? It would be inexcusable for this drug to take the usual five to eight years or more to become available in the United States.

Except for red tape, enough preliminary testing could be com- pleted in a few weeks or months. Volunteers for whom nothing else works would be willing to try the drug, after brief tests in animals. Only cultural inertia stands in the way -- in particular, the unwil- lingness to respond to AIDS as an emergency, instead of business as usual.

References

De Clercq E., Holy A., Rosenberg I., Sakuma T., Balzarini J., and Maudgal P.C. A novel selective broad-spectrum anti-DNA virus agent. Nature volume 323 number 2, pages 464-467, October 1986.

De Clercq E., Sakuma T., Baha M., Pauwels R., Balzarini J., Rosenberg I., and Holy A. Antiviral activity of phosphonylmethoxyalkyl derivi- tives of purine and pyrimidines. Antiviral Research number 8, pages 261-272, 1987.

Snoeck R., Sakuma T., De Clercq E., Rosenberg I., and Holy, A. (S)-1- (3-Hydroxy-2-Phosphonylmethoxypropyl)Cytosine, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication. Antimicrobial Agents and Chemotherapy volume 32 number 12, pages 1839-1844, December 1988.

Webb R.R. II, Wos J.A., Bronson J.J., and Martin J.C. Synthesis of S-N-1-3 Hydroxyl-2-Phosphonylmethoxypropylcytosine S- HPMPC. Tetrahedron Lett. 29 (43) pages 5475-5478, 1988.

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