AIDS TREATMENT NEWS Issue #236, December 1, 1995
John S. James

While the recent media coverage may seem excessive -- especially since PMPA has never been taken by even a single person, and human toxicity is unknown -- we believe that the new results are of first-rate importance. Besides the obvious potential uses in preventing infection after needlestick injury, and in preventing maternal-infant transmission (which is believed to usually occur at the time of birth), PMPA is clearly an important lead as a possible treatment for established infection. Of course no one knows if it will be useful for this purpose until it is tried.

AIDS TREATMENT NEWS could not finish an in-depth investigation of PMPA in time for this issue. But due to the widespread interest, we wanted to mention a few background points:

* Some people have tended to dismiss the finding that this drug can protect monkeys after exposure, since PMPA is chemically very close to PMEA, which is well known and already in clinical trials. We believe such quick judgment is a mistake. Even though the chemical change is small, PMPA is a new chemical entity. Even a small chemical change can have a huge impact on the safety, efficacy, and clinical potential of a new drug.

* PMPA, PMEA, another derivative of PMEA called bis-POM PMEA, as well as some other antivirals now being developed for human use, are members of a new class of drugs called nucleotide analogs (as opposed to nucleoside analogs such as AZT and ddI). Like nucleoside analogs, nucleotide analogs stop HIV replication by providing false building blocks which are incorporated into new viral particles when they are formed. But nucleotide analogs do not need the chemical processing inside the cell which nucleoside analogs do; therefore, they are potentially able to work in all cells, not only cells which can provide the processing which nucleoside analogs require.

* Nucleotide analogs are being developed by Gilead Sciences, Inc., of Foster City, California, not only for use in treating HIV, but also for treating CMV and other viruses. At this time it appears that the first nucleotide analog likely to reach widespread human use for treating HIV may be bis-POM PMEA -- because it seems to have a better therapeutic window between active and toxic doses than PMEA itself, it can be taken orally, and it is already in human trials. No one knows how bis-POM PMEA will compare with PMPA.

* It may be hard to tell quickly how well nucleotide analogs are working. For reasons which are unknown, viral load usually shows only modest reductions -- comparable to that from AZT -- even when other information suggests that these drugs may be working better than the viral load changes imply. (We would suggest using symptom-reduction trials to study this kind of drug -- small, rapid human trials to see if an anti-HIV drug can help people recover from ongoing AIDS-related symptoms which have been resistant to conventional treatments. For more information, see "Confirmatory" Trials: Symptom Reduction As Efficacy Measure, AIDS TREATMENT NEWS # 229.)

* PMPA illustrates some of the problems of delay in AIDS drug development. The newly-published results on protecting monkeys with PMPA were mostly available about a year ago (untreated monkeys were clearly infected at three weeks after exposure to the virus, but the paper reports results for up to 56 weeks after exposure). During this year few people knew about PMPA, which was previously mentioned in only two published AIDS-related articles, both highly technical; many who might have been involved in advancing this line of work were not. (We do not blame Gilead Sciences for the delay, as it was not their study, but a government study -- and Gilead's plate is full with at least six different treatments it is now developing for HIV and related conditions, as well as other treatments for other diseases. The paper was submitted to SCIENCE in April 1995, and accepted in September.)

PMPA is now undergoing standard animal toxicology testing, in preparation for human trials as a potential treatment. The first human test, however, will only use a single dose, to determine whether the drug can be absorbed orally (it was injected in the monkey-protection study). If the drug is not orally available, development will probably wait until an oral version can be designed. For years there has been a myth that an injected HIV treatment would not be acceptable in the marketplace; and there is also a regulatory disincentive to proceed immediately with a treatment that must be injected, as the company will later have to start over again if it wants an oral version.

These delays do not appear to be anyone's fault. But they do show that we have a problem which needs to be addressed. It is not being addressed today.

References

1. Tsai CC, Follis KE, Sabo A, and others. Prevention of SIV Infection in Macaques by (R)-9-(2- Phosphonylmethoxypropyl)adenine. SCIENCE. November 17, 1995; volume 270, pages 1197-1199.

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