GMHC Treatment Issues; Vol 9, Number 9 - September 1995
Vincent Pieribone

Two factors are at work that allow HIV to quickly become resistant to many drugs. One is the fact that when HIV inserts itself into new cells, the reverse transcriptase enzyme that makes DNA genes from the virus's RNA makes mistakes, thereby producing mutated progeny which are slightly different from their parents. Many of the mutations cause the new virus to be defective while other mutations have little effect on the virus's life cycle. Some mutations also may allow the virus to resist the activity of therapeutic drugs.

When a drug is administered to a person, it may inactivate or kill 99.9 percent of all the virus in a person's body. Still, the remaining 0.01 percent that survives exposure to the drug will be "selected for" and can then grow and fill the 99.9 percent void. The survival and expansion of the unaffected, or "fit," virus is an example of classical Darwinian evolution in action.

The second attribute of HIV that allows it to produce resistant viruses quickly is the high rate at which HIV reproduces in an infected person. Over one billion virions are produced in an infected person each day. The larger the population of virus and the faster replication takes place, the faster mutant resistant virus arises and repopulates the body after the drug is applied.

Taking Advantage of Resistance

Several investigators are seeking to develop more effective drugs that paradoxically take advantage of HIV's aptitude. This approach is now proving productive in the area of non- nucleoside reverse transcriptase inhibitors (NNRTIs), a powerful class of drugs hobbled by the almost instantaneous emergence of resistant HIV when the virus comes in contact with them.

The Upjohn company had developed a series of non-nucleoside reverse transcriptase inhibitors called BHAPs (named for their chemical structure). The most developed one is called delavirdine. Delavirdine very effectively blocks HIV in cell cultures and reduces its deleterious effects. After a short period of time, however, the levels of HIV in the culture dish increase and eventually destroy the cells in culture.

When the HIV reverse transcriptase (RT) is purified from the delavirdine-resistant cultures, it turns out that the enzyme has several mutations in its structure that reduce delavirdine's ability to bind with it. Upjohn has now taken the next step in attempting to beat the virus. By creating a panel of reverse transcriptase molecules that are resistant to delavirdine and employing them in test tube assays, Upjohn has identified a whole new set of drugs that are effective against the mutated RT enzyme.

These drugs, when used in conjunction with delavirdine, strongly retard the emergence of resistant viruses. The obvious question is, can the virus mutate to produce a resistant strain that is not susceptible to either delavirdine or the new compounds? This dual resistance is a theoretical possibility, but there is certainly a limit to the total number of mutations that the RT molecule can endure without suffering a loss in activity.

Most RT inhibitors bind to reverse transcriptase's active site, where the enzyme fashions a DNA version of HIV's genes from the viral RNA and the available nucleotides in the cell. Drug resistant RT usually has mutational changes in this active site, and these major alterations can hinder the enzyme's activity. By forcing two sets of alterations (in response to delavirdine and the new compounds), Upjohn's scientists feel that they have "pushed" mutations in the RT molecule to a point where the enzyme barely works. Although resistant, breakthrough HIV does emerge after prolonged exposure of cultures to both compounds, this virus is defective and may not cause the damage that the normal virus does (represented in cell cultures by the killing of all the immune cells).

Since recent studies appear to indicate that CD4 cells are being produced at a phenomenal rate even in the face of massive HIV production, there is substantial belief that just slightly retarding HIV's reproduction rate could lend a strong advantage to the infected person. Upjohn refuses to comment very much on its second generation RT inhibitors, but they are moving into preclinical trials at present and reportedly look very promising.

Other New NNRTIs

Upjohn is the only company to screen compounds specifically for activity against mutant, drug-resistant reverse transcriptase. Others have used a less sophisticated approach that merely looks for especially effective NNRTIs that trigger resistance mutations different from those caused by the NNRTIs currently in clinical trials, such as delavirdine or nevirapine. Because of their power, HIV might be slow to resist these "second generation" NNRTIs, and because of the lack of cross-resistance with nevirapine and delavirdine, the new compounds might work well in combination with the older members of the NNRTI family.

One second generation NNRTI found through this simpler screening process is UC10, which is owned by Uniroyal. UC10 is much more potent than the other NNRTIs and has good bioavailability in dogs and mice. In the test tube, the combination of very low doses of UC10 with delavirdine and TSAO, a novel nucleoside analog, completely shuts down HIV replication, without the virus ever breaking through.

A review of this lab data was published in a recent issue of the Proceedings of the National Academy of Sciences (June 1995, pages 5470-74). Unfortunately, TSAO, which may be essential to the combination's effectiveness, breaks down too quickly in the body to be used in people.

Uniroyal has no medical division and at present will not comment on UC10's future.

Meanwhile, the June, 1995 issue of Antimicrobial Agents and Chemotherapy (pages 1329-35) carried a report on a new NNRTI developed by Eli Lilly and Company in collaboration with Medivir in Sweden. (See also Treatment Issues, July/August, 1995, page 10.) In the laboratory, this "PETT" compound (LY300046-HCl) does lose some of its effect on reverse transcriptase resistant to nevirapine, but increasing the concentration allows the compound to regain its inhibitory action.

Lilly last year sold LY300046-HCl to Medivir, and a paper on the results of a phase I trial in humans will come out soon. But the Swedish company at this point has few funds to further pursue LY300046-HCl or the possibly more desirable variants it has created.

In contrast, a partnership between Hoechst-Roussel and Bayer is starting up a comprehensive clinical trials program for HBY 097, another new-type NNRTI with enhanced potency. Resistance to HBY 097 reputedly occurs only through a single novel mutation that is slow to develop and also disables the reverse transcriptase enzyme. In the resistant virus, RT activity is reduced 25-fold. A new twelve-week clinical trial, which will gauge antiviral activity and pharmacokinetics of HBY 097 alone and in combination with AZT, is about to begin at Stanford and New York Universities. Other sites will be added and up to 180 people enrolled.

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