AIDS TREATMENT NEWS #139, November 22, 1991
John S. James

In the laboratory, viral resistance is caused by a single mutation that results in a change at position number 181 in the reverse transcriptase enzyme. It makes the virus ten to one hundred fold less sensitive to L-661, making the drug an ineffective inhibitor against the resistant strain. This same mutation also makes the virus resistant to most other drugs of the same class (non-nucleoside reverse transcriptase inhibitors, such as BI-RG-587 and the TIBO derivatives), even though it has never been exposed to them. Resistant virus has been found at the seventh week of treatment in all seven volunteers so far analyzed.

The new data does show that L-661 has biological activity against HIV in humans; p24 antigen levels fall quickly in some patients after treatment begins. But these levels come up again as the viral resistance develops.

L-661 will still be tested in combination with AZT, because it is hoped that combination treatments can help delay the emergence of drug resistance. (To avoid resistance entirely, a drug combination must completely shut down all variants of the organism, either by killing them or by otherwise preventing them from multiplying.) The resistant virus to L-661 is still susceptible to AZT.

A new Merck drug, L-229, is closely related to L-661 but can reach higher blood levels in humans, because it binds less to plasma proteins. Therefore it may be able to shut down the virus more quickly and minimize the emergence of resistance, especially if used in combination with AZT or other anti-HIV drugs.

According to spokesman John Doorley, Merck hopes that L-229 will eventually supercede L-661. But first there must be more preliminary testing of L-229, especially to show that it has biologic activity against HIV in humans (as L-661 is known to have). Because L-661 is further along in its development, it is important to continue to test the combination of L-661 with AZT to provide data on the combination, to help the design of the trials with L-229, to determine if L-661 resistance still occurs in the presence of AZT, and to gain additional data on the effectiveness of these compounds as single agents.

Resistance to Class of Drugs

Several new antivirals -- Boehringer Ingelheim's BI-RG-587, Janssen's TIBO derivative R82150, and the new Upjohn BHAP drugs -- have the same mechanism of action as L-661 and L-229. All of them inhibit the enzyme reverse transcriptase, which is required by HIV but not used by the human body. But unlike AZT, ddC, and ddI, which also inhibit reverse transcriptase, the new drugs are not nucleoside analogs; they do not act as false building blocks of the virus. For this reason, the new class of drugs (Merck's L-661 and L-229, and the related compounds being developed by other companies) are called non-nucleoside reverse transcriptase inhibitors. It is hoped that they will be less toxic than AZT and other nucleoside drugs, and therefore can be used in larger doses.

But viral resistance seems to be a big problem with this class of drugs. And it is known that if HIV becomes resistant to BI-RG-587, or TIBO derivative R82150, it will be resistant to L- 661 also. (The new BHAP drugs are chemically similar and are likely to share this cross resistance.)

If a virus becomes resistant after treatment with a drug, will it revert to a sensitive strain if the drug is removed? No one knows at this time; Merck will test volunteers who stop taking L-661 to see if their virus becomes sensitive. (In many cases, viruses or other organisms which become resistant to a drug do become susceptible again if the drug is stopped, because the resistant strains are less able than the non-resistant ones to survive in the body when the drug is not present. This is not surprising, since if the resistant organisms were more able to survive, they would already have become the predominant strains and the drug would never have worked in the first place.) In laboratory cultures, however, virus which has become resistant to L-661 does not spontaneously become susceptible.

Volunteers in trials of non-nucleoside reverse transcriptase inhibitors should realize that there is a risk that they could develop resistant viral strains which might later prevent them from benefiting from other drugs in the same class. This would only be a problem if (1) more effective non-nucleoside reverse transcriptase inhibitors are developed, and (2) the virus does not revert to drug-sensitive strains after the drug is stopped or replaced with AZT.

Merck's researchers have not found any virus which is resistant to both L-661 and also to AZT -- a fact which supports trying the treatments in combination.

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