Treatment Issues, Vol 11, No 4/5; April 1997
Dave Gilden

Reading delavirdine's package insert is a scary experience that will put off most people from trying the compound. In the first place, resistant HIV emerges within a few weeks of taking the drug, due to a single mutation. That mutation most often occurs at reverse transcriptase's amino acid 103. This same mutation also reduces HIV's sensitivity to Du Pont Merck's experimental and much more active NNRTI DMP 266. It would be a shame to lose some of the advantages of DMP 266 through previous use of delavirdine. Largely because of its resistance problem, delavirdine provided no statistically significant benefit in two of the three clinical trials that led to its approval. One of these, ACTG 261, involved participants who had no prior therapy or less than six months of AZT. Preliminary analyses of the viral load and CD4 count data in ACTG 261 indicate that AZT/ddI is virtually equal to AZT/ddI/delavirdine or ddI/delavirdine and decidedly better than AZT/delavirdine. In another study, the AZT/delavirdine combination did do better than AZT alone in a cohort with six months or less of prior AZT therapy. This improvement was not apparent when evaluating CD4 count changes, only in terms of viral load. (A further reduction in HIV levels of only about 0.1 log -- 20% -- after week eight could be attributed to delavirdine. At week four, this difference briefly reached 0.5 logs or 67%.)

Then there is the problem that delavirdine therapy requires taking four 100 mg pills three times a day. This comparatively large burden, of course, comes in addition to the other antiviral drugs with which delavirdine must be taken (delavirdine monotherapy is strongly advised against). With the recommended regimen, delavirdine blood levels vary considerably from person to person, and on average women achieve 31% higher levels than men. Delavirdine is metabolized by the liver and inhibits the same CYP3A hepatic enzyme that the protease inhibitor ritonavir does (though not to the same extent). Like ritonavir, delavirdine comes with a long list of warnings concerning drugs whose blood levels it raises due to this suppression of liver metabolism. Delavirdine also causes skin rashes, usually (but not always) temporary, in about 20% of patients. Finally, it causes birth defects in rats. This is not a very attractive drug. Except, except. . . One of the pieces of information that led the FDA to OK delavirdine was some data from Paul Bellman, M.D., a New York City AIDS specialist in private practice. Taking advantage of the preapproval delavirdine expanded access program, Dr. Bellman added the compound to the regimens of 60 of his patients who were experiencing rising viral loads despite being on AZT/3TC/indinavir. (In some patients, the AZT was switched to d4T at the same time). Lo and behold, 15 of the 27 patients whose records have been made available experienced a rapid viral load decline amounting to more than one log (90%) by the second or third month. Dr. Bellman has no way of checking, but he thinks that the people failing the indinavir regimens were not achieving high enough blood levels of this protease inhibitor, possibly due to poor absorption in the digestive tract. Delavirdine conceivably could have raised the patients' average indinavir levels by two-fold or more, due to its effect on the liver, where 80% of indinavir is broken down.

Dr. Bellman observes, "Delavirdine added to nucleoside analogs does not have these benefits. But adding delavirdine, a potent drug, to indinavir makes it potent, too. So now there are two potent new drugs in the patient's antiviral combination."

Dr. Bellman combines delavirdine with the standard indinavir dose of 800 milligrams three times a day. Upjohn, though, recommends that indinavir should be reduced to 600 mg three times a day when co-administered with delavirdine. The worry with high indinavir levels in the body is that some of the compound will end up in the kidneys as an extremely painful precipitate or sediment. Dr. Bellman says he has noticed no increase in this kidney stone problem, which strengthens his feeling that his failing patients had abnormally low indinavir levels to begin with.

The doctor's whole strategy rests on his personal intuition. He has not actually monitored the indinavir levels in any of his patients since such a test is not commercially available. His experience points out a gap in current research -- why people fail treatment regimens is not examined systematically. In particular, the drug levels achieved in patients are rarely looked at.

Merck, which developed indinavir, is now collecting blood samples from people who have not responded well to the compound. The reasons why people fail seem varied, according to Merck researcher John Condra. He says, "We don't have any evidence that failures have low blood levels. This is one possibility. Among the other explanations are drug resistance and inadequate compliance." If the problem is failure to take indinavir on schedule or to take it with food rather than on an empty stomach, this should be corrected first before adding delavirdine. If the problem is indinavir-resistant HIV and not low indinavir levels, the benefits and dangers of adding delavirdine are uncertain. Adding to the mystery, Dr. Bellman notes that he has seen patients continue to fail when delavirdine was added to their indinavir regimen and then succeed on indinavir plus nevirapine. But nevirapine reduces indinavir levels rather than raising them. Like the reasons for protease inhibitor failure, protease inhibitor/NNRTI combinations have suffered from lack of attention. Manufacturers in the past have tried to position their NNRTIs as substitutes for the more expensive protease inhibitors in combination regimens with nucleoside analogs. It nonetheless makes more sense to combine NNRTIs with protease inhibitors rather than nucleoside analogs since then two different HIV enzymes and points on the virus lifecycle are attacked rather than just one. In one small Vancouver trial, for people with AIDS who had failed all nucleoside analogs, the combination of 3TC, indinavir and nevirapine was surprisingly successful (see Treatment Issues article Protease Inhibitors: Resistance, Resistance, Resistance, February 1997, page 6). Also, the two-drug combination of DMP 266 and indinavir in trials has suppressed HIV as effectively as most three drug combinations.

Dr. Bellman's results in his first patients are drawing increasing attention in New York City and elsewhere. The complete results are not in, though. For most of these initial patients, adding delavirdine to indinavir did not drive HIV down to undetectable levels (below 400 HIV RNA copies/ml of plasma). This leads to fears that long-term stability will not be maintained, given HIV's propensity to develop resistance to either of these two compounds when residual viral replication is possible during treatment. The clock may be set back, but usually it is still ticking; successful ways to recover from treatment failure need further elaboration.

Part of that solution appeared to be Upjohn's "spawn of delavirdine," a series of altered delavirdine compounds that the company tested in the lab and found to be active against delavirdine-resistant HIV. These compounds were described in a series of four papers over the past year, but Upjohn now says it has no attention of developing them further because they exhibited poor stability in animal studies. More recently, Upjohn has come up with a new set of NNRTIs, the "pryrimidine thioethers," which also are potent against delavirdine-resistant HIV as well as nonresistant virus. Their absorption and stability reportedly are excellent in rats, but Upjohn is still evaluating their future development. There is considerable speculation in the AIDS community that Upjohn is pulling back from HIV research. It will be interesting to see what the company does.

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