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Gay Men's Health Crisis
Delavirdine Enters Efficacy Trials
Gabriel Torres, M.D.
June 1, 1994
GMHC Treatment Issues 1994 Jun 1; 8(4): 4

Delavirdine (also known as U-90152) is a new anti-HIV drug manufactured by Upjohn Company. It belongs to the class of compounds called non-nucleoside reverse transcriptase inhibitors (NNRTIs). These compounds block HIV replication by inhibiting the same enzyme, reverse transcriptase, that is blocked by nucleoside analogs like AZT, ddI, ddC and d4T. NNRTIs strongly protect uninfected cells from HIV, but they have been plagued by HIV's ability to rapidly develop resistance to them.

It is hoped that delavirdine, when combined with other drugs such as AZT, ddI, other NNRTIs, or protease inhibitors, can slow down emergence of viral resistance. Precisely because of this resistance, delavirdine is unlikely to be effective as a single agent. Combining the drug with additional antiviral agents, though, might so reduce HIV replication that resistance to any of the components in the combined regimen will take much longer to evolve. Also, the development of resistance to delavirdine seems to increase HIV's sensitivity to other NNRTIs.

Delavirdine's long-term side effects still need to be evaluated, as does its activity during pregnancy. The influence of the drug on fetal development and its ability to reduce mother-to-child HIV transmission remain unknown.

Laboratory Studies In the test tube, very low concentrations of delavirdine can totally stop HIV-1 from infecting new cells and causing cell death. It is also more potent than AZT and is effective against AZT- and ddI-resistant strains of HIV in the laboratory.[1] In AZT- or ddI-sensitive strains, delavirdine has been found to be synergistic with AZT or ddI (the effect of the combined treatment is greater than the sum of the individual drugs' effects).[2] The compound is synergistic with the first version (now canceled) of Upjohn's protease inhibitor, too.[3] Delavirdine can also reduce the formation of syncytia (clumping of cells which leads to rapid T cell destruction).[1] Unfortunately, when delavirdine is introduced to HIV-infected cell cultures, viral strains that are ten- to 100-fold less sensitive to the drug emerge. This drug resistance is triggered by single changes (or point mutations) in the amino acid sequence of the reverse transcriptase enzyme. One such mutation (at amino acid number 236) causes high-level resistance to delavirdine but sensitizes the virus to other NNRTIs such as nevirapine, TIBO compounds and Merck & Co.'s L-drug (L-697). Yet, it does not change sensitivity to nucleoside analogs such as AZT and ddC.[4] Animal Studies Animal studies using delavirdine have focused on determining its toxicities and adverse effects. The lowest dose in animals in which notable toxicity has been observed is 50mg per kilogram of body weight per day. This dose produced inflammation of blood vessels (vasculitis) in dogs over a two week period. Higher doses caused gastrointestinal ulcerations, bone marrow toxicity and lung inflammation. The drug also led to birth defects in pregnant rats at extremely high doses. Since the drug is so potent, there is a wide margin of safety - low doses can be effective in achieving levels in the body that inhibit the virus.

Phase I Human Studies Two clinical studies in normal healthy male volunteers have been completed. These placebo-controlled studies showed that the drug was tolerated in single doses of up to 300mg and multiple doses of up to 100mg four times daily without side effects; headache occurred frequently in both the delavirdine and placebo groups. Two multiple-dose safety, tolerance, and pharmacokinetic studies in 87 HIV-positive volunteers have been completed. It appears that the drug is well tolerated when given orally in amounts up to 400mg three times daily in combination with AZT and up to 300mg four times daily in combination with AZT and ddI. The most frequent side effect is a rash that appears after one week on the drug. The rash occurred in 27 percent of patients who took delavirdine in combination with AZT and in 38 percent of those who took it in combination with AZT and ddI. Most patients were subsequently rechallenged with a lower dose once the rash had resolved. They were able to tolerate their original assigned doses after two weeks on the lower dose. Increases in liver function tests occurred in two patients and resolved after all antiretroviral agents were discontinued. A new crystal form of delavirdine has also been developed by Upjohn that seems to be more heat-stable. The new form is being used for the large scale clinical trials initiated this spring.

New Delavirdine Clinical Trials Upjohn is launching three new clinical trials of delavirdine in multiple centers throughout the United States. The first trial is a double-blind randomized study of three doses of delavirdine in combination with AZT versus AZT alone. The trial will measure delavirdine's efficacy based on changes in HIV viral load, CD4 cell counts, and disease progression. HIV-positive persons with CD4 cell counts of 200 to 500 who have had less than six months of prior AZT therapy are eligible for this two-year trial. According to trial plans, 1,200 to 1,500 participants will be enrolled. It is hoped that women will make up 20 percent of the participants. The delavirdine doses used will be 200, 300 or 400mg three times daily in combination with AZT at 200mg three times daily. The addition of ddI will be allowed in all treatment groups if a study participant experiences a fall in CD4 count to below 50 percent of baseline on two consecutive occasions or develops an AIDS-defining illness.

The study will exclude persons with previous ddI, ddC, 3TC or d4T therapy, patients unable to take AZT, and those who have received therapeutic vaccines. The use of drugs that can interact with delavirdine and lower its blood levels will not be allowed within 21 days of study entry. These include a large number of drugs used to treat opportunistic infections and other conditions, including ketoconazole, fluconazole and itraconazole for fungi; isoniazid and rifampin for tuberculosis, rifabutin for mycobacterium avium complex (MAC); and astemizole and loratadine, which are anti- histamines.

A second parallel study will compare delavirdine in combination with didanosine (ddI) versus ddI alone. This trial will follow people with HIV who have CD4 counts less than 300 and previous experience on AZT but less than four months on ddI. Plans are to enroll between 800 and 950 patients for a two-year time period.

This study, too, will exclude patients with prior ddC, d4T or NNRTI therapy. There is some concern that such people will develop HIV strains resistant to ddI in addition to ddC. This will be a problem for those in the ddI-only arm. The trial also will exclude patients requiring therapy with rifampin, rifabutin or the anti-histamine terfenadine (seldane).

Both studies will compare the emergence of drug-resistant HIV in patients on the delavirdine combinations versus those on nucleoside analog monotherapy. One interesting aspect of these studies is that they will also measure the cost- effectiveness and quality of life effects of adding delavirdine to AZT or ddI monotherapy.

Finally, a third study is being conducted by Upjohn for patients who have participated in previous delavirdine studies. It will evaluate and compare the use of delavirdine in triple combination with ddI and AZT or ddC and AZT. This third trial is expected to enroll over 4,000 people.

For information on the delavirdine trials contact 800/TRIALS- A. A number of trial sites will be located in the New York area at various sites, including the Community Research Initiative on AIDS (contact Bette Smith at 212/924-3934), St. Vincent's Hospital (contact Daisy Soto, R.N., 212/604-8920), Beth Israel Medical Center (contact Carsandra Sanders, P.A., at 212/420-4519), Mt. Sinai Medical Center (contact Eileen Chusid, Ph.D., at 212/241-3933).

References: 1. Dueweke TJ, et al. Antimicrobial Agents and Chemotherapy, 1993; 37(5): 1127-31.

2. Chong KT, et al. Ninth International Conference on AIDS, 1993; abstract PO-A25-0606.

3. Chong KT, et al. Ninth International Conference on AIDS, 1993; abstract PO-A25-0557.

4. Dueweke TJ, et al. Proceedings of the National Academy of Science USA, 1993; 90(10):4713-7.

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