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
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.
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. 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). The compound is synergistic with the first version
(now canceled) of Upjohn's protease inhibitor, too.
Delavirdine can also reduce the formation of syncytia (clumping
of cells which leads to rapid T cell destruction).
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.
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
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
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
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).
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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