GMHC Treatment Issues 1994 Apr 1; 8(2): 1
This article was compiled by Dave Gilden with the assistance of
Ben Cheng, Rick Loftus and others. Much of the information
contained below was obtained through private conversations with
company sources who did not want to be identified.
Protease inhibitors are the one class of new, promising anti-
HIV therapies likely to be available in the near future. It is
hoped that by attacking HIV from a different direction, the new
compounds will represent a great step forward in treating AIDS.
Dr. Margaret Johnston, one of the chief AIDS researchers at the
National Institutes of Health, recently told the Wall Street
Journal, "I really have my fingers crossed because after the
protease inhibitors, I don't see much in drug development."
At least a dozen companies are now developing protease
inhibitors. In preliminary lab experiments, some of their
products have exhibited great potency against HIV. Yet Johnston
would do well to keep her fingers crossed. Protease inhibitors
have been beset by several serious practical problems. Now that
larger trials are beginning, Treatment Issues presents a review
of this fresh class of drugs and the strategies of the
companies that are developing them.
What are Protease Inhibitors?
Protease inhibitors act at a late stage in HIV's replication
process, after the copy of HIV's genes within a cell have
initiated mass production of new viral components. The proteins
within HIV's outer envelope first come out of the cell's
protein factory in a long connected string that must be cut up.
HIV protease is an enzyme that acts like a chemical scissors.
It snips out the parts for the virus core so that they
reassemble in the proper configuration. This snipping process
occurs as newly formed virus particles bud out of the cell.
Protease inhibitors lock onto and sheathe the protease's active
site (the blade of the scissors, as it were). In doing so, they
disrupt the creation of mature virus particles
HIV protease is quite small and as such makes an ideal target
to stop HIV replication. It is a member of the aspartyl-
protease enzyme family that also includes the major human
enzymes renin (which regulates kidney activity) and pepsin
(which digests protein in the stomach). The human enzymes have
a somewhat different, asymmetric structure, though, and should
not be affected by a molecule aimed at the HIV protease.
Early studies confirmed that the HIV protease enzyme is
essential for viral infectivity and replication and that the
virus particles produced without protease are faulty and cannot
infect other immune system cells.[3,4]
As was hoped, protease inhibitors effectively prevented the
production of infectious virus in chronically infected
cells. Current anti-HIV drugs such as AZT act against
another HIV enzyme, reverse transcriptase, which helps the
virus insert its genes into newly infected cells. They do not
influence viral production in the chronically infected cells,
in which HIV has already taken up.
Difficulties in Developing Protease Inhibitors
As usual there is a great leap between theory and practice.
Researchers encountered many early obstacles to developing
First, a given compound may have been a potent inhibitor of
protease in chemical experiments, but it had poor or no anti-
HIV effects in cell cultures. Secondly, poor oral absorption
or rapid breaking down of the compound in the liver made it
necessary to administer the protease inhibitor intravenously or
ingest large amounts of it orally. Thirdly, unexpected
toxicities, particularly in the liver where the compounds are
metabolized, appeared in animal and human safety studies.
Lastly, most of the protease inhibitors are very hard to
manufacture, a problem that exacerbates the difficulties in
maintaining adequate amounts in the body.
It is still unclear whether there will be any drug interactions
between protease inhibitors and other medications and whether
this will affect drug absorption and action. As most drugs are
metabolized in the liver, such interactions are likely. Further
studies are needed to understand how to integrate protease
inhibitors into overall therapy for HIV disease.
The rapid emergence of viral resistance to AZT and other
reverse transcriptase inhibitors (ddI, ddC, d4T), along with
their toxicities, limits their long-term usefulness in the
treatment of HIV. Protease inhibitors may be less prone to this
failure. It is thought that HIV is less able to alter the
structure of the protease enzyme than that of reverse
transcriptase. Resistance to protease inhibitors may be slower
to develop and at a lower level than for reverse transcriptase
But resistance has already been observed for some protease
inhibitors. Combining a protease inhibitor with a reverse
transcriptase inhibitor may delay development of resistance. In
test tube experiments, when a protease inhibitor was combined
with AZT or ddC (or alpha interferon) additive or synergistic
anti-HIV interactions were seen. It is also hoped that the
protease inhibitors will have antiviral activity against HIV
strains that are resistant to AZT.
Summary of the Status of Individual Protease Inhibitors
Most major issues surrounding protease inhibitors boil down to
one main question: Do economically affordable treatment
regimens produce adequate blood levels of the drug? At the
point when blood levels of the drug are at their lowest point
(this is the trough level), concentrations must be well above
those needed to stop nearly all viral replication. At that same
time, the level of drug in the blood must be well below toxic
(To put this in technical jargon: Trough levels of the drug
should be multiples of the IC90 level, and the therapeutic
index should be high. IC90 is the drug concentration that shuts
down 90 percent of HIV activity. The therapeutic index is the
ratio between a toxic dose of a drug and an effective one.)
If effectiveness can be ensured without compromising safety,
the chance of drug-resistant HIV strains or cumulative toxicity
emerging is diminished.
Drug developers are gradually overcoming some of the obstacles
to an effective protease inhibitor. More potent and more orally
available substances are slowly moving into clinical trials. In
the following sections, we describe the status of the most
advanced protease inhibitors and how well their industrial
sponsors have coped with the problems inherent to this new
Hoffmann-La Roche's "saquinavir" (formerly Ro 31-8959) was the
first anti-HIV protease inhibitor tried in humans. The Phase I
safety and pharmacokinetic studies were done in England, France
Roche's molecule was one of the original series of compounds
that were very potent against HIV but not very bioavailable
when taken by mouth. Absorption of saquinavir is only 4
percent. Saquinavir also turned out to be extraordinarily
difficult to manufacture. The seventeen steps involved take
nearly a year to complete.
Results from the European studies show that this drug is very
well tolerated with almost no side effects. At the highest dose
given (600mg three times a day), saquinavir showed some
antiviral activity (there were increases in CD4 cell counts, a
drop in viral load and a decrease in HIV p24 protein).
However, the maximum response seemed to occur four to six weeks
after starting therapy. In the French study, CD4 cell counts
were essentially back to baseline by week sixteen. Better
antiviral activity was observed when the Roche drug was
combined with AZT. Then, CD4 cell increases were higher and
sustained past sixteen weeks, the cutoff point for the trial
Another combination trial is being conducted by the NIH's AIDS
Clinical Trial Group (ACTG 229). The trial compares saquinavir
plus AZT versus saquinavir plus AZT plus ddC versus AZT plus
ddC alone. Additionally, a trial of saquinavir versus AZT
versus the two combined is in progress at Mt. Zion Hospital in
San Francisco. Data from these trials are expected very soon.
Two multicenter pivotal phase III trials should begin very
1. A US 40-center study of 1200 HIV-positive volunteers with
CD4 counts between 50 and 300 and prior, unsatisfactory
experience with AZT. To be eligible, volunteers also must not
have been on ddC, ddI or d4T for more than two weeks. There are
four arms to the trial: Saquinavir at 600mg three times a day;
ddC monotherapy; and two combination arms (ddC plus either 200
or 600mg saquinavir three times a day). Treatment will continue
for 48 weeks. The primary endpoint will be time to first
AIDS-defining clinical event or death. Immunologic and
virologic lab values will be secondary endpoints. This trial is
already underway at a few sites. For more information call
2. An international study of 1800 HIV-positive volunteers (600
in the US, 1200 abroad) without prior experience with AZT.
Treatment will continue for 18 months. This trial is similar to
the US trial in design except that AZT will be used instead of
ddC. Roche plans to start the international study in March.
The Roche phase III trials has raised a number of criticisms.
The first of these concerns uncertainty about the optimum dose
of saquinavir. The impact previously seen on lab values (CD4
count, etc.) is rather minor and temporary. Moreover, a
suboptimum dose of the drug may increase the likelihood of
resistance developing. Given saquinavir's lack of toxicity so
far, dosages could be increased to attain maximum benefit. Why
didn't Roche perform a small multiple dose-escalation trial
before the initiation of these large multinational trials?
Dr. Thomas Merigan at Stanford University is now embarking on
such a dose-escalation study. Doses two to four times the
amount Roche is administering in its phase III trials will be
examined. Dr. Merigan describes the trial as a quick, four
month look at sixteen volunteers (CD4 count range: 200-500) to
see how larger amounts of saquinavir affect virus levels and
the rise of drug-resistant strains. (Drug resistance is known
to have occurred in one Italian patient and may be the reason
for the drug's very transient effect in the French single agent
study). The results could push Roche to develop a second
generation, more advanced protease inhibitor, or at least a
version of saquinavir that is more absorbable, a process that
will take two to four years to complete.
Roche would be hard-pressed to expand production quickly to
supply everyone in a large trial, let alone all the HIV-
positive people in the world, with the higher doses Dr. Merigan
is trying out. But the main reason for not moving on to larger
doses with the present formulation appears to be the drug's
prohibitive manufacturing cost. The price of treatment with the
high dose regimen would be more than the market could bear, Dr.
Suppose, though, that Merigan finds that saquinavir produces
significant benefit at the higher doses while Roche's large
phase III trials detect just a mediocre benefit. Will the FDA
approve the drug at the lower (1800mg/day) dose? There is the
risk that a two-tiered standard of care will arise, in which
only the richest receive the really effective high dose.
Large numbers of people receiving too small a dose is likely to
spread resistant HIV strains far and wide, eventually
destroying saquinavir's usefulness. An analogous phenomenon is
occurring with tuberculosis.
It could be, too, that the large phase III trials will not
really be large enough or long enough to document benefit if
that benefit turns out to be slight. While Roche and the FDA
sort out the issues, there at present are no plans to institute
an expanded access program for the drug. The problem once again
seems to be the difficult, expensive production process. For
now, you can only obtain Roche's protease inhibitor by entering
a clinical trial - that is, you risk getting AZT or the still
more problematic ddC, either alone or in combination with only
a modest amount of saquinavir.
The development of these two trials occurred without a great
deal of interaction with community representatives. This could
well be due to the history of conflicts between Roche and AIDS
activists. It is time to put these issues behind. Roche is
simply too big a player in AIDS drug development to be allowed
to develop a critical AIDS therapy without continued dialogue
with community representatives. Broad ranging discussions are
in everyone's interest.
Dr. Roy Vagelos, Merck's chairman, has targeted the development
of a useful anti-HIV agent as both a corporate and personal
goal. To date, Merck's programs (vaccines, monoclonal
antibodies, and reverse transcriptase inhibitors) have yielded
disappointments. Merck researchers discovered the structure of
the HIV protease molecule, and protease inhibition is now the
cornerstone of their HIV research effort, a program designed to
get answers quickly.
The first results on Merck's protease inhibitor (L-735,524)
were very encouraging. In fact, they were the best data for any
anti-HIV drug to date. Blood levels of people on L- 735,524
showed a vast decrease in HIV activity. The detectable amount
of HIV core protein (p24) went down to zero, and the level of
HIV genetic material (RNA) in the blood was reduced by 99
percent. Significant CD4 count rises and weight gains also
Four of the first patients on L-735,524 have continued with the
drug, and, unfortunately, the follow-up data are not so good.
Blood tests are available for three of the individuals. In all
three cases, HIV RNA started to rebound after week twelve and
by six months was back at the original, baseline level. CD4
counts and p24 levels remained improved, but the latest
measurements show a worsening in those values, as well. (Both
of these parameters reflect immune system competence. The level
of free p24 depends on the amount of antibody the immune system
produces against that protein.) The reason for this relapse is
almost certainly due to the development of drug-resistance.
L-735,524 is administered every four hours, and the minimum
concentration in that four hour period is considered barely
sufficient. (It equals the IC 90 level.) Merck has never tried
to push their medication to see what the maximum tolerable
doses are. The company stopped escalating the dose when the
first signs of altered liver function (elevated levels of
transaminase and bilirubin) developed.
Merck has responded to this new development (the HIV RNA
analysis only became available at the end of January) by
boosting the dosage of L-735,524 for all participants in its
current 60-person trial. (The dose has been raised from 200 or
400mg six times a day to 600mg six times a day, the highest
Merck dares go.) Larger clinical trials have been put off
indefinitely while Merck tests L-735,524 in combination with
AZT and ddI.
Either of these strategies might put off the time when
resistant mutants become predominant in the body. But Merck
researchers were hoping for a "home-run" drug that completely
stopped HIV. Still, the Merck drug seems to produce a profound
antiviral effect - better than either AZT or the Roche protease
inhibitor. This drug could provide significant clinical
benefits to patients. There is a risk that Merck will too
quickly abandon a compound that represents a tangible
improvement over past drugs. The company should make sure that
this does not happen. Trials of L-735, 524 in targeted
populations, such as patients with advanced disease who cannot
take AZT, could be initiated without delay. Merck reports that
it is actively working on the development of other protease
compounds in addition to L-735,524, although it is not believed
that any of them have gone into animal tests yet. Despite some
disappointments, the company has been able to initiate trials
and get answers in a rapid period of time. In addition, it has
maintained a continued and open dialogue with community
representatives about its entire drug development program.
These are no small accomplishments.
Abbott is now on its third protease inhibitor. The first, A-
77003, was discontinued last summer. That substance had to be
delivered by a central catheter 24 hours a day and caused
severe vein irritation without achieving much benefit. In
February 1994, Abbott halted development of its oral protease
inhibitor, A-80987. Last fall, an eight-week, four- arm
efficacy trial of A-80987 found that the high and medium
dosages (given in six daily doses) were associated with a
reduction in p24 blood levels. However, there was no reduction
in viral load and some liver toxicities were reported.
Abbott has concluded that protease inhibitors can work and is
continuing to search for a nontoxic version. The company is now
preparing for human testing of its third compound, A- 84538.
This compound is about as potent in suppressing HIV replication
as AZT is in susceptible viral strains. Moreover, it is equally
active in strains that are AZT-resistant. But A-84538 can cause
liver and eye problems. Extensive ocular exams will be required
in the trial.
Abbott seems finally to have arrived at a very bioavailable
formulation - 80 percent is absorbed when fed to rats - but
A-84538 is so unstable that study participants will not be able
to take it home with them. They will have to visit the clinic
every day to get their daily dose in a liquid solution.
Abbott may have a while to go before developing a protease
inhibitor that has antiviral activity and relatively low
toxicity. The company's program is small, although it does
include some high quality researchers.
Abbott has been tight-lipped about its plans. In the past, its
relations with the AIDS community has been contentious due to
the plodding pace of its AIDS drug development programs. The
present protease inhibitor program, with all its false and
confusing starts, threatens to repeat past troubles.
Searle has two lead protease inhibitors. The first, SC-52151,
appears to be less attractive than the second generation
compound, SC-55389A. SC-52151 has less bioavailability, a
shorter half-life in the body and less distribution in tissues
due to protein binding. In addition, shifts in anti- viral
potency were observed after HIV was exposed to SC-52151 for one
year in the lab, implying the development of resistance. No
toxic effects have been seen in animals receiving 600mg per
kilogram of body weight for four weeks. Lab tests with
chronically infected cells found that SC-52151 is about ten
times as potent in suppressing HIV as AZT. Searle claims to be
advancing as fast as possible with its molecules. Phase II
studies of SC-52151 are beginning in Berlin. SC-52151's
bioavailability rate when taken orally is 20 percent, much
higher than for Roche's protease inhibitor, but the drug has to
be administered in a 70 percent alcohol solution. Clinical
trials of SC-55389A will begin later in 1994. Oral
bioavailability for this substance is 70 percent in dogs, one
of the highest rates seen so far.
Levels for SC-52151 fall to the subtherapeutic levels (below
the IC90 threshold) between dosages. This is not encouraging.
HIV might rebound relatively quickly in this situation. It will
be interesting to compare SC-52151 with the human data for the
second generation compound, SC-55389A. With its longer
half-life in the body and less protein binding, SC- 55389A
should reach higher concentrations than its predecessor.
Additionally, it can be given in a pill form. If the data
confirms its superior profile, SC-55389A will become Searle's
Vertex/ Burroughs Wellcome
Vertex is a small biotechnology company based in Cambridge,
Massachusetts and founded in 1989 by Joshua Boger, previously
the senior researcher at Merck. Vertex's claim to fame is
rational drug design. This approach integrates biology,
biophysics, and medicinal chemistry to create highly specific
small-molecule drugs based on the atomic structure of proteins
involved in disease. Its three main areas of drug development
are HIV, drug-resistant cancer and hemoglobin disorders (sickle
cell anemia and thalassemia).
Burroughs Wellcome Co. has signed a five-year HIV protease
inhibitor development deal with Vertex involving as much as $32
million plus a royalty payment based on sales. Wellcome will
fund the clinical trials and receive worldwide marketing rights
to the compound.
Wellcome's investment is good news - both for Vertex and for
people with HIV. For Vertex, the deal essentially removes most
of the development risks. If the deal reflects the quality of
the preclinical data (so far unreleased), Vertex's molecule,
VX478, may have terrific stability and safety in the body.
Also, the molecule's structure is simple and easy to
manufacture. (It is rumored that when Wellcome management were
shown the structure at the end of negotiations, it sold the
Vertex officials claim their drug has the potential to pack the
"big wallop" that would knock out HIV. They say that the
minimum level of VX478 between doses is ten to one hundred
times more powerful than the Merck drug's minimum. For added
protection, they envision starting combination drug trials from
the very beginning - no doubt with Burroughs Wellcome's AZT.
Human trials have been temporarily put on hold while Vertex's
new partner evaluates trial design. But the compound is now
fully funded and in the hands of an experienced development
team. Considering Burroughs Wellcome's investment and track
record, one can predict that the development program will be
large and aggressive.
Agouron is a small biotechnology company based in La Jolla,
California. Like Vertex, it specializes in designing
therapeutic molecules. Agouron has developed three non- peptide
molecules that inhibit HIV protease in laboratory tests. Using
its structural design approach, the company has altered the
molecules in ways that change their potency, bioavailability
and solubility in lipids (to improve their ability to cross the
blood brain barrier). Final preclinical kinetics and toxicology
will be performed during the first half of 1994, and a decision
will be made on which compound will go into humans.
The oral bioavailability in animal models ranges between 20 and
50 percent. The compound appears to have a good toxicity
profile - toxic levels of each compound are many multiples of
the effective (IC90) concentration. The company predicts that
twice-daily administration will be sufficient for these drugs.
But very little can be said from the preclinical data. Once
again, the great hurdle will be whether any of these compounds
achieves a minimum concentration in the body high enough to
stop HIV replication.
Agouron has approximately $30 million in cash and is burning
approximately $15 million annually even before it starts human
trials with these compounds. A corporate partner may now be
difficult to find because of the number of protease inhibitors
entering clinical trials. If Agouron's compounds look good in
preclinical testing, it would be a tragic error to slow their
development due to a shortage of cash.
Many other institutions have protease inhibitors in
development, including Pfizer, Ciba-Geigy (CGP-53437),
Hoechst-Bayer (Hoe/Bay-793, which is being dropped but may lead
to better compounds), Upjohn (U-75875), Sanofi (SR- 41476),
Kyoto Pharmaceutical University in Japan (KNI-272), Nippon
Mining, Parke-Davis, and, reportedly, SmithKline Beecham,
Syntex, and the National Cancer Institute. Some of these
compounds are not yet ready for human trials, and others are
Glaxo reported last summer that their penicillin-based protease
inhibitors had pharmacokinetics problems and had been canceled.
A Du Pont Merck protease inhibitor (DM-323) was recently
canceled, too, but a second generation molecule is under
Protease inhibitors have a definite theoretical appeal as a
therapeutic strategy. The first data indicate that they do have
some efficacy - at least as good as reverse transcriptase
inhibitors like AZT - although there are a number of practical
For many uses, protease inhibitors may represent an improvement
on reverse transcriptase inhibitors like AZT. But the ethics of
clinical trials is such that they will be tested against the
standard of care, which means AZT for some patients and ddI or
ddC (and d4T, should it be approved) in others. Protease
inhibitors will be unavailable for the foreseeable future to
those who wish to avoid the toxicities of AZT and similar
medications. To fulfill protease inhibitors' promise any time
soon, research on them must be accelerated, with the most
promising compounds given priority development.
Getting Quicker Answers About Protease Inhibitors Protease
inhibitors are the only new AIDS therapy on the verge of
acceptance. Quick public access - or rapid abandonment if
protease inhibitor research reaches a dead end - should be a
high priority for government and industry. These steps could be
taken to facilitate development every step of the way:
1. Establish clear, identifiable standards for FDA approval
Evaluation of protease inhibitors begs for standardization.
The FDA needs to make clear what it will accept as proof of
efficacy. The same old problem of surrogate markers has come
up again. As it stands now, we may have to wait for data on
clinical markers (worsening of symptoms or death) to
demonstrate efficacy. Yet a number of tests that measure
viral load now can give a very rapid picture of how HIV is
responding to therapy. Researchers, government officials,
and community representatives need to reach a consensus
about how to evaluate these compounds and which particular
measurements of viral burden, tests such as polymerase chain
reaction (PCR), "quantitative competitive" PCR and branched
chain DNA, are most reliable.
2. Pursue partial cures. Many companies are looking for the
"home-run" protease that eliminates HIV, but development of
partially effective therapies, the "singles" and "doubles,"
must not be abandoned. These latter compounds could be more
potent and less toxic than the nucleoside analogs and help a
great many individuals. When necessary, the National
Institutes of Health (NIH) should step in and provide
funding for trials of these drugs in special populations.
These populations include people with advanced AIDS, where a
particular drug may bring temporary but important antiviral
effects and clinical benefits.
3. Initiate combination trials. It is doubtful that protease
inhibitors will ever be a cure for AIDS all by themselves.
They may be used with a wide variety of other antiviral
drugs (including reverse transcriptase inhibitors) and
immune modulators. Other compounds such as various cytokines
and antioxidant nutrients could be part of the package. A
legitimate evaluation of protease inhibitors requires that
they be tested as real people will use them - not alone or
only together with a given company's other products. Once we
have a better idea of protease inhibitors' potential, the
government could sponsor massive trials that compare people
on their usual, multifaceted regimens with people following
both their normal regimens and taking one (or several?)
4. Test several protease inhibitors together. It would be
relatively easy and inexpensive to find out how the
different protease inhibitors act together - both in lab
cell cultures and soon thereafter, in people. This would
provide important information as to whether the use of
different protease inhibitors could impact the development
of resistance. For instance, researchers might begin testing
the Roche compound and the Merck compound together in lab
cells to see how they interact. This work could be sponsored
by the pharmaceutical industry's Inter-Company Collaboration
for AIDS Drug Development or by the NIH.
5. Assist small, cash poor companies. Some companies are
pushing ahead just because they have the resources to do so
while some underfunded companies are languishing even though
they may have a better compound. The present climate for
investment in biotechnology is not good; the government has
a responsibility to see that financial considerations are
not the main arbiters of which protease inhibitors become
available to the public. When necessary, public funds could
be made available to further research on promising products
(with, of course, the public assured of a fair return on its
6. Government should work with industry. NIH officials should
meet with all the companies currently developing HIV
protease inhibitors to underscore the importance of
developing effective anti-HIV therapies that could be
available within the next two years. Industry and government
can work together to maximize the chances for success with
this class of compounds. - D.G./D.G.
More Problems with Resistance
As Treatment Issues went to press, a new study of protease
inhibitor-resistant HIV appeared in the March issue of the
Journal of Virology.* It described the protease produced by HIV
mutant strains that are resistant to Abbott Laboratories'
original protease inhibitor, A-77003, and similar compounds.
The report's chief author was prominent HIV virologist David Ho
of the Aaron Diamond Foundation in New York. Dr. Ho's group
found that two alterations in the amino acid sequence of HIV
protease is enough to allow the enzyme to continue normal
functioning in the face of large amounts of A-77003. In rare
cases, a single change was sufficient to accomplish this.
Based on his observations Dr. Ho told Treatment Issues, "We
looked at the Abbott protease inhibitor, but this has
implications for all the others too. Protease inhibitors are
just another drug to use, with reasonable activity for a
If the observations hold up for different protease inhibitors,
then these drugs will probably encounter many of the same
problems as AZT, though HIV's protease enzyme is perhaps not as
capable of change as HIV's reverse transcriptase enzyme is.
And trying high doses to delay the evolution of resistant
strains may be counterproductive: If a few resistant mutants
exist before introducing the protease inhibitor, or can easily
evolve through a single mutation, then high dose therapy will
just increase the speed with which the resistant HIV becomes
predominant by quickly killing off the normal, susceptible
Still, Dr. Ho noted that combinations of different protease
inhibitors may "back the virus into a corner." Combination
therapy could require an impractical number of structural
changes to create a protease enzyme resistant to all the
inhibitors it faces.
This strategy does not work with reverse transcriptase,
however, because the various modifications in the enzyme's
structure can coexist in a functional molecule. Also, some
mutations confer cross-resistance to a number of reverse
The same may be true for the protease molecule. Evolution is a
very dynamic, unstoppable process. As Dr. Robert Schooley of
the University of Colorado put it, "Resistance [to protease
inhibitors] is predictable. Its emergence is a consequence of
the drugs' effectiveness. We'll need to find strategies to get
* Ho DH, et al. Journal of Virology, 1994; 68(3):2016-2020.
1 Navia MA, et al: Nature, 1989; 337(6208):615-620.
2 Kohl NE, et al: Proceedings of the National Academy of
Sciences of the USA, 1988; 85(13):4686-4690.
3 Kageyama S et al: Antimicrobial Agents and Chemotherapy,
4 Schatzl H, Archives of Virology, 1991; 120(1-2):71-81.
5 Lambert DM, et al: Antimicrobial Agents and
Chemotherapy, 1992; 36(5):982-988.
6 Vacca JP, et al: Journal of Medical Chemistry, 1991;
7 Otto MJ, et al: VIII International Conference on AIDS,
abstract ThA 1505. July 1992.
8 Johnson VA, et al: Journal of Infectious Diseases, 1992;
9 Delfraissy JF, et al: IX International Conference on
AIDS, abstract WS-B26-3. June 1993.
10 Torres G: GMHC Treatment Issues, 1993; 7(7):4.
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