       Protease Inhibitors

       A new family of drugs for the treatment of HIV infection
       What they are, how they work, when to use them

       Martin Markowitz, MD

       Dr. Markowitz is a staff investigator at the Aaron Diamond
       AIDS Research Center and Assistant Professor of Medicine at
       the New York University School of Medicine in New York City.

       (Note: This is the text only of the Protease Booklet and does
       not contain the illustrations.)

       Protease inhibitors are drugs that slow down the spread of
HIV-the virus that causes AIDS-inside the body. Using measurements
of HIV circulating in the blood, studies of protease inhibitors in
people with HIV show that these drugs are more powerful than the
first group of drugs used to treat HIV (the reverse transcriptase
inhibitors): Certain protease inhibitors can reduce the amount of
virus in a person infected with HIV by as much as 99%. But a
protease inhibitor alone is not a cure for HIV infection or AIDS.
The researchers studying these drugs still have a number of
questions about how well they will work and how they should be used.

       This booklet answers some of the basic questions about
protease inhibitors. For the questions that can't be answered now,
the booklet tries to give the best information available. This
information will change as protease inhibitors are used by more
people with HIV infection and as more is learned about how they
work. So decisions about using protease inhibitors-in clinical
trials and later when they are approved-should be made with the help
of your physician and the team of healthcare workers involved in the
clinical trials.

       Words printed in italics the first time they appear in this
booklet are explained in the word list starting on page 14.


       1.  What are HIV infection and AIDS?

       Like other viruses, HIV depends on the cells it infects to
make new copies of itself. These new copies of HIV go on to infect
other cells. In this way, HIV spreads throughout the billions of
cells in the body. One of HIV's favorite targets is a white blood
cell called a T helper cell or CD4 cell. These blood cells are
important because they tell other infection-fighting cells when to
start working. HIV destroys CD4 cells, and when the number of CD4
cells drops to a certain level because of ongoing HIV infection, the
body's immune system weakens. As a result, organisms such as fungi,
viruses, and parasites that can live inside most people without
causing disease can cause serious infections in people with HIV.
When these infections occur, or when the number of CD4 cells drops
below a certain level, a person with HIV infection is said to have
AIDS.


       2.  What is HIV protease?

       To make new copies of itself inside infected cells, HIV
depends on several enzymes that it brings into the cell or makes
inside the cell. All of these enzymes have specific jobs in the HIV
replication (copy-making) process. Protease is one of HIV's enzymes,
and it is required to continue the process of HIV infection. Its job
comes near the end of the HIV replication process. By then, HIV has
already entered the cell's nucleus and has made long chains of
proteins and enzymes that will form many new copies of HIV. But
before they can start working correctly, the long chains have to be
cut into smaller pieces (Figure 1). The HIV protease enzyme  is like
a "chemical scissors" because it cuts the long chain into shorter
pieces.

       3.  What are protease inhibitors and how do they work?

       Protease inhibitors are drugs that resemble pieces of the
protein chain that protease normally cuts. By "gumming up" the
protease "scissors," HIV protease inhibitors prevent protease from
cutting long chains of proteins and enzymes into the shorter pieces
that HIV needs to make new copies of itself (Figure 1). New copies
of HIV are still made and still push through the wall of the
infected cell (Figure 2) even if the long chains aren't cut up into
the correct smaller pieces. But these new copies of HIV are
"defective" (not completely formed), so they can't go on to infect
other cells. Protease inhibitors can greatly reduce the number of
new, infectious copies of HIV made inside cells. If protease
inhibitors succeed in making most new HIV viruses defective, HIV
infection would not spread inside the body as quickly as it does
now. Sometimes you will see the term proteinase inhibitor. It is the
European name for protease inhibitor.

       4.  Will protease inhibitors get rid of HIV?

       A protease inhibitor alone will not get rid of HIV in an
infected person's body. Even though these drugs can reduce the
amount of virus by 99%, more virus can remain elsewhere in the body.
Because some infected cells are "dormant" or "latently
infected"-meaning they are already infected but still waiting to
make new virus-researchers doubt that any one drug can remove all
the virus in an infected person. Some virus will stay in the body in
latently infected cells. Even so, if protease inhibitors do greatly
slow the pace at which HIV makes new copies of itself, fewer new
cells would be infected by HIV, and cells already infected will
eventually die. As a result, because there is less virus, fewer CD4
cells would be infected, fewer would be destroyed, and an
HIV-infected person could stay healthier longer. So controlling the
amount of virus would help a person fight off other infections
longer and continue to live an active life.

       5. How do protease inhibitors differ from other available
          anti-HIV drugs?

       The main ways protease inhibitors differ from the other
anti-HIV drugs used now are in their target and in their strength.
These other drugs are called reverse transcriptase inhibitors
because they disturb the job of an HIV enzyme called reverse
transcriptase.

       Reverse transcriptase is the enzyme HIV uses to change its
chemical (or genetic) message into a form that can easily be
inserted inside the nucleus of the infected cell (Figure 2). This
step in the HIV replication process happens soon after HIV infects a
cell-much earlier than the step in which protease inhibitors are
involved (Figure 2). Because protease inhibitors and reverse
transcriptase inhibitors work at two separate steps in the HIV
replication process, some studies are testing the use of drugs from
both groups at the same time to treat HIV infection. This strategy
of combining drugs is similar to the way doctors fight diseases like
tuberculosis (TB) and leukemia (a cancer of the blood).

       In the United States, physicians may prescribe five reverse
transcriptase inhibitors. The common names of these drugs are: . AZT
(Retrovir, zidovudine) . ddI (Videx, didanosine) . ddC (Hivid,
zalcitabine) . d4T (Zerit, stavudine) . 3TC (Epivir, lamivudine) The
drug names inside parentheses ( ) are the official brand name
followed by the generic name of each agent. Protease inhibitors also
differ from reverse transcriptase inhibitors in their strength.
Results from laboratory tests and tests in people show that certain
protease inhibitors are many times more powerful than reverse
transcriptase inhibitors in slowing the replication of HIV and in
increasing the number of CD4 cells in the body.

       6.  What protease inhibitors are being studied now?

       Four protease inhibitors are in the final stages of testing
in people with HIV as this booklet is being written.

       * One of them, saquinavir (Invirase), has already been
         approved for use by the Food and Drug Administration (FDA)
         in the United States for use with the drugs called reverse
         transcriptase inhibitors. (See 5 above.)

       * Two other protease inhibitors, indinavir (Crixivan) and
         ritonavir (Norvir), will probably be approved early in
         1996.

       * Large national trials for a fourth protease inhibitor,
         nelfinavir (Viracept), are under way.

       Even before drugs are approved, they are available to some
people who are willing to participate in clinical trials of these
drugs. Drug makers also sometimes make still-unapproved drugs
available through compassionate use programs. But because protease
inhibitors are more difficult to make than other drugs, supplies for
such programs have been limited. Usually, these programs are open
only to people with low CD4 counts.

       7.  Can protease inhibitors be combined with other drugs?

       Most AIDS experts agree that it will make sense to combine
protease inhibitors with drugs that attack HIV at different stages
of its replication process. In fact, if protease inhibitors appear
to be safe and effective when given alone  in early, small trials in
people with HIV infection, they are usually combined with other
types of drugs in larger trials.

       It is still too early to tell which combinations will work
best. The best combination for one person may not be the best for
another. Each combination involving protease inhibitors will have to
be looked at carefully to make sure that the combination does not
cause a lot of new side effects or increase the side effects of the
other drugs. And it is important to remember that individuals will
differ from others not only in how well a combination works for
them, but also in what side effects may develop.

       There is a simple explanation for why HIV drug experts don't
expect bad interactions between protease inhibitors and the reverse
transcriptase inhibitors like AZT: Protease inhibitors are processed
by the liver, and drugs like AZT are processed inside nonliver cells
and eliminated from the body through the kidneys. But other drugs
used by people with HIV and AIDS are processed by the liver, just as
protease inhibitors are. So the chance for interactions between
those drugs and protease inhibitors is higher.

       People with HIV infection who are taking other
drugs-especially antibiotics, anti-TB drugs, antihistamines (for
allergies), antifungals, and antidepressants-should ask their
primary care physician about possible drug interactions when
considering whether to start treatment with a protease inhibitor.


       8.  What side effects do protease inhibitors have by
           themselves?

       Like almost all strong medicines, protease inhibitors have
side effects. It is hard to tell how serious or how frequent these
side effects will be until many people begin taking protease
inhibitors regularly. But, so far, there is some good news. In
general, the side effects of the protease inhibitors being tested
are different from side effects seen during treatment with reverse
transcriptase inhibitors. That means that side effects alone may not
prevent people from taking protease inhibitors and reverse
transcriptase inhibitors at the same time.

       9.  What is resistance and how big of a problem is it?

       Resistance is the ability of HIV to change its chemical (or
"genetic") structure so that it resists the effects of drugs. All
viruses and bacteria can change themselves in this way. Resistance
may develop to every anti-HIV drug in use today when given as
"monotherapy" (one drug at a time). With some drugs it happens very
quickly, and with others it takes longer.

       Resistance is a complicated problem. HIV drug experts are
still trying to figure out exactly what it means for people who are
taking drugs for HIV infection. Resistance to a drug may not
necessarily mean that a person should stop taking that drug and will
never be able to take it again.

       Some studies of reverse transcriptase inhibitors show that
certain patterns of resistance can be a plus instead of a minus.
Researchers found that the chemical change that causes resistance to
3TC reverses the resistance to AZT. Some experts think this is why
3TC and AZT work together so well. Also, all of the viruses in an
infected person's body don't suddenly become resistant to a drug at
the same time. So a drug can continue to be effective against the
many nonresistant viruses still in the body. If a protease inhibitor
is taken with other anti-HIV drugs-AZT and 3TC, for example-those
other drugs might be able to attack the viruses that are resistant
to the protease inhibitor. And the protease inhibitor could attack
all the other viruses that are not resistant to it.

       As with other drugs, each protease inhibitor differs in how
quickly resistance to it develops. And everyone with HIV will differ
in how quickly their HIV viruses will become resistant to different
protease inhibitors. Resistance will develop more slowly in people
with only a little virus in their body and with relatively high CD4
counts. In people with a lot of virus in their body, resistance will
probably develop more quickly.

       10. What is cross-resistance?

       HIV can become resistant to two or more drugs at the same
time. When it does, HIV is said to be cross-resistant to those
drugs. Researchers studying the protease inhibitor indinavir found
that HIV in some people first became resistant to the drug and then
became resistant to several other protease inhibitors when they were
tested later.

       AIDS experts agree that cross-resistance is a problem that
must be studied closely. But most say it is too soon to understand
the relationship between resistance to drugs and how best to treat
HIV, because new findings are made every day. For example,
researchers studying saquinavir say recent studies suggest that
high-level cross-resistance will not be a problem in individuals
first treated with this protease inhibitor. And other research shows
that viruses that become resistant to several protease inhibitors
are still susceptible (not resistant) to some of the newer protease
inhibitors being developed.

       At this point, most experts believe that people will be able
to take two protease inhibitors at the same time-or one after
another. It is too early to tell, though, what will be the best way
to use these drugs. But it seems clear that suppressing the activity
of HIV by using protease inhibitors in combination with other
anti-HIV drugs is the best defense against resistance.

       (TABLES)

       PROTEASE INHIBITORS IN THE FINAL STAGES OF DEVELOPMENT

 Drug name(s)*   	 Maker           	Stage of development

 Invirase            Hoffmann-            Approved for use in
 (saquinavir,        La Roche             combination with reverse
 RO-31-8959)                              transcriptase inhibitors
                                          (AZT, ddI, ddC, d4T, 3TC)

 Norvir		Abbott               In final trials in people
 (ritonavir,                              with HIV infection; could be
 ABT-538)                                 approved in early 1996

 Crixivan            Merck                In final trials in people
 (indinavir,                              with HIV infection; could be
 MK-639)                                  approved in early 1996

 Viracept            Agouron              Will begin final trials in people
 (nelfinavir,                             with HIV infection in early
 AG-1343)                                 1996

       * The first drug name in each group, spelled with a capital
         letter, is the brand name-the official name a drug gets
         when it is approved by the FDA or is close to being
         approved. The second name in each group, spelled without a
         capital letter, is the generic name-the one that is usually
         used during later trials of a drug. The third name, which
         always has a number in it, is the name a company uses when
         it first starts to test a drug. With reverse transcriptase
         inhibitors, the drug names most often used-AZT, ddI, ddC,
         d4T, and 3TC-are abbreviations of the chemical names of the
         drugs.




       PROTEASE INHIBITORS IN THE EARLY STAGES OF DEVELOPMENT

 Drug name(s)*       Maker                Stage of development

 VX-478,             Glaxo-Wellcome/      In early trials in people
 141W94              Vertex               with HIV infection

 KNI-272             Nikko Kyoto          In early trials in people
 (kynostatin)        Pharmaceutical       with HIV infection
                     and National
                     Cancer Institute

 U-103373            Upjohn               In early trials in people
                                          with HIV infection

 CGP-53437           Ciba-Geigy           In laboratory tests

 Hoe/Bay-793         Hoechst-Bayer        In laboratory tests

 SR-41476            Sanofi               In laboratory tests


       Other companies, including Boeringher Ingelheim,
Bristol-Myers Squibb, Lilly, Parke-Davis, Sandoz, Searle, and
SmithKline Beecham,  have been working on protease inhibitors.

       * See the footnote to the first table for an explanation of
         the different types of drug names.

       Protease inhibitor word list


AIDS:  Advanced infection with HIV, marked by certain conditions
       that do not occur in people with healthy immune systems, or
       by a decrease in CD4 cells below the level of 200 copies per
       microliter of blood.

CD4 cells:  White blood cells that help direct the body's
       infection-fighting cells. They're named after the CD4
       molecules they carry on their surface. Also called T helper
       cells.

CD4 count: The number of CD4 cells in a tiny drop of blood (a
       microliter, or about 1/5000th of a teaspoon). Because HIV
       attacks CD4 cells, their number falls as the infection gets
       more serious.

clinical trial:  A study of the effects of one or more drugs in people.

Compassionate use program:  A plan through which the maker of a new
       drug can give that drug to some people who need it even
       before it is approved by the Food and Drug Administration
       (FDA). Such programs often include people outside the United
       States.

cross-resistance:   Resistance of HIV to more than one drug at the
       same time.

enzyme:   A kind of protein that causes chemical changes inside
       cells.

genetic: Having to do with genes, tiny segments of chemicals
       inside all viruses and cells that carry the information
       needed to make proteins that perform basic functions (such as
       the replication of viruses).

HIV: The human immunodeficiency virus. It attacks
       infection-fighting blood cells (CD4 cells) and other cells
       and causes AIDS.

immune system: The network of organs and cells in the body that
       recognizes and fights off infections and other "foreign"
       invaders.

infectious:   Having the ability to infect (get inside) uninfected
       cells.

protease:   An enzyme that HIV uses to make new copies of itself
       inside infected cells.

protease inhibitor (PRO-tee-aze in-HIB-it-ter):   A drug that stops
       protease from making new copies of HIV that can infect other cells.

proteins:   Complex compounds that are a major part of cells in all
       plants and animals. Their makeup depends on the particular
       genes inside each cell. The genes of viruses such as HIV also
       make specific proteins inside infected cells. proteinase
       inhibitor:   Another name for protease inhibitor, often used
       in Europe.

resistance:   The ability of HIV to change its chemical (or genetic)
       structure so that it resists the effects of drugs.

replication:   The process by which HIV makes new copies of itself
       inside infected cells.

reverse transcriptase (ri-VERS tran-SKRIP-taze):  An HIV enzyme that
       lets the virus's genetic message get inside the genetic
       machinery of infected cells.

reverse transcriptase inhibitor:   A drug that stops reverse
       transcriptase from doing its job efficiently inside infected
       cells.

side effects:   The unwanted (sometimes harmful) effects of drugs.

T helper cells:   White blood cells that help direct the body's
       infection-fighting cells. Also called CD4 cells.

The International Association of Physicians in AIDS Care (IAPAC)
thanks the following members of the Protease Inhibitor Booklet
Advisory Committee for their thoughtful recommendations on this
project:

       Karen Cashmere
       Dianne Denton
       Linda Distlerath, PhD, JD
       Pearl Leung
       Jules Levin
       Joanna Peterkin, MD
       John C. Pottage, Jr., MD
       Angela Shiloh-Cryer
       Barry Teeters
       David L. Thomas
       Mabrey Russell Whigham, III

IAPAC also thanks the participants in our focus groups for their
important contributions to this project. The English, French,
German, Italian, Portuguese, and Spanish versions of this booklet
will be made available through more than 20,000 physicians' offices,
clinics, and AIDS service organizations  in 41 countries throughout
the world. The contents of this booklet represent the opinions of
the author and do not necessarily reflect the official policy of the
International Association of Physicians in AIDS Care, or the
institutions with which the author is affiliated. This booklet was
developed and distributed through an unrestricted grant from Abbott
Laboratories, Abbott Park, Illinois. This booklet is an educational
service of the International Association of Physicians in AIDS Care.

Copyright-1996 International Association of Physicians in AIDS CAre
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