                                  [Image]

                   Combination Therapy for HIV Infection

           Why to use more than one drug, and which drugs to use

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

                       Published by IAPAC March, 1997


Contents

Introduction

1. What are HIV infection and AIDS?

2. What are the different types of drugs that attack HIV, and how do they
   work?

3. Why does combination therapy make sense?

4. What drug combinations work well together?

5. What other kinds of combinations are doctors testing and thinking
   about?

6. What should your goal be with combination therapy?

Combination therapy word list.

Acknowledgements

Introduction

Words printed in italics the first time they appear are linked to
explanations in the Word List page. Click on the word on the Word List
page, and you'll be returned to the word's place on this page.

Combination therapy is the use of two or more drugs at the same time
for the same disease. Doctors have known for a long time that the best
way-often the only way-to control some diseases is to combine several
drugs. For example, tuberculosis (TB) and some kinds of cancer are
best treated with combination therapy.

When drugs were developed to treat infection with HIV-the virus that
causes AIDS-they became available one at a time. And most doctors used
them one at a time to try to slow down HIV infection and help infected
people live longer. As more and more anti-HIV drugs were approved for
use, some doctors began giving them together. Studies were planned to
see if two drugs worked better than one, then if three drugs worked
better than two. Time after time, these studies demonstrated that what
works for tuberculosis and cancer also works for HIV infection: Taking
a combination of drugs directed against the virus is better than
taking only one.

This booklet answers some of the basic questions about combination therapy
for HIV infection: Why does combination therapy work better than one-drug
therapy? What anti-HIV drugs are available? Which ones work best together?
Of course, we don't have a final answer to the last question, because many
combinations of drugs have not been compared in carefully planned studies.
But the studies that have been done have convinced almost all doctors that
combination therapy offers the best hope for slowing down HIV infection.


1. What are HIV infection and AIDS?

Like other viruses, HIV makes new copies of itself inside the cells it
infects. These new copies of HIV go on to infect other cells. In people
infected with HIV, over 10 billion new copies of the virus can be made
every day. So, if the virus is not stopped from making new copies, it is
easy for HIV to spread quickly throughout the billions of cells in the
body.

One of HIV's favorite targets is a white blood cell called a CD4 cell.
These blood cells are important because they tell other infection-fighting
cells when to start working. HIV infection lowers the number of CD4 cells
(the CD4 count) over time. 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, the body can't fight off infections and cancers. When these
infections or cancers occur, or when the CD4 count drops below 200, a
person with HIV infection is said to have AIDS.


2. What are the different types of drugs that attack HIV, and how do they
   work?

HIV belongs to a group of viruses called retroviruses. So any drug used to
attack HIV is called an anti-retroviral. But it's simpler just to think of
them as anti-HIV drugs. Right now, in the United States, doctors can
prescribe nine anti-HIV drugs (see Table). Several others are still going
through the testing required in people with HIV infection before they can
be approved for wide use.

These drugs fall into three groups. The first five anti-HIV drugs were all
nucleoside analogs, sometimes called nucleoside analog reverse
transcriptase inhibitors or just nucleosides. The most recently approved
anti-HIV drug is in another group called the non-nucleoside reverse
transcriptase inhibitors (NNRTIs) or, simply, non-nucleosides. In between
the five nucleosides and one non-nucleoside came three protease inhibitors.
Researchers are working on other drugs in all three groups.

   Available anti-HIV drugs, and some of their differences (as of March,
                                   1997)

  Drug names*    Studied most  How given     Special       Side effects
                in combination            features and
                    with:                  comments**

 Nucleoside analog reverse transcriptase inhibitors

 Retrovir       ddI, ddC, 3TC, Two or    Reaches HIV in Anemia (low number

 (zidovudine,   saquinavir,    three     spinal cord andof red blood

 AZT)           ritonavir,     times     brain; often   cells),
                indinavir,     daily     combined with  granulocytopenia
                nevirapine               3TC; probably  (low number of
                                         should not be  white blood
                                         given with d4T;cells), muscle
                                         works best in  weakness
                                         cells actively
                                         producing new
                                         HIV

 Videx          AZT, d4T,      Twice     Effectivness inPancreatitis

 (didanosine,   indinavir,     daily, 1  combination    (inflammation of

 ddI)           nevirapine     hour      with AZT       the pancreas),
                               before or demonstrated inperiperal
                               2 hours   large studies; neuropathy
                               after     recent smaller (numbness or pain
                               eating    study shows    starting in the
                                         good results infeet or hands),
                                         combination    diarrhea
                                         with d4T;
                                         combination
                                         with ddC should
                                         probably be
                                         avoided; most
                                         active in
                                         "resting"
                                         infected cells
 Hivid          AZT,           Three     Effectiveness  Periperhal

 (azlcitabine,  saquinavir     times     in combination neuropathy

 ddC)                          daily, 1  with AZT       (numbness or pain
                               hour      demonstrated instarting in the
                               before or large studies; feet or hands),
                               2 hours   combination    pancreatitis
                               after     with ddI shoudl(inflammation of
                               eating    probably be    the pancreas)
                                         avoided; most
                                         active in
                                         "resting"
                                         infected cells

 Zerit          ddI, 3TC,      Twice     Reaches HIV in Peripheral

 (stavudine,    nelfinavir (a  daily     spinal cord andneuropathy

 d4T)           protease                 brain;         (numbness or pain
                inhibitor now            effectiveness  starting in the
                being tested)            in combination feet or hands)
                                         with ddI or 3TC
                                         indicated in
                                         recent studies;
                                         probably should
                                         not be given
                                         with AZT; works
                                         best in cells
                                         actively
                                         producing HIV

 Epivir         AZT; d4T; AZT  Twice     Combination    In adults, side

 (lamivudine,   + 3TC is well  daily     with AZT well  effects mostly

 3TC)           studied with             studied and    mild: headache,
                all protease             popular with   nausea, fatigue;
                inhibitors               doctors;       children who have
                                         effectiveness  had pancreatitis
                                         in combination (inflammation of
                                         with d4T       the pancreas)
                                         indicated by   shoudl use AZT +
                                         recent studies;3TC only if they
                                         most active in cannot take other
                                         "resting"      anti-HIV drugs
                                         infected cells
 Protease inhibitors

 Invirase       AZT, ddC, AZT  Three     As it is made  Mostly mild side

 (saquinavir)   + ddC;         times     now, saquinavireffects; nausea,
                ritonavir***   daily     appears to be  diarrhea
                                         the weakest
                                         protease
                                         inhibitor, but
                                         its activity
                                         increases
                                         greatly when it
                                         is combined
                                         with ritonavir;
                                         can be given
                                         twice a day
                                         with ritonavir
                                         but the best
                                         dose for the
                                         combination is
                                         still unknown.
                                         A new version
                                         of saquinavir
                                         now being
                                         studied looks
                                         stronger than
                                         the first
                                         version
 Norvir         AZT + 3TC, AZT Twice     First protease Nausea, numbness

 (ritonavir)    + ddC;         daily,    inhibitor shownaround mouth,
                saquinavir***  with      to prolong     diarrhea common,
                               meals if  survival in    especially in
                               possible  people with    first weeks of
                                         advanced       therapy; doctors
                                         disease; being advised to start
                                         studeing with  with 300 mg twice
                                         AZT + 3TC in   a day, then build
                                         people soon    up to the full
                                         after they are dose, 600 mg twice
                                         infected with  a day, within 2
                                         HIV            weeks

 Crixivan       AZT, AZT +     Three     Study in       Painful kidney

 (indinavir)    3TC, AZT + ddI times     combination    stones (drinking
                               daily, 1  with AZT + 3TC lots of water,
                               hour      demonstrating  especially in
                               before or long control ofsummer, lowers
                               2 hours   HIV in large   chance of this
                               after     majority of    side effect)
                               eating,   people; being
                               or with a studied with
                               light,    AZT + 3TC in
                               low-fat   people soon
                               meal      after they are
                                         infected with
                                         HIV

 Viracept       d4T, AZT + 3TC Three     If taken with  Diarrhea usually

 (Nelfinavir)                  times     Videx, take    goes away by

 Approval of                   daily     more than 2    itself or can be
 Viracept                      with food hours before orcontrolled by
 imminent                                1 hour after   taking imodium
                                         Videx; should
                                         not be taken
                                         with Viramune

 Non-nucleoside reverse transcriptase inhibitors

 Viramune       AZT, AZT + ddI Once      Reaches HIV in Rash usually goes
 (nevirapine)                  daily for spinal cord andaway by itself;
                               first 2   brain; most    report severe rash
                               weeks,    effective when to doctor
                               then      combined with  immediately
                               twice     AZT + ddI in
                               daily     people who have
                               with or   never taken
                               without   these drugs;
                               food      this triple
                                         combination
                                         being studied
                                         in children;
                                         lowers levels
                                         of protease
                                         inhibitors
                                         indinavir and
                                         saquinavir in
                                         blood
 Rescriptor     AZT, ddI, AZT  Three     Raises levels  Rash usually goes
 (delavirdine)  + ddI          times     of indinavir   away by itself;

 Approval of                   daily     and saquinavir report severe rash
 Rescriptor                              in blood       to doctor
 pending                                                immediately

 *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 studies of a drug. The nucleosides are usually referred
 to by abbreviations of the chemical names of the drugs - AZT, ddI, ddC,
 d4T, 3TC.

 **All anti-HIV drugs have interactions with many of the other drugs
 people with HIV infection or AIDS may be taking. Some of these other
 drugs may not be taken with anti-HIV drugs. You should ask your doctor to
 review this list of other drugs. Make sure the doctor who treats your HIV
 knows about all of the other drugs you are taking, including both drugs
 prescribed by other doctors and drugs for which you do not need a
 prescription.

 ***Saquinavir and ritonavir are the first protease inhibitors to be
 studied in a double protease inhibitor combination. Early results suggest
 that the combination is effective in people with CD4 counts between 100
 and 500.

The nucleosides and non-nucleosides both have the same "target." They
inhibit (slow down) the action of the HIV enzyme called reverse
transcriptase. Reverse transcriptase is important because it changes HIV in
a way that lets it become part of the infected cell inside the cell's
command center, its nucleus (Figure 1). If reverse transcriptase doesn't do
its job properly, HIV can't take over the infected cell from inside the
nucleus and can't start making new copies of itself.

The nucleoside reverse transcriptase inhibitors are all in one group
because the molecules that make them up are linked together in similar
ways. Non-nucleoside reverse transcriptase inhibitors are completely
different from nucleosides in how their molecules are linked. It's not
important to understand these differences in molecule links. The important
thing is that both nucleosides and non-nucleosides inhibit the action of
the same HIV enzyme, reverse transcriptase, even though they do it in a
different way.

Protease inhibitors get their name because they slow down the action of
another HIV enzyme, protease. Protease goes to work inside infected cells
after proteins made by HIV come out of the nucleus (Figure 1). It works
like a "chemical scissors," cutting up these long chains of HIV proteins
and enzymes into smaller pieces. HIV needs these smaller pieces to make
active new copies of itself. Protease inhibitors gum up the protease
"scissors." The result is that new copies of HIV aren't made the right way
and they can't go on to infect new cells.

The important point is that protease inhibitors and reverse transcriptase
inhibitors (nucleosides and non-nucleosides) work at different steps in the
process that HIV goes through when it makes new copies of itself inside
cells.

Figure 1. Nucleoside and non-nucleoside drugs interfere with the
          action of an HIV enzyme called reverse transcriptase, just after
HIV enters a cell (1). Reverse transcriptase is necessary for HIV to change
its genetic material into a form that gets inside the cell nucleus (2),
where it becomes part of the cell's genetic material and makes long chains
of proteins. The HIV enzyme protease is like a chemical "scissors" that
cuts these long chains into short chains (3). Short protein chains are
needed to form active new copies of HIV. Protease inhibitors gum up the
"scissors" (4) and stop protease from cutting up the long chains of
proteins. As a result, the new copies of HIV are empty (5) and can't go on
to infect new cells. (Illustrations by Neil O. Hardy)


3. Why does combination therapy make sense?

Combination therapy makes sense for lots of reasons. Here are the most
important ones:

   * It takes a lot to stop HIV. HIV makes new copies of itself inside
     infected cells at a very fast rate. Every day, billions of new copies
     of HIV are made. Every day, millions of infected cells die. One drug,
     by itself, can slow down this fast rate of infection. Two drugs can
     slow it down more. In fact, sometimes two drugs can be more than twice
     as good as one drug. In other words, when the right two drugs are
     added together, 1 plus 1 equals more than 2.

   * Anti-HIV drugs from different drug groups attack the virus in
     different ways. In section 2, we saw how different anti-HIV drugs
     attack HIV at different steps in the process it goes through to make
     copies of itself (Figure 1). Think of the HIV enzymes reverse
     transcriptase and protease as "targets" that can be shot at with
     different groups of drugs. Drugs that hit the reverse transcriptase
     target stop HIV just after it enters a cell, and drugs that hit the
     protease target stop HIV just before it leaves a cell. Hitting two
     targets increases the chance of stopping HIV and protecting new cells
     from infection. That's why nucleosides (which aim at reverse
     transcriptase) and protease inhibitors (which aim at protease) work so
     well together. If non-nucleosides and protease inhibitors are given
     together, they may raise or lower levels of each other in the body.
     The first studies to show how these drugs interact have now been
     completed. See "A non-nucleoside and a protease inhibitor."

   * Different anti-HIV drugs can attack the virus in different types of
     cells and in different parts of the body. HIV gets inside several
     different types of cells in different parts of the body. And the drugs
     we have to treat HIV differ in how well they attack the virus in these
     different cells. For example, the nucleosides AZT and d4T and the
     non-nucleoside nevirapine get inside cells in the spinal cord and the
     brain better than other drugs. So doctors often like to make one of
     those drugs part of any combination, because it's important to go
     after HIV wherever it may be hiding. Laboratory studies also show that
     the nucleosides AZT and d4T work best in infected cells that are
     actively producing new copies of HIV, while the nucleosides ddI, ddC,
     and 3TC work best in cells that are infected but "resting" and not yet
     actively producing new HIV. But the actual effect this difference may
     have in people with HIV has not been determined. The table shown above
     summarizes what's known about how well different drugs work in
     different cells and parts of the body.

   * Combinations of anti-HIV drugs may overcome or delay resistance.
     Resistance is the ability of HIV to change its structure in ways that
     make drugs less effective. HIV has to make only a single, small change
     to resist the effects of some drugs. For other drugs, HIV has to make
     several changes. When one drug is given by itself, sooner or later HIV
     makes the necessary changes to resist that drug. But if two drugs are
     given together, it takes longer for HIV to make the changes necessary
     for resistance. When three drugs are given together, it takes even
     longer. Some people have taken three-drug combinations for a year or
     more with no signs of emerging resistance.

   * If anti-HIV drugs are combined in the right way, their side effects
     will not be increased. All anti-HIV drugs have side effects-the
     unwanted (sometimes harmful) effects that almost all drugs produce
     (see Table). Some different anti-HIV drugs have the same side effects.
     When doctors plan combination therapy, they try to give drugs that
     have different side effects. Doing so reduces the chance that any
     single side effect will be so bad that a person has to stop taking the
     drug (or drugs) that cause it. The main goal of combination therapy is
     to find the strongest combination of drugs with the lowest level of
     side effects.


4. What drug combinations work well together?

   * Nucleoside-nucleoside combinations. Because nucleosides were the first
     anti-HIV drugs available, combinations of two nucleosides are the
     best-studied double therapies for HIV infection. Large studies in the
     United States, Europe, and Australia showed that AZT + ddI or AZT +
     ddC work better than AZT alone. These studies showed this difference
     both by counting clinically significant signs of HIV disease and by
     measuring CD4 counts and amounts of virus in the blood. Another large
     study in Canada, Europe, Australia, and South Africa showed that
     adding 3TC to AZT, to AZT + ddI, or to AZT + ddC lowered the chance
     that HIV disease would get worse. Smaller studies showed that AZT +
     3TC, ddI + d4T, and d4T + 3TC are effective in lowering amounts of
     virus in the blood and helping raise CD4 counts. It's likely that
     double-nucleoside combinations will be a part of anti-HIV therapy for
     a long time.

   * A protease inhibitor plus two nucleosides. An important question is
     whether a nucleoside-nucleoside combination is a good way to begin
     treating a person with HIV infection, or whether therapy should start
     with an even stronger combination: two nucleosides plus a protease
     inhibitor. So far, every study that has compared two nucleosides plus
     a protease inhibitor with a double-nucleoside combination showed that
     three drugs given together result in a larger and longer-lasting
     reduction in the amount of virus in the blood when compared with
     double-nucleoside combinations or with protease inhibitors used as
     single agents. Indinavir + AZT + 3TC is stronger and lasts longer than
     AZT + 3TC. Indinavir + AZT + ddI is stronger than AZT + ddI.
     Saquinavir + AZT + ddC is stronger than AZT + ddC. Because these
     trials all had the same result, it makes sense when starting treatment
     to begin with a strong three-drug combination whenever possible.
     Combination therapy offers the best chance to control HIV infection
     over a long period of time.

   * A non-nucleoside and two nucleosides. The best results with the
     non-nucleoside nevirapine were in a study combining it with two
     nucleosides: AZT and ddI. As with protease inhibitors (see previous
     paragraph), the three-drug combination is stronger than the
     double-nucleoside combination. When combined with only one nucleoside,
     nevirapine did not work as well.

   * A non-nucleoside and a protease inhibitor. The first studies of
     possible interactions between non-nucleosides and protease inhibitors
     are now finished. Although these interactions can vary from person to
     person, nevirapine generally lowers levels of indinavir and saquinavir
     in the blood and delavirdine raises blood levels of these two drugs.
     Nevirapine has little effect on levels of ritonavir. More study of
     delavirdine and ritonavir is needed, but results so far suggest that
     neither drug greatly affects levels of the other drug. Doctors are
     advised to combine non-nucleosides and protease inhibitors with
     caution until there are specific recommendations for doing so.

   * Important notes about three-drug combinations. People who are about to
     start therapy with a combination containing a protease inhibitor or a
     non-nucleoside should remember two things:

       1. If you're already taking one or more nucleosides and not doing
          well, it's best to start taking a protease inhibitor or a
          non-nucleoside with a different nucleoside combination-either one
          that you have never taken before or at least one that you have
          not taken in a long time. Just adding a protease inhibitor or a
          non-nucleoside to nucleosides that are failing is not a good
          idea, because it's likely that virus resistant to all the drugs
          will emerge rapidly.

       2. Combinations that include a protease inhibitor or a
          non-nucleoside must be taken exactly as recommended by the drug
          manufacturer. Skipping doses or cutting back on how many pills
          you take every day will give HIV a good opportunity to become
          resistant to a drug. And sometimes HIV that has become resistant
          to one drug will also be resistant to other drugs that you have
          never taken before.


5. What other kinds of combinations are doctors testing and thinking about?

Researchers are already testing a double protease inhibitor combination:
ritonavir + saquinavir. Results so far show that these two drugs do a good
job of attacking HIV together. Four different dose combinations are being
studied, but the safest and most effective dosing schedule isn't known yet.
However, it is known that saquinavir may be taken twice a day with
ritonavir rather than three times a day-the schedule used when saquinavir
is given in combination with nucleosides. The new version of saquinavir is
being studied with the protease inhibitor nelfinavir, which will probably
be approved for use in 1997.

Researchers are also testing the combination of ddI and hydroxyurea, an
anticancer drug. Some early results show that the combination lowers the
level of virus in blood better than ddI alone. More recent studies of ddI +
d4T + hydroxyurea show decreases in levels of virus but little effect on
CD4 counts. Hydroxyurea must be used with caution because it can quickly
lower levels of white blood cells (which include CD4 cells) and of
cell-like structures that help the blood clot.

The HIV enzymes reverse transcriptase and protease are not the only viral
targets to aim at. Scientists are beginning to look at other steps in the
process HIV uses to make new copies of itself, to see if there are still
more ways to control HIV infection. Some drugs that attack these other
targets are in early testing stages.

Finally, an entirely different type of treatment may make anti-HIV drugs
even more effective. It's called immunotherapy or immune-based therapy. The
idea is to take advantage of proteins in the body that either speed up or
slow down the activity of CD4 cells and other important immune system
cells. The result could be to expose HIV that is "hiding" inside resting
cells where anti-HIV drugs can't reach it. Other goals would be to slow the
production of proteins that speed up the HIV copy-making process and to
help the immune system fight the harmful effects of HIV. One immunotherapy
that uses the protein interleukin 2 (or IL-2) is already being studied in
combination with anti-HIV drugs. Many doctors are eager to learn how they
might use immunotherapy as an additional weapon to stop HIV infection.


6. What should your goal be with combination therapy?

The goal of any therapy should be to control the disease being treated as
completely as possible. Because nucleosides, non-nucleosides, and protease
inhibitors are anti-viral drugs, the most immediate way to measure how well
they are controlling HIV disease is to measure the amount of virus in the
blood. This is similar to measuring blood pressure to test the effect of
drugs taken to lower blood pressure in a person whose blood pressure is too
high.

Your doctor can use tests that measure virus in blood-called viral load
tests-in combination with CD4 counts, to see how well a combination of
drugs is working for you, and to see how long it works. The best way to use
these tests is for your doctor to measure your viral load and CD4 count
before you start therapy or change therapy, then every 3 or 4 months, or
perhaps more often depending on your situation. For some people, many
combination therapies get rid of so much HIV in the blood that the virus
can no longer be detected by extremely powerful viral load tests. For
others, virus can still be detected in the blood even after they take these
drug combinations.

The time it takes to have "undetectable" virus varies from person to
person. Much depends on where you start: Sometimes, a higher viral load
when you start therapy means it will take longer for virus to become
undetectable in blood. Also, once your viral load goes down, from time to
time you may have an increased viral load measurement. If that happens, you
shouldn't panic and decide you want to change your drug combination
immediately. You should talk to your doctor about the best way to deal with
the change in viral load. Your doctor may want to get another viral load
test right away to see if the first test showing an increase was accurate.

Ideally, a strong combination of anti-HIV drugs should make HIV become
undetectable and stay undetectable. But for some this may not always be
possible-and they may do very well even if they cannot reach and maintain
the goal of undetectable virus. But that is the goal you and your doctor
should shoot for.


Copyright (c) 1997 International Association of Physicians in AIDS
Care.  Reproduced by permission.

