International Association Physicians in AIDS Care (IAPAC), Medical Publications Corporation, 225 W. Washington St., Suite 2200, Chicago, IL 60606
By Martin Markowitz, MD; 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. Revised and Published by IAPAC October, 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

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.

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.

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.

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. Since then, two non-nucleoside reverse transcriptase inhibitors (NNRTIs) or, simply, non-nucleosides, have been approved, and four protease inhibitors have been approved. Researchers are working on other drugs in all three groups.

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.

• 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.

• 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.

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.

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.

©1997, International Association of Physicians in AIDS Care

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