Print this page    •   Back to Web version of article

Combination Therapy for HIV Infection:
Why to use more than one drug, and which drugs to use

Martin Markowitz, MD

October 1997


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 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.

Return to Contents

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.

Return to Contents

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 eleven 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. 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.

Available anti-HIV drugs, and some of their differences (as of August, 1997)
Drug names*Studied most in combination with:How givenSpecial features and comments**Side effects
Nucleoside analog reverse transcriptase inhibitors
Retrovir (zidovudine [ZDV], AZT)ddI, ddC, 3TC, saquinavir, ritonavir, indinavir, nelfinavir, nevirapineTwo or three times dailyReaches HIV in spinal cord and brain; often combined with 3TC; probably should not be given with d4T; works best in cells actively producing new HIVAnemia (low number of red blood cells), granulocytopenia (low number of white blood cells), muscle weakness
Videx (didanosine, ddI)AZT, d4T, indinavir, nevirapineTwice daily, 1 hour before or 2 hours after eatingEffectivness in combination with AZT demonstrated in large studies; recent smaller study shows good results in combination with d4T; combination with ddC should probably be avoided; most active in "resting" infected cellsPancreatitis (inflammation of the pancreas), periperal neuropathy (numbness or pain starting in the feet or hands), diarrhea
Hivid (azlcitabine, ddC)AZT, saquinavirThree times daily, 1 hour before or 2 hours after eatingEffectiveness in combination with AZT demonstrated in large studies; combination with ddI shoudl probably be avoided; most active in "resting" infected cellsPeriperhal neuropathy (numbness or pain starting in the feet or hands), pancreatitis (inflammation of the pancreas)
Zerit (stavudine, d4T)ddI, 3TC, nelfinavirTwice dailyReaches HIV in spinal cord and brain; effectiveness in combination with ddI or 3TC indicated in recent studies; probably should not be given with AZT; works best in cells actively producing HIVPeripheral neuropathy (numbness or pain starting in the feet or hands)
Epivir (lamivudine, 3TC)AZT; d4T; AZT + 3TC is well studied with all protease inhibitorsTwice dailyCombination with AZT well studied and popular with doctors; effectiveness in combination with d4T indicated by recent studies; most active in "resting" infected cellsIn adults, side effects mostly mild: headache, nausea, fatigue; children who have had pancreatitis (inflammation of the pancreas) shoudl use AZT + 3TC only if they cannot take other anti-HIV drugs
Protease inhibitors
Invirase (saquinavir)AZT, ddC, AZT + ddC; ritonavir***Three times dailyAs it is made now, saquinavir appears to be 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 versionMostly mild side effects; nausea, diarrhea
Norvir (ritonavir)AZT + 3TC, AZT + ddC; saquinavir***Twice daily, with meals if possibleFirst protease inhibitor shown to prolong survival in people with advanced disease; being studied with AZT + 3TC in people soon after they are infected with HIVNausea, numbness around mouth, diarrhea common, especially in first weeks of therapy; doctors advised to start with 300 mg twice a day, then build up to the full dose, 600 mg twice a day, within 2 weeks
Crixivan (indinavir)AZT, AZT + 3TC, AZT + ddIThree times daily, 1 hour before or 2 hours after eating, or with a light, low-fat mealStudy in combination with AZT + 3TC demonstrating long control of HIV in large majority of people; being studied with AZT + 3TC in people soon after they are infected with HIVPainful kidney stones (drinking lots of water, especially in summer, lowers chance of this side effect)
Viracept (Nelfinavir)d4T, AZT + 3TCThree times daily with foodIf taken with ddI, take more than 2 hours before or 1 hour after ddIDiarrhea usually goes away by itself or can be controlled by taking imodium
Non-nucleoside reverse transcriptase inhibitors
Viramune (nevirapine)AZT, AZT + ddIOnce daily for first 2 weeks, then twice daily with or without foodReaches HIV in spinal cord and brain; most effective when combined with AZT + ddI in people who have never taken these drugs; this triple combination being studied in children; lowers levels of protease inhibitors indinavir and saquinavir in bloodRash usually goes away by itself; report severe rash to doctor immediately
Rescriptor (delavirdine)AZT, ddI, AZT + ddIThree times dailyRaises levels of indinavir and saquinavir in bloodRash usually goes away by itself; report severe rash to doctor 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 1Figure 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)

Return to Contents

3. Why does combination therapy make sense?

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

Return to Contents

4. What drug combinations work well together?

Return to Contents

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.

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.

Return to Contents

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.

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.

Return to Contents

From the International Association of Physicians in AIDS Care Web Site ©1997, Medical Publications Corporation.

Reproduction of any part of this Web site without written permission is prohibited. This information shall not, in whole or in part, be redistributed, reproduced or entered into a computer for redistribution or reproduction, without prior permission.

Requests for permssion for reproduction should be directed to:

Paul M. Rathe
International Association of Physicians in AIDS Care
Medical Publications Corporation
225 W. Washington St., Suite 2200
Chicago, IL 60606
Telephone: 312-419-7074
FAX: 312-419-7079

This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly. You can find this article online by typing this address into your Web browser:

General Disclaimer: is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, consult your health care provider.