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Protease Inhibitors

What They Are, How They Work, When to Use Them

Revised and published in September, 1997

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.

Contents:

Introduction
  1. What are HIV infection and AIDS?
  2. What is HIV protease?
  3. What are protease inhibitors and how do they work?
  4. Will protease inhibitors get rid of HIV?
  5. How do protease inhibitors differ from other available anti-HIV drugs?
  6. What protease inhibitors are being studied now?
  7. Should protease inhibitors be combined with other drugs?
  8. Can protease inhibitors be combined with each other?
  9. What side effects do protease inhibitors have?
  10. What is resistance and how big a problem is it?
  11. What is cross-resistance?

Protease Inhibitor Word List.


Introduction

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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 other 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 should be made with the help of your physician (and, if you are in a clinical trial studying a protease inhibitor, with the help of the team of health care workers involved in the clinical trial).

Are protease inhibitors as effective for women as they are for men with HIV infection? Although a few small studies have tried to answer this question, they ahve found no definite evidence of any difference. Women with HIV infection - as well as men - should discuss any recent health changes when ever they meet the physician who prescribes their HIV medicines. Women should also be aware that protease inhibitors can make oral contraceptives containing ethinyl estradiol less effective by lowering the amount of the oral contraceptive that circulates in the blood. So women taking protease inhibitors should use a different means of contraception.

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 words place on this page.

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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 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 through 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 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.

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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.

 Figure 1. HIV (the AIDS virus) can make new copies of itself inside an infected cell. One step in making these new copies is to cut long chains of proteins and enzymes into shorter chains. The "scissors" HIV uses to cut these chains is one of its enzymes, called protease. Protease inhibitors gum up the protease "scissors" and stop them from cutting. As a result, the new viruses produced can't infect other cells. (See Figure 2. (Illustrations by Neil O. Hardy)

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 (its "command center") 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.

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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 without protease inhibitors.

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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 in blood 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.

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

Figure 2Figure 2. (1) HIV enters an uninfected cell. (2) reverse transcriptase inhibitors can stop duplication of HIV's genetic material. (3) Without reverse transcriptase inhibitors, HIV's genetic material can get inside the cell's nucleus--its command center--where it makes long c hains of proteins and enzymes. (4) Protease inhibitors can stop the cutting of long chains of HIV proteins and enzymes into short chains. (5) Protease inhibitors result in the formation of "empty" viruses that can't in fect new cells. (6) Without protease inhibitors, short chains of HIV proteins and enzymes make new viruses that can infect other cells.

The main way protease inhibitors differ from the other anti-HIV drugs is 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 genetic message into a form that can easily be inserted inside the nucleus of the infected cell (Figure 2).

This step in the HIV copy-making 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, HIV experts believe that the best way to give a protease inhibitor is to combine it with reverse transcriptase inhibitors. If a person has been taking one or two reverse transcriptase inhibitors for a long time and is not doing well, a protease inhibitor should be started with one or two different reverse transcriptase inhibitors.

In the United States, physicians may prescribe seven reverse transcriptase inhibitors. These drugs fall into two groups called the "nucleoside" reverse transciprtase inhibitors and the "non-nucleoside" reverse transcriptase inhibitors. The common names of the nucleosides are:

  • AZT (Retrovir, zidovudine)
  • ddI (Videx, didanosine)
  • ddC (Hivid, zalcitabine)
  • d4T (Zerit, stavudine)
  • 3TC (Epivir, lamivudine)
The common names of the nonnucleosides are:
  • Viramune (nevirapine)
  • Rescriptor (delavirdine)

Doctors are advised to combine nonnucleosides and protease inhibitors with caution until there is more specific information on how they affect each other. In general though, early studies show that nevirapine decreases the amount of indinavir (Crixivan) and saquinavir (Invirase) in the body and that delavirdine increases the amount of indinavir and saquinavir. Neither nevirapine nor delavirdine seems to have a large effect on ritonavir (Norvir). Both nonnucleosides are also being studied with the newest protease inhibitor, nelfinavir (Viracept).

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.

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6. What protease inhibitors
are being studied now?

Four protease inhibitors are now available in the United States and another may be approved in 1998. (See table.) Saquinavir (Invirase), ritonavir (Norvir), indinavir (Crixivan), and nelfinavir (Viracept) have been approved by the US Food and Drug Administration (FDA) for use in combination with nucleoside reverse transcriptase inhibitors. (See 5 above.) A newer version of saquinavir, which gets into the blood better than the version already approved, will be considered for approval in 1997.

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, only people with low CD4 counts or people in whom other drugs have failed may take advantage of these programs.

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7. Should protease inhibitors be
combined with other drugs?

Yes. Protease inhibitors should only be taken in combination with the other anti-HIV drugs. (See 5 above.) But it is still too early to tell which combinations will work best. The best combination may differ for different people.


Protease Inhibitors Approved or in Later Stages of Development
Drug Name(s)* Maker Status
Indinavir
(Crixivan)
MerckApproved for use with nucleoside reverse transcriptase inhibitors.
Nelfinavir
(Viracept)
Agouron Approved for use with nucleoside reverse transcriptase inhibitors.
Ritonavir
(Norvir)
AbbottApproved for use with nucleoside reverse transcriptase inhibitors.
Saquinavir
(Invirase)
Hoffmann-LaRoche Approved for use with nucleoside reverse transcriptase inhibitors; a new version of saquinavir that gets into the blood better than the first version will be considered for approval in 1997.
141W94,
VX-478
Glaxo-Wellcome/Vertex Being studied in people with HIV infection; may be considered for approval in 1998.
*The first drug name in each group is the generic name - the name usually used in the final clinical trials of a drug. The name in parenteses () is the brand name - the official name a drug gets when it is approved by the FDA or is close to approval. 141W94 and VX-478 are code numbers given to the same drug. Other companies are also working on protease inhibitors not listed here.

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, ddI, ddC, d4T, and 3TC: Protease inhibitors and nucleosides are processed in completely different ways inside the body, so they are unlikely to interfere with each other. But other drugs used by people with HIV and AIDS - including the nonnucleoside reverse transcriptase inhibitors nevriapine and delavirdine - are processed by the liver, just as protease inhibitors are. So the chance for interactions between those drugs and protease inhibitors is higher. (See 5 above). Physicians have to be careful about mixing protease inhibitors with certain antibiotics, anti-TB drugs, antihistamines (for allergies), antidepressants and oral contraceptives that containe ethinyl estradiol.

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8. Can protease inhibitors be
combined with each other?

A study of ritonavir plus saquinavir is showing that this combination can be effective in lowering the amount of HIV in the body and in raising CD4 counts, even for some poeple in whom other anti-HIV therapies have failed. This combination is attractive for several reasons. First, ritonavir slows the rate at which saquinavir leaves the body, so more saquinavir is around longer to attack the virus. Second, the chance for cross-resistance between the two drugs is low. (See 11 below.) Third, the drugs have to be taken only twice a day when used together.

Studies combining other protease inhibitors - including ritonavir plus indinavir, and nelfinavir plus the new version of saquinavir - are also beginning. However, unwanted side effects involving the liver can be a problem for some people taking two protease inhibitors. So, when physicians give two protease inhibitors at the same time, they have to watch closely for the first warning signs of liver problems.


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

Like almost all strong medicines, protease inhibitors have side effects. People with HIV infection who are thinking about taking a protease inhibitor should ask their primary care physician to discuss the possible side effects listed by the manufacturer of each drug.

The main side effects of ritonavir are nausea, diarrhea, and numbness around the mouth, especially in the first weeks of therapy. It may be possible to avoid these side effects by gradually increasing the amount of the drug for the first two or three weeks and by adding other drugs only at the end of that time. One dosing pattern that works for many people is 300 mg of rintonavir twice a day for two to three days, 400 mg twice a day for two to three days, 500 mg twice a day until side effects fade, then the full dose of 600 mg twice a day.

Indinavir causes painful kidney stones in some people, so it's important to drink lots of water when taking this drug, especially in summer or whenever water is lost because of sweating.

Nelfinavir sometimes causes diarrhea, which is usually mild and may go away by itself. Sometimes physicians prescribe a common anti-diarrhea drug like Immodium to help control this diarrhea.

The first version of saquinavir causes mostly mild side effects, mainly nausea and vomiting. It is too early to tell whether that will change much with the new version of saquinavir.

The FDA warned doctors that there may be a slightly increased risk of diabetes with all of the protease inhibitors. Although there have been only a few cases of diabetes associated with taking protease inhibitors, physicians are advised to pay attention to sugar levels in blood in anyone taking these drugs. The FDA also recommended watching closely for uncontrolled bleeding in hemophiliacs taking protease inhibitors.

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10. What is resistance
and how big 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. 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.

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. Protease inhibitor experts agree that the best way to avoid or delay resistance to a protease inhibitor is to take the drug exactly as recommended by the drug manufacturer, to be especially careful not to skip taking the drug, and to take the protease inhibitor in combination with one or more nucleoside reverse transcriptase inhibitors (AZT, ddI, ddC, d4T, and 3TC) - or possibly with a combination of nucleoside and nonnucleoside reverse transcriptase inhibitors (nevirapine and delavirdine).

But the most important thing to remember about taking protease inhibitors is that, if you're already taking one or more reverse transcriptase inhibitors and not doing well, it's best to start taking a protease inhibitor with reverse transcriptase inhibitors that you have never taken before or at least have not taken in a long time.

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11. 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. If HIV changes its genetic structure in certain ways to resist one drug (drug A), it may happen that those same changes make HIV resistant to one or more other drugs (B and C). So, even if a person has not actually taken drugs B and C, HIV may be resistant to them - if it is already resistant to drug A.

Cross-resistance is a complex and controversial problem that resistance experts continue to study closely. In carful laboratory tests, these experts try to define the genetic changes HIV needs to make to become resistant to different protease inhibitors. But these experts all agree that what they learn about resistance in the laboratory cannot always explain how resistance may actually happen in each person taking a protease inhibitor.

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©1996 International Association of Physicians in AIDS Care

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