Protease Inhibitors: How & When to Use Them

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 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 section answers some of the basic questions about protease inhibitors. For the questions that can't be answered now, this page 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.

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 cells. 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.

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 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?

Figure 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 chains 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 infect 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 used now is in their target. 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 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, most HIV experts believe that the best way to give a protease inhibitor is to combine it with at least one or, if possible, two 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.

6. What protease inhibitors are being studied now?

Three protease inhibitors have been approved for use in the United States and one is in the final stages of testing in people with HIV infection as this information is being written. (See tables.)

Indinavir (Crixivan), ritonavir (Norvir), and saquinavir (Invirase) have been approved by the U.S. Food and Drug Administration (FDA) for use in combination with reverse transcriptase inhibitors. (See 5 above.) A newer version of saquinavir, which gets into the blood better than the version already approved is being studied now.
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. These programs are open only to people with low CD4 counts.

7. Can protease inhibitors be combined with other drugs?

Yes. In fact, most AIDS experts agree that protease inhibitors should only be taken in combination with the anti-HIV drugs called reverse transcriptase inhibitors. (See 5 above.)

Protease inhibitors in the final stages of development
(as of 7/31/96)

Drug name(s)*		Maker			Stage of development

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

Norvir (ritonavir, 	Abbott			Approved for use in 
combination 
ABT-538)					with reverse transcriptase 
inhibitors

Crixivan (indinavir, 	Merck			Approved for use in 
combination 
MK-639)						with reverse transcriptase 
inhibitors

Viracept (nelfinavir, 	Agouron			In final trials in people 
with HIV
infection
AG-1343)

*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, ddl, ddC, d4T, and 3TC--are 
abbreviations of the
chemical 
names of the drugs.

Protease inhibitors in the early stages of development
(as of 7/31/96)

Drug name(s)*		Maker			Stage of development

VX-478, 141W94		Glaxo-Wellcome/		In early 
trials in people 
			Vertex			with HIV infection
			
	
KNI-272 (dynostatin)	Nikko Kyoto 		In early trials in 
people 
			Pharmaceutical and 	with HIV infection
			National Cancer Institute

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

CGP-53437		Ciba-Ceigy		In laboratory tests

Hoe/Bay-793		Hoechst-Bayer		In laboratory tests

SR-41476		Sanofi			In laboratory tests

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

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

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 make sure their primary care physician reviews possible drug interactions when considering whether to start treatment with a protease inhibitor.

8. Can protease inhibitors be combined with each other?

There is some evidence that certain protease inhibitors can be combined with certain others. But studies combining two protease inhibitors are just beginning, and such combinations may have side effects involving the liver until these studies figure out how much of each drug should be taken. If some protease inhibitors do work well together, they would make it even harder for HIV to spread inside the body.

The first protease inhibitor combination being studied in people is ritonavir (Norvir) plus saquinavir (Invirase). There are two reasons why this combination is attractive: First, the chance for cross-resistance to the two drugs is low. (See 11 below.) Second, ritonavir slows the rate at which saquinavir leaves the body, so more saquinavir is around longer to attack the virus.

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.

Some people have had a hard time with side effects like nausea and diarrhea when they start taking ritonavir (Norvir). 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 reverse transcriptase inhibitors only at the end of that time. One dosing pattern that works for many people is 300 mg of ritonavir 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, than the full dose of 600 mg twice a day. It is important to be taking the full dose of ritonavir after three weeks.

10. 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. 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. 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 reverse transcriptase inhibitors (AZT, ddI, ddC, d4T, and 3TC).

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. 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 certain protease inhibitors at the same time--or perhaps one after another with other anti-HIV drugs.

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