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Resistance to Drugs for HIV Infection
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| Words in italics when they first appear are explained in the Resistance Word List. | |
Eleven drugs are approved by the U.S. Food and Drug Administration (FDA) to treat HIV infection and AIDS (Table 1). Others will soon be considered for approval by the FDA. Doctors now know that the best way to use these anti-HIV drugs is to give several of them at the same time. Combining drugs in this way is called combination therapy.
Even though certain anti-HIV drug combinations do a good job controlling HIV in an infected person's body, these therapies still haven't cured anyone of HIV infection or AIDS. One reason for that is a problem we've had since there was only one drug to treat HIV infection--resistance.
Resistance is a complicated problem that researchers are working hard to understand. Section 3 of this booklet explains some of the important things we've learned. The most important thing you should know is that resistance is exactly what it sounds like--the ability of HIV to resist the effects of anti-HIV drugs. When HIV becomes resistant to an anti-HIV drug, that drug is much less effective--sometimes completely ineffective--in stopping HIV from spreading in an infected person's body.
The drugs we have to fight HIV fall into two groups. Both groups have the same goal. They try to stop HIV from making copies of itself, which HIV does inside cells in an infected person's body. We call this copy-making replication.
To make copies of itself, HIV has to use several enzymes. Two of HIV's most important enzymes are reverse transcriptase and protease. Because anti-HIV drugs slow down, or inhibit, the working of these two enzymes, they are called either reverse transcriptase inhibitors or protease inhibitors (Table 1). We divide the reverse transcriptase inhibitors into two groups called nucleosides and non-nucleosides. Table 1 lists available anti-HIV drugs and those that may be approved soon. The table also explains some things we know about resistance to each drug.
| Drug | Resistance |
|---|---|
| Nucleosidesa | |
| Retrovir (zidovudine, AZT) |
Resistance develops over several months to years. High-level resistance requires several mutations.b |
| Videx (didanosine, ddl) |
Resistance develops slowly and is associated with only a few mutations. |
| Hivid (zalcitabine, ddC) |
Resistance develops slowly and is associated with only a few mutations. High-level resistance is uncommon, but ddC can fail for other reasons. |
| Zerit (stavudine, d4T) |
Resistance is uncommon and is not clearly associated with specific mutations, but d4T can fail for other reasons. |
| Epivir (lamivudine, 3TC) |
High-level resistance is associated with one mutation and may develop quickly if 3TC is given in a combination that does not stop HIV replication completely. So 3TC should be used only as part of the strongest combinations. |
| Ziagen (abacavir, 1592)c |
Early studies suggest only moderate resistance. Virus resistant to one other nucleoside usually stays susceptible to abacavir. But virus resistant to several other nucleosides at the same time is usually resistant to abacavir. |
| Nucleotide reverse transcriptase inhibitor | |
| Preveon (adefovir dipivoxil)c |
Early studies suggest slow emergence of resistance, but more study is needed. |
| Non-nucleosides All non-nucleosides shore some common resistance mutations. | |
| Viramune (nevirapine) |
High-level resistance may develop quickly if nevirapine is given in a combination that does not stop HIV replication completely. |
| Rescriptor (delavirdine) |
High-level resistance may develop quickly if delavirdine is given in a combination that does not stop HIV replication completely. |
| Sustiva (efavirenz, DMP 266)c |
High-level resistance may develop quickly if efavirenz is given in a combination that does not stop HIV replication completely. |
| Protease inhibitors Although this table lists some of the differences in resistance to protease inhibitors, there are more similarities than differences. All protease inhibitors share some common resistance mutations. | |
| Fortovased (saquinavir) |
Resistance to saquinavir is associated with one or two mutations that are also seen with other protease inhibitors. |
| Norvir (ritonavir) |
Resistance to ritonavir is associated with a somewhat predictable series of several mutations that are seen with other protease inhibitors. |
| Crixivan (indinavir) |
Resistance to indinavir is associated with an unpredictable series of several mutations that are seen with other protease inhibitors. |
| Viracept (nelfinavir) |
Resistance is associated with a mutation not seen with the other protease inhibitors. However, as with other protease inhibitors, people in whom nelfinavir fails may get less benefit from a second protease inhibitor. |
| (amprenavir, 141 W94)c |
Resistance is associated with a mutation not seen with the other protease inhibitors. More research on crossresistance is needed. |
| aOne group of mutations can make HIV resistant to all the
nucleosides.
bMutations are changes in one of the genes of HIV that result in resistance to anti-HIV drugs. See Section 3. cThese drugs were not approved by the FDA when this booklet was printed but could be approved soon. dFortovase is a new type of saquinavir that is more effective than the first type available, which was called Invirase. | |
Anti-HIV drug combinations don't always completely stop HIV replication, the steps HIV takes to make new copies of itself inside cells. When combinations do work, sometimes they work only for a while. There are several reasons why anti-HIV drugs may fail.
First, the drug or drugs may not be strong enough to stop HIV replication completely. We now know that all one-drug therapies are too weak to stop replication of HIV. And fairly good two-drug combinations, like AZT plus 3TC or d4T plus 3TC, usually control HIV only for a few months. So far, there are only two two-drug combinations that can stop HIV completely for a year or longer: two protease inhibitors, and a protease inhibitor plus the new non-nucleoside efavirenz (Sustiva). But even two-drug combinations don't work for most people. That's why doctors now give three or even four anti-HIV drugs at the same time. These three- or four-drug combinations have the best chance of controlling HIV for years in most people who take them.
Second, too little drug may get into the blood, where it flows to infected cells throughout the body. Absorption is the word used to describe how well a medicine gets from the stomach into the blood, and then into cells in the body. Some drugs aren't absorbed well when they're taken as pills or capsules. And every person differs in how well he or she absorbs each drug. Also, other drugs being taken at the same time as anti-HIV drugs or food eaten around the time a drug is taken can interfere with absorption (Table 2).
Third, some anti-HIV drugs have to change into an active form once they are inside the body. This is called activation. How well the drugs change into an active form depends on the drug itself, the person taking it, other drugs that person may be taking, and possibly what anti-HIV drugs a person has taken earlier.
It's very important for your doctor to be aware of the factors that influence drug strength, absorption, and activation.
Fourth, drugs can fail if a person does not take them on time. Skipping doses has the same effect as poor drug absorption or poor drug activation: Not enough active drug gets to cells infected with HIV. A person taking anti-HIV drugs can control this problem, which is called poor adherence or poor compliance. Your doctor, or someone working with your doctor, should give you advice on how to take your anti-HIV drugs on time. You can also get good advice from HIV/AIDS community groups. Table 3 gives some pointers on sticking with your daily drug plan.
These four problems can all lead to resistance, as the next section of this booklet explains. Resistance happens when a person is taking anti-HIV drugs--but is not getting enough drug into the body to stop HIV replication completely.
Anti-HIV drug therapies can also fail for reasons not related to how much drug gets into the body. For example, the type of HIV in an infected person's body can slowly change to attack different kinds of cells and so spread the infection. Or HIV can slowly change into a type that causes cells to bunch together and die quickly. Scientists are still trying to figure out exactly why these changes occur. One thing is certain: These changes usually happen after a person has been infected with HIV for a long time. So it's best to control HIV before these changes begin.
An HIV-positive person carries many different variants (slightly different types) of the HIV that first infected that person. To understand why, you have to know that the information HIV needs to copy itself is carried on genes, just as the information needed to make a new human is carried on the genes that come from the mother and father. The genes inside the HIV virus change a little bit every time HIV replicates (makes new copies) inside infected cells. These gene changes are called mutations. If nothing stops HIV replication for months or years, more and more different types of HIV keep piling up in the body. But only one type of HIV, called the wild-type virus, replicates better than all the other types (Figure 1).
Resistance is the ability of some variants, or types, of HIV in an infected person to replicate fairly well even when a drug is stopping replication of other types of HIV, like the wild-type virus. Let's say a person is taking only the drug AZT (a practice that was common several years ago but should never be recommended to control HIV today). A type of HIV that replicates well when a person is taking AZT, is said to be "resistant to AZT." Because that AZT-resistant HIV replicates faster than the wild-type HIV or other types of HIV in a person taking AZT, the AZT-resistant HIV soon outnumbers the other types of HIV in that person (Figure 1). At that point, the person is said to be resistant to AZT," and AZT is no longer doing its job of slowing HIV replication. So taking a drug doesn't cause the virus to become resistant to that drug--it just lets virus with certain mutations replicate better than other viruses.
Among the many different types of HIV that may be in an infected person's body, there is a specific type that begins to replicate faster when that person takes 3TC, for example, and a specific type that replicates faster when that person takes the protease inhibitor nelfinavir (Viracept), and so on for the other anti-HIV drugs. (See Sections 6, 7, and 8 for details.) The only way to stop these drug-resistant types of HIV from replicating faster is to stop all replication. And the only way to stop all replication is to give enough strong anti-HIV drugs at the same time to a person who does not already have virus resistant to all those drugs.
| 1. The type of HIV that replicates (copies itself) best when no drugs are being taken is called the "wild-type" virus (white circle). | 2. But an infected person carries many other types of HIV that differ from the wild-type virus because of small changes, or mutations, in their genes (black, gray, and blue circles). | 3. When a person starts taking an anti-HIV drug, one of these other HIVs, the black virus perhaps, may replicate better than the wild- type virus. So it starts to outnumber the other HIVs. | 4. The drug stops or slows replication of some viruses. So, for a while, the amount of HIV in the blood ("viral load") goes down, But the mutant HIV (black) keeps replicating. | 5. If the infected person keeps taking that same drug, eventually there is as much virus in the blood as there was before treatment started. And most of it is now said to be resistant to the drug being given. |
 | ||||
| The only way to stop replication of drug-resistant viruses is to take enough anti-HIV drugs to stop replication completely. | ||||
Doctors can tell if a person is resistant to certain drugs by looking at HIV viruses collected from blood samples of that person. There are two ways to do this. The first is to look for certain changes, or mutations, in the HIV genes in virus collected. After carefully studying many people taking anti-HIV drugs, researchers have figured out that specific mutations lead to resistance to specific drugs. With certain drugs, like 3TC or non-nucleosides, a single mutation is enough to cause high levels of resistance. Other drugs, like AZT and some protease inhibitors, usually require the build-up of several mutations before high-level resistance results. (See Sections 6, 7, and 8 for details.) Because this method of detecting resistance looks for specific mutations--changes in genes--we call it genotypic testing.
The second method measures the level of resistance--in other words, how well a particular virus replicates in cells growing in the laboratory when those cells are treated with one or more drugs. This method also starts with HIV collected from a blood sample. That virus is used to infect cells in a lab dish. Researchers can then measure how fast the virus grows when they add different amounts of an anti-HIV drug to infected cells in the dish. If virus collected from an individual grows fast even when high levels of a drug are added to the cells, that person is said to have high-level resistance to the drug being tested. Or we say the virus is no longer sensitive" to the drug being tested. The technical term for this type of resistance testing is phenotyping (or phenotypic testing).
These tests for resistance greatly increased our understanding of how HIV behaves during drug therapy. But sometimes too much is made of resistance test results. For example, some hoped it would be easy to figure out which protease inhibitors are best to take first, and which are best saved for later, by comparing the mutations usually linked to resistance to different drugs. But resistance is often too complicated to let us make easy rules based on resistance tests. That's one reason why resistance tests some doctors use when treating people with HIV infection do not always give the right, or useful, answers. (See Sections 5 and 9.)
Cross-resistance is resistance to one drug that develops while a person is taking another drug in the same drug group--for example, resistance to the protease inhibitor ritonavir when a person is taking the protease inhibitor indinavir.
How does cross-resistance happen? Suppose a person starts anti-HIV therapy with AZT plus 3TC but no other drugs. Resistance to 3TC (and eventually to AZT) will develop in everyone who takes just AZT plus 3TC, because this combination is not strong enough to stop replication of HIV completely. When this happens, AZT and 3TC have lost control of HIV replication. At this point, the person taking AZT plus 3TC has lots of HIV viruses resistant to 3TC. These viruses are resistant to 3TC because of a single gene change, or mutation. HIV with that specific mutation is resistant not only to 3TC, but also partially resistant to ddI, ddC, and abacavir (1592) even though that person has never taken ddI, ddC, or abacavir. We say that virus is cross-resistant to 3TC, ddI, ddC, and abacavir.
Soon after we started studying protease inhibitors, we learned that cross-resistance among these drugs can develop easily. The reason is that many of the same mutations are involved in resistance to all of the protease inhibitors. It's true that the main mutations we see first in virus resistant to saquinavir (Invirase or Fortovase), or to nelfinavir (Viracept), or to amprenavir (141W94) differ from the main mutations we usually see with indinavir (Crixivan) and ritonavir (Norvir). These findings led some to hope that a person could start therapy with a combination containing saquinavir, for example, and still be able to take indinavir or ritonavir later if resistance to the first protease inhibitor developed. Now we know that's not always true. Resistance experts agree that there is no best first protease inhibitor" for everyone.
This does not necessarily mean that a person who has resistance to one protease inhibitor will get no benefit from other protease inhibitors. Some therapies including one or two protease inhibitors that a person has not taken before can be effective even after that person has resistance to another protease inhibitor. (See Section 10.) But the best chance to stop HIV is with the first drug combination given.
The nucleoside reverse transcriptase inhibitors--AZT (Retrovir), ddI (Videx), ddC (Hivid), d4T (Zerit), 3TC (Epivir), and abacavir (Ziagen), and a similar drug called adefovir (Preveon)--differ in how resistance to them develops. In general, there seem to be three basic resistance patterns--one for AZT, another for ddI, ddC, and d4T, and yet another for 3TC. The drugs abacavir and adefovir are now being studied in many people with HIV infection. So we are starting to learn about resistance to these drugs in people taking them. Unfortunately, some viruses mutate in a way that makes them resistant to all nucleosides now approved by the FDA. These multinucleoside resistant" viruses have been found most often in people who have taken AZT plus ddI.
Because AZT is the oldest anti-HIV drug, we have learned a lot about resistance to it. If AZT is given alone or in a weak combination, resistance usually develops over a period of several months to years. In most people, at least two key HIV mutations must appear before a person has high-level resistance to AZT. HIV that has high-level resistance to AZT may replicate faster in some cells than nonresistant virus. If that turns out to be true, it could mean that high-level resistance to AZT will result in the faster development of AIDS. On the other hand, some people who took AZT by itself for a year or more got good results when they added two strong drugs--indinavir (Crixivan) and 3TC--to their therapy. This finding indicates that some resistance to AZT does not make AZT completely useless when combined with other drugs that a person has not taken before.
Resistance to ddI is very slow to develop, and researchers have not found high-level resistance to ddC or d4T either in people taking these drugs or in laboratory resistance studies. Although resistance experts have linked specific mutations to ddI and ddC, they have not done so for d4T. It is difficult to say what this slow, low-level resistance actually means for people taking ddI, ddC, or d4T. We do know each of these three drugs will fail if given alone or in weak combinations. But all three drugs can be useful parts of strong (three- or four-drug) combination therapies.
When it comes to resistance, 3TC is unlike all the other nucleosides. Resistance to 3TC appears quickly, as a result of a single mutation, if 3TC is taken alone or as part of a weak combination. But if a person does not have virus resistant to 3TC, it can be a valuable part of strong three-drug combinations. For this reason, 3TC should be used only as part of strong combinations. Avoiding resistance to 3TC is especially important because ddI, ddC, and abacavir may be less effective against virus resistant to 3TC. (See Section 5.)
Early studies of abacavir (1592) show that people who take this drug have virus with some of the same mutations found with ddI, ddC, and 3TC. But abacavir is like AZT in one way: Several mutations are needed before high-level resistance develops. Some studies show that people with virus resistant to ddI, ddC, or 3TC got good results from abacavir. But if patients had several mutations seen with other nucleosides, including AZT, abacavir was much less effective. In general, it seems that people who have taken several other nucleosides for a long time may get little benefit from 1592 alone. But it is still difficult to reach firm conclusions about resistance to abacavir. Studies going on now will tell us more.
Adefovir is a little different from the nucleosides, but it too is a reverse transcriptase inhibitor. It appears that viruses with mutations common to AZT, ddI, d4T, and 3TC can be controlled by adefovir. But some viruses resistant to ddC are cross-resistant to adefovir. So far, it seems that mutations to adefovir appear slowly when the drug is given. But it's still too early to tell what will happen when lots of people start taking this drug, especially people who have taken other reverse transcriptase inhibitors for a long time.
Two non-nucleoside reverse transcriptase inhibitors, nevira-pine (Viramune) and delavirdine (Rescriptor), have been approved for use in the United States as this booklet is being written. A third, efavirenz (Sustiva, once called DMP 266), is now being studied in many people with HIV infection and will be considered for US approval soon.
The mutations that appear first in the virus of people taking these drugs differ somewhat for each non-nucleoside. All three share some of the same mutations, however, so cross-resistance among the non-nucleosides is common. As a result, people who have virus highly resistant to one non-nucleoside would not be expected to benefit much from another.
In general, high-level resistance to non-nucleosides occurs quickly if these drugs are given alone or in weak combinations. As with other anti-HIV drugs, resistance develops much more slowly, or not at all, when non-nucleosides are given as part of stronger combinations that reduce HIV in blood to below detectable levels. For example, one large study of nevirapine plus AZT and ddI showed that HIV resistant to nevirapine did not appear in most people who took their drugs on schedule and controlled replication of their HIV. In another study, virus resistant to delavirdine appeared more slowly when delavirdine was combined with both AZT and ddI rather than with either AZT or ddI. Studies of efavirenz plus indinavir showed that this is a strong combination in people who have never taken a non-nucleoside or a protease inhibitor before.
Resistance and cross-resistance to the protease inhibitors are complicated problems that have led to much debate and to some misunderstandings among physicians and people with HIV infection. Now, with four protease inhibitors being used to treat large numbers of HIV-positive people, most experts agree on a few things.
First, although the resistance mutations that appear first differ from drug to drug, viruses resistant to the protease inhibitors share several common mutations.
Second, as with other anti-HIV drugs, mutations are most likely to appear if the dose of the protease inhibitor is too low, if the protease inhibitor is not taken on time every day or is not well absorbed by the body, or if the protease inhibitor is given alone or in a weak combination. Weak combinations include those in which a protease inhibitor is added to two drugs that are no longer controlling replication of HIV. Treatment with a protease inhibitor should always begin with at least two other strong drugs that a person has not taken before.
Third, cross-resistance can occur no matter which protease inhibitor a person takes first. A person may get some benefit from other protease inhibitors once one protease inhibitor has failed. But successful treatment with a protease inhibitor--even with two protease inhibitors given together--is less likely after failure of a first protease inhibitor.
Fourth, the first version of saquinavir, called Invirase, is somewhat weaker than ritonavir, indinavir, or nelfinavir. The newer version of saquinavir, called Fortovase, is more effective. Studies going on now will help determine how strong Fortovase is compared with other protease inhibitors and how resistance to it may develop.
Another new protease inhibitor, called amprenavir (or 141W94), could be considered for approval soon. As with nelfinavir (Viracept), the first mutation usually seen with amprenavir is not seen in most viruses resistant to the other protease inhibitors. But virus resistant to amprenavir does share other mutations with viruses resistant to the other protease inhibitors. So, at this point, we cannot say that amprenavir will differ much from other protease inhibitors when it comes to resistance or cross-resistance.
Because resistance is probably the main reason why anti-HIV drugs fail, everything possible should be done to prevent it. The doctors best prepared to help you prevent resistance are the ones who keep up with the many new findings in HIV research. These doctors spend a large part of their time caring for people with HIV infection. Studies of HIV-positive people show that doctors with lots of HIV experience get the best results.
If you're looking for a doctor to treat your HIV infection, try to find one with experience. Call your state or local AIDS hotline, get in touch with national or local HIV/AIDS support groups, talk to other people with HIV infection. If you are part of a health plan that picks a doctor for you, insist on getting a doctor who regularly cares for people with HIV infection.
If you have not taken anti-HIV drugs before, and if you and your doctor agree that you should start, you have an excellent chance of preventing resistance or delaying it for a long time. The key is to begin therapy with a combination of drugs that can stop replication of HIV and make it impossible to find HIV in your blood. We also know that the sooner you start a strong combination, the better chance it will have of preventing or delaying resistance.
With the drugs we have now, the combinations that stop replication best are three- or four-drug combinations that include at least one protease inhibitor. Two nucleosides will not get the job done. Recent studies showed that resistance to 3TC occurs relatively quickly in people who begin treatment only with AZT plus 3TC or d4T plus 3TC.
Making HIV undetectable in blood is just one goal when starting an anti-HIV drug combination. Your doctor should also think of the starting combination as the first of a series of combinations you may eventually take. If that first combination fails, resistance could be the reason. So your doctor will want to be thinking ahead to a second, backup combination of drugs most likely to control HIV that is resistant to one or more drugs in the first combination.
Once you begin taking any anti-HIV combination, the most important thing you can do is take your drugs on schedule, exactly as your doctor instructs. Skipping doses is one of the surest ways to let resistance develop. So be certain that you understand your drug schedule, and ask your doctor for specific advice about staying on schedule. Table 3 lists a few tips that may help.
Even if you stick with your anti-HIV drug schedule, too little of the drug may get into your body because of other drugs you are taking. Sometimes, other drugs may have the opposite effect: They may increase levels of anti-HIV drugs in your body. If levels of some drugs get too high, they could cause serious problems. You and your doctor should go over the list of all drugs you're taking to make sure that none will increase or decrease levels of anti-HIV drugs too much (Table 2). This list of drugs should include oral contraceptives (birth control pills) and drugs that you can get without a doctor's prescription.
Very little is known about how illegal street drugs affect anti-HIV drugs. In some cases, though, people taking anti-HIV drugs and illegal drugs have had serious problems. Some have died. If you take illegal drugs, your doctor can get you into a program to help you stop. Stopping illegal drugs is as important to your health as taking anti-HIV drugs.
Food affects how well some anti-HIV drugs get into your body (Table 2). The nucleoside ddI must be taken on an empty stomach. The protease inhibitor indinavir (Crixivan) should be taken on an empty stomach or with a low-fat snack. The protease inhibitors saquinavir (Invirase or Fortovase), ritonavir (Norvir), and nelfinavir (Viracept) should be taken with food.
Many people with HIV infection want to know if they should be tested for resistance just as they are for HIV levels in blood ("viral load") and CD4 count. Some resistance tests being studied for use in doctors' offices are accurate and reliable. But we still can't say whether these resistance tests will help your doctor plan and switch therapies better. For example, one study found that knowing the level of resistance to AZT couldn't help doctors figure out the best time to switch to ddI. Another study found that indinavir (Crixivan) failed in some people before a resistance test could show that indinavir was losing control of HIV. For now, the best tools your doctor has to plan and switch anti-HIV combinations are (1) a list of the anti-HIV drugs you've already taken, (2) your viral load, and (3) your CD4 count.
| Drug | Drugs that can increase amount of column 1 drug in the body | Drugs that can decrease amount of column 7 drug in the body | Advice on eating and taking column 1 drug |
| Nucleosides | |||
| Retrovir (zidovudine, AZT) |
Antifungals:
fluconazole Antimicobacterials: atovaquone Other drugs: probenecid (possibly), valproic acid |
Antimicobacterials: rifampin | --- |
| Videx (didanosine, ddI) |
Antivirals: ganciclovir | Anti-HIV drugs: delavirdine (when given at the same time as ddI) | Take 1 hour before or 2 hours after eating |
| Hivid (zalcitabine, ddC) |
Other drugs: cimetidine, probenecid | Other drugs: metoclopramide, some antacids | --- |
| Zerit (stavudine, d4T) |
--- | Anti-HIV drugs: AZT taken before d4T may decrease the ability of d4T to become active inside cells | --- |
| Epivir (lamivudine, 3TC) |
Antimicobacterials: trimethoprim | --- | --- |
| Studies of abacavirc and adefovirc are underway. | |||
| Non-nucleosides | |||
| Viramune (nevirapine) |
Antimicrobacterials: macrolide
antibiotics Other drugs: cimetidine |
Antimicobacterials: rifabutin, rifampin | --- |
| Rescriptor (delavirdine) |
Antifungals:
ketoconazole Antimicrobacterials: clarithromycin Other drugs: fluoxetine |
Anti-HIV drugs: ddI (when given
at the same time as delavirdine),
nelfinavir. Antimicrobacterials: rifabutin, RIFAMPIN*. Other drugs: some antacids, carbamazepine, cimetidine, famotidine, nizatidine, phenobarbital, phenytoin, ranitidine |
Can be taken with or without food; tablets can be dissolved in water before taking |
| Sustiva (efavirenz, DMP 266)c |
Antifungals: fluconazole | --- | Can be taken with or without food |
| Protease inhibitors | |||
| Fortovase
and Invirased (saquinavir) |
Anti-HIV drugs:
delavirdine, nelfinavir,
ritonavir Antifungals: ketoconazole Antimicobacterials: clarithromycin Other drugs: ranitidine |
Anti-HIV drugs: nevirapine Antimicrobacterials: rifabutin RIFAMPIN* |
Take with meals or within 2 hours of eating |
| Norvir (ritonavir) |
Anti-HIV drugs:
delavirdine Antifungals: fluconazole, ketoconazole Antimicobacterials: clarithromycin |
Anti-HIV drugs:
nevirapine Other drugs: rifampin |
Take with food if possible, must be kept refrigerated |
| Crixivan (indinavir) |
Anti-HIV drugs:
delavirdine, nelfinavir Antifungals: ketoconazole Antimicrobacterials: clarithromycin |
Anti-HIV drugs: nevirapine,
efavirenz Antifungals: fluconazole Antimicobacterials: RIFAMPIN* |
Take 1 hour before or 2 hours after eating, or with a low-fat snack or light meal; drink at least 1½ quarts of liquid during day |
| Viracept (nelfinavir) |
Anti-HIV drugs:
delavirdine, indinavir,
ritonavir Antifungals: ketoconazole |
Antimicrobacterials: rifabutin, RIFAMPIN* | Take with food |
| (amprenavir, 141 W94)c |
--- | Anti-HIV drugs: efavirenz Antimicrobacterials: rifabutin, RIFAMPIN* | Can be taken with or without food |
| *Drugs printed in CAPITALS should not be taken with the anti-HIV drugs
listed.
aNot all drug interactions are dangerous. Some may even be helpful. Your doctor can use this list as a reminder of possibly dangerous interactions between anti-HIV drugs and other drugs you're taking.
| |||
Many people who began treatment with one anti-HIV drug at a time are now resistant to most anti-HIV drugs. That doesn't mean there's no way left to control their HIV infection. We know, for example, that some resistant viruses replicate much more poorly than nonresistant (wild-type) virus, so a drug is not necessarily useless if virus has become resistant to it.
Researchers have started several studies to figure out the best combinations for people in whom earlier therapies failed. One combination that has been tried in people with lots of earlier drug experience uses two protease inhibitors. Often, two nucleosides are added to the two protease inhibitors. So far, doctors have the most experience with ritonavir (Norvir) plus saquinavir (Invirase) plus nucleosides. But other double protease inhibitor combinations are being studied as well.
Other doctors are getting good results by combining a protease inhibitor (often indinavir [Crixivan]) with a non-nucleoside (either nevirapine [Viramune] or delavirdine [Rescriptor]), plus one or more nucleosides. Researchers are also testing indinavir plus the non-nucleoside efavirenz (Sustiva) and nelfinavir (Viracept) plus efavirenz. But the first efavirenz combination studies tested the drug in people who had never taken a non-nucleoside or a protease inhibitor. At the largest AIDS center in Amsterdam, physicians are trying nevirapine, ddI, and a drug called hydroxyurea for people in whom a protease inhibitor has failed.
One thing people should not do is add one new drug to a combination that is failing. Doing that is a good way to cause resistance to the new drug. If possible, it would be better to wait until you can combine at least two new anti-HIV drugs with one or two other anti-HIV drugs to which you're least likely to be resistant.
(Words that appear in italics are explained elsewhere in this list.)
absorption: How well a medicine gets from the stomach into the blood and then into cells.
activation: The chemical changes some drugs go through inside cells before they can stop HIV replication.
adherence: The practice of taking medicines on time, exactly as directed by your doctor. Adherence is extremely important in preventing resistance to anti-HIV drugs. Another word for adherence is compliance.
AIDS: Acquired immunodeficiency syndrome, or advanced infection with HIV. An HIV-positive person has AIDS if the CD4 count goes below 200 or if certain other infections or cancers appear during HIV infection.
CD4 cells: Cells that are important in directing the body's attack against viruses like HIV and other causes of disease. CD4 cells are the main target of HIV.
CD4 count: The number of CD4 cells in a droplet of blood. A low CD4 count is a sign of advanced HIV infection. A CD4 count under 200 means a person has AIDS. A normal CD4 count is between 600 and 1000.
cells: The smallest, self-contained parts of blood, muscle, skin, bone, and all other parts of the body. (See CD4 cells.)
combination therapy: Two or more drugs given at the same time to treat the same disease. Strong combinations of anti-HIV drugs prevent or delay resistance.
compliance: See adherence.
cross-resistance: Resistance to one drug resulting from treatment with another drug in the same drug group.
enzyme: A kind of protein that causes chemical changes in the body.
genes: Strings of chemicals (DNA or RNA) in cells and viruses that carry information about making new cells or viruses.
genotypic testing: Testing for a change (or mutation) in parts of the genes of HIV that make HIV resistant to one or more drugs.
HIV: human immunodeficiency virus, the virus that causes AIDS.
mutations: Changes in the genes of HIV, for example, those that may make HIV resistant to one or more drugs.
non-nucleoside: One type of reverse transcriptase inhibitor.
nucleoside: One type of reverse transcriptase inhibitor. These drugs are imitation or false building blocks" of genes that fool reverse transcriptase when it is replicating the viral genes.
phenotypic testing (or phenotyping): Testing for the ability of a drug to stop replication of HIV in infected cells in the laboratory. Resistant virus will replicate even when high levels of a drug are added to the infected cells.
protease: An enzyme that helps newly formed HIV particles become able to infect new cells.
protease inhibitors: Anti-HIV drugs that interfere with, or inhibit, the action of protease.
proteins: Complex compounds that are a major part of cells in all plants and animals. Inside cells, HIV can make certain proteins that it needs to create new copies of itself.
replication: The process by which HIV makes new copies of itself inside cells.
resistance: The ability of HIV to continue to grow in the presence of anti-HIV drugs--or, more simply, the ability of certain types of HIV to replicate well during treatment with one or more anti-HIV drugs.
reverse transcriptase: An enzyme that HIV needs to make viral DNA and get inside the nucleus (command center) of a cell, a step necessary for replication.
reverse transcriptase inhibitors: Anti-HIV drugs that interfere with, or inhibit, the action of reverse transcriptase. These drugs are divided into two groups: nucleosides and non-nucleosides.
viral load: The amount of HIV in a tiny droplet of blood. A high viral load is a sign of advanced HIV infection. An undetectable viral load does not mean HIV has disappeared from the body.
wild-type virus: The type of HIV that replicates best in a person not taking anti-HIV drugs.
This booklet was funded through an unrestricted educational grant from Bristol-Myers Squibb, Princeton, New Jersey.
It is provided as an educational resource to the members of the International Association of Physicians in AIDS Care.
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