When we talk about HIV treatment, the issue of resistance almost always comes up. HIV drug resistance can seem to be a hopelessly complicated topic. But having a basic understanding of what resistance is, what causes it, and how it's measured can have a big impact on the success of antiretroviral treatment.
This overview is intended to help people better understand the basics of drug resistance (hopefully without being too complicated) in order to get the full benefit of treatment.
Drug resistance isn't anything new and certainly isn't limited to HIV. Most of us are familiar with drug resistance in situations outside of HIV. You may have experienced or read about wide-spread resistance to antibiotics, drug-resistant tuberculosis, or vaginal yeast infections that don't respond to conventional treatment.
The goal of any pathogen -- or germ -- is to survive and reproduce. Most medications are designed either to kill the offending germ or to stop it from reproducing, ideally resolving the infection. But if a germ continues to reproduce while you're on treatment, it may change -- or mutate -- so that the treatment can no longer kill the germ or stop it from reproducing. Over time, the treatment no longer works.
This is called drug resistance.
The goal of HIV treatment is to lower the amount of virus in your body (viral load) and increase your CD4 cell count so that the immune system is better able to deal with infections.
Many complex steps are necessary for HIV to make copies of itself. Two of these steps involve specific enzymes -- reverse transcriptase and protease. All but one of the antiretrovirals approved by the Food and Drug Administration to treat HIV interfere with the virus's replication process by attaching -- or binding -- to one of these enzymes, effectively stopping HIV from replicating.
Without treatment, HIV usually reproduces very rapidly in the body, creating billions of new viral particles every day. Since HIV replication involves so many complex steps, the virus makes a lot of mistakes. And as sophisticated as HIV is, it's also a somewhat messy virus. It isn't able to correct mistakes it makes as it reproduces. These mistakes in HIV's genetic structure are called mutations.
Up to 90% of new viruses end up with a mutation (or mutations) that keep them from being able to infect a new CD4 T-cell or complete the replication process. Unfortunately, that still leaves millions of new viruses that go on to produce new copies of HIV. Many of these viruses also contain mutations, but they aren't harmful enough to interfere with HIV's ability to replicate.
HIV Drug Resistance
Simply put, HIV drug resistance means that an antiretroviral drug -- or combination of drugs -- can't prevent or reduce HIV replication. Our main concern is the mutations that affect currently available antiretrovirals. Specific mutations that stop a drug from being able to bind to either the reverse transcriptase or protease enzyme can make the drug less effective. This can have a negative effect on how well treatment works.
Reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors bind to HIV's reverse transcriptase enzyme. Protease inhibitors bind to the protease enzyme.
Drug resistance doesn't happen because HIV is smart. The virus doesn't have a brain and can't think about how to get around a drug. Mutations that cause resistance occur naturally and randomly. We sometimes think of HIV as intelligent and cunning, but, in fact, it survives simply because it can. It uses what it needs to replicate -- white blood cells (usually CD4 cells), certain enzymes, and other materials it brings with it.
Drug Resistance Before Starting Treatment
Mutations in the genetic structure of the reverse transcriptase and protease enzymes can occur before you begin antiretroviral treatment and, more often, when you're on treatment.
When HIV enters your body, it makes both perfect copies of itself -- called wild-type virus -- and copies with random mutations. As both the wild-type and mutated HIV continue to replicate, populations of mixed viruses develop in your body.
Wild-type virus is the most fit and best able to replicate, so most of the HIV in your body is wild-type virus. Even though mutations continue to randomly occur, most of them are harmless and will have little or no effect if and when you begin treatment.
Unfortunately, many people who have never been on treatment have HIV that's resistant to one or many HIV drugs. If you're HIV-negative and engage in risk behaviors with someone whose virus is resistant to one or more antiretroviral, you could be infected with your partner's drug-resistant HIV.
Recent data show that 10-30% of new infections (generally defined as having been infected over the past three years) involve HIV that's resistant to at least one drug. As many as 10% of new infections involve HIV that is resistant to at least two drugs. And a recent study found that 3% of new HIV infections involved strains of HIV that were resistant to drugs in three classes of antiretrovirals (reverse transcriptase inhibitors, non-nucleosides, and protease inhibitors).
It's also possible for someone with HIV to be infected again, with drug-resistant HIV, possibly HIV that's resistant to many drugs. This is called superinfection. We don't know how often superinfection occurs, but there are several reports showing that it's possible.
If you're infected with drug-resistant HIV -- either initially or through superinfection -- you have fewer treatment options even before you start therapy. This could affect the likelihood of treatment being successful.
Drug Resistance While on Treatment
Most mutations that can influence the effectiveness of combination therapy happen while you're on treatment. When you first start antiretroviral treatment, the amount of HIV in your body goes down dramatically.
No combination completely stops HIV from reproducing, but treatment significantly lowers levels of all viral populations in the body, both wild-type and mutated virus. Just as wild-type virus is the most fit and most able to replicate, it's also the most sensitive to antiretroviral treatment.
When you have a viral load test soon after you begin treatment and see a dramatically lower number, most of that decrease is due to the affect of the drugs on your wild-type virus.
The flip side of wild-type virus's sensitivity to antiretrovirals is that any HIV in your body with certain mutations in the reverse transcriptase or protease enzymes has a survival advantage. Depending on the mutations, the drug can't bind to the enzyme and can't interfere with HIV's replication process.
This is called selective pressure. Drug-resistant virus is able to replicate despite the presence of the drug.
Even though there's less HIV in your body, the virus with the relevant mutation(s) can become the dominant strain over time. As the mutated virus continues to replicate, it makes copies of HIV with that same mutation and other mutations can also develop.
The Xerox Machine
The HIV replication process is a bit like using a Xerox machine. You start with a nice, clear original of your document (the wild-type). You make a copy of the original and, in the process, you may copy a speck of dirt (a mutation) that's on the glass of the copier.
When you make a copy of the copy, that speck of dirt is copied, too. As you go on to make copies from each copy, the mutation continues to show up -- along with many others. After a while, your original document has become an unreadable blur, complete with many Xeroxed specks of dirt (multiple mutations).
As discussed above, most mutations harm the virus, making HIV unable to complete the replication process (an unreadable blur). But other mutations severely limit a drug's effectiveness. The drug can no longer bind to the enzyme that HIV uses to replicate. As a result, the amount of drug-resistant virus increases and so does your viral load.
Drug resistance would usually happen very quickly if you took only one antiretroviral. For example, only one mutation (called the M184V) in the reverse transcriptase enzyme makes HIV completely resistant to both Epivir (3TC, lamivudine) and Emtriva (emtricitabine). If you took either of these drugs alone, your virus would develop resistance within just a couple of weeks.
Resistance to the non-nucleosides is similar. One mutation (the K103N) in the reverse transcriptase enzyme can cause HIV to become highly resistant to all three non-nucleosides -- Viramune (nevirapine), Sustiva (efavirenz), and Rescriptor (delavirdine). This is an example of cross-resistance. Depending on the mutation, if HIV develops resistance to one drug, it can be resistant to other drugs in the same class because of the same or similar resistance patterns -- even if you've never taken those other drugs.
Some antiretrovirals require more than one mutation in the relevant enzyme to cause resistance to that particular drug. This is especially true with protease inhibitors.
Each antiretroviral is associated with at least one mutation -- called the primary mutation -- that causes the most drug resistance. Other mutations -- called secondary mutations -- sometimes make HIV less sensitive to a drug, but they don't usually cause complete resistance unless the primary mutation is also present.
As more mutations -- both primary and secondary -- occur, the likelihood of HIV becoming resistant to a given antiretroviral increases. The concept of multiple mutations can be difficult to understand. This is about when many of us throw up our hands in surrender. Some people dutifully track the primary and secondary mutations of every available antiretroviral and those that are in development, but it isn't necessary for everyone to do that.
You don't need all of that information in your head in order to make informed decisions about treatment or to develop treatment strategies. Coming up with good questions to ask your healthcare provider and knowledgeable advocates can be as valuable as memorizing the mutations that keep a drug from working.
Now some good news. Having resistance to a drug doesn't necessarily mean that it can't still be useful. A drug that your virus is resistant to may still work for you, just not as well as it used to. There are varying degrees of resistance -- partial and complete. And although mutations like the ones described above can cause complete resistance to one (or more) drug, mutated HIV is almost always sensitive to the other drugs in a combination. That's why we use multiple drug regimens.
HIV with specific mutations may be resistant to one of the drugs in your combination, but the other antiretrovirals in the regimen bind to the protease enzyme or to a different part of the reverse transcriptase enzyme and successfully stop HIV replication.
The bottom line concerning the development of drug resistance is that the less virus there is (the lower your viral load), the less likely it is that HIV will develop mutations.
Peak and Trough Levels
- This graph shows levels in your body of an antiretroviral that's dosed twice a day.
- The first dose is taken at 7 am.
- The amount of drug quickly rises to the highest level (peak) and then slowly begins to fall, reaching the lowest level (trough) before 7 pm -- time for the next dose.
- Cmax is the maximum concentration of the drug in your blood. The Cmax should be low enough to keep short-term side effects like nausea or headaches from being intolerable.
- If drug levels rise above the peak (Cmax) -- because you took more than the prescribed dose, for example -- the side effects can be serious.
- Cmin is the minimum concentration of a drug in your body between one dose and the next.
- If drug levels fall below the trough (Cmin), the drug may not be effective. If drug levels drop too low, HIV can replicate freely and may develop resistance to the drug.
- When doses are taken at the right time, drug levels stay within the therapeutic range -- between the Cmax and the Cmin -- ensuring that there is enough drug in your body to slow down or stop HIV from reproducing.
- But if you miss your 7 pm dose (dotted line), the trough level gets way too low (see the colored area).
- The chance of developing resistance to the drug increases greatly, since there isn't enough drug in your body to control HIV replication.
Adherence, Absorption, and Pharmacokinetics
Often, a combination stops working no matter how adherent a person is. This doesn't usually happen quickly -- certainly nowhere near as quickly as it would if you took only one or two drugs. But it can still happen. When it does, some healthcare and service providers assume that the individual isn't adhering to his or her regimen. That's sometimes the case, but other things can also contribute to the development of resistance while you're on treatment.
If the amount of drug in your body falls below therapeutic levels -- for any reason -- you won't have enough of the drug in your system to stop or slow down HIV replication. The drug may inhibit wild-type virus from replicating, but it won't have an effect on HIV with mutations that keep that drug from binding to the relevant enzyme. This allows the mutated HIV to continue to reproduce, creating more viruses with that same mutation.
Poor adherence can cause drug resistance to develop. Adherence means taking your medications on time, taking the prescribed dose, and taking them the correct way (with or without food, for example).
After you take a dose, levels of the drug quickly rise to the highest level (peak) and then slowly begin falling, reaching the lowest level (trough) before you take the next dose. Skipping doses or not taking a drug correctly can cause the trough level to get too low.
When the amount of drug in your body falls below the trough level, the chance of developing resistance is increased since HIV can reproduce more freely and accumulate more mutations. (See graphic.)
Some people who are meticulous about adherence get very nervous if they miss even one dose, afraid that their HIV will immediately become resistant to their regimen. Missing the occasional dose isn't a big problem. Resistance develops when you regularly miss doses.
According to estimates, you need to be up to 95% adherent in order for your regimen to be most effective. This degree of adherence is very high. For example, if you're on a twice-a-day regimen, it means missing fewer than four doses a month. And if you're on a once-a-day regimen, it means missing one dose a month -- at most. Poor adherence can cause drug resistance and, possibly, cross-resistance, too.
If you have trouble sticking to your schedule, be honest with your healthcare provider about it. He or she may be able to prescribe a simpler regimen or help you come up with strategies that work for you. If not, in the long run it may be better for you not to be on antiretrovirals until the reasons for your difficulties with adherence have been addressed.
Poor absorption can also affect levels of a drug. If a drug isn't properly absorbed into your bloodstream, drug levels can be too low. This would allow HIV to reproduce without interference and, in the process, accumulate drug-resistant mutations.
If you vomit or have diarrhea shortly after taking your dose, for example, the drug you just took could be expelled from your gut right away, reducing or eliminating the amount of drug absorbed.
As mentioned above, some antiretrovirals have food restrictions, most of which are necessary for the drugs to be absorbed properly. If these food restrictions aren't followed, drug levels can become too low to be effective. Most antiretrovirals don't have any food restrictions these days, but some do. For example, both Kaletra (lopinavir/ritonavir) and Viracept (nelfinavir) should be taken with a meal or light snack. Reyataz (atazanavir) should be taken with food, ideally a complete, nutritious meal.
Drug absorption can also be reduced if you have an intestinal infection. So if you're having nausea, abdominal pain, constipation, diarrhea, or any other symptoms of a possible infection, have it checked out.
Pharmacokinetics -- the way that a drug is absorbed, distributed, metabolized, and eliminated from the body -- can also affect the development of HIV drug resistance.
Some people process drugs faster or slower than other people do, which can speed up or slow down the rate at which a drug clears your body. So if two people take the exact same dose of a drug, the level of drug may be higher in one person than it is in the other one. Factors that can contribute to this include weight, height, age, and, possibly, race and gender.
We all know that people metabolize food differently -- some of us eat as much as we want and stay thin, while other people carefully watch their diet and continue to gain weight. These differences in metabolism are similar to the way we process other substances, including drugs.
The prescribed dose of an antiretroviral is based on the dose that was found to be safest and most effective in clinical trials for most trial participants. Some people may be able to take a lower dose and keep their viral load low or undetectable, while others might need a higher dose to get the same response. There's a lot we don't know about this issue, including how to figure out who may need a dose that's lower or higher than the one that's prescribed.
Finally, many over-the-counter and prescription medications, illegal drugs, herbs, vitamins, and supplements interact with a lot of the antiretrovirals and shouldn't be taken together. Many antiretrovirals also interact with each other. Interactions are complex. Some lower antiretroviral drug levels, which could allow the development of mutations. Pay attention to possible interactions and tell your provider about everything that you're taking.
Drug Resistance When Stopping Treatment
People sometimes stop treatment -- because of toxicity, because another health problem requires a treatment interruption, because they've been responding well and decide to discontinue therapy for a while, or because they're just plain tired of taking medication. If you stop treatment for any reason, work closely with your healthcare provider. Careful planning is important.
Depending on your regimen, if you stop all of your antiretrovirals at once, your virus could develop resistance to one or more of the drugs you were taking. This is most likely to happen if one of your drugs has a long half-life, meaning that drug levels stay high in your body for a long time after you take a dose.
For example, it can take up to three weeks for Sustiva (efavirenz) to be eliminated from your body after you stop taking it. If you stop Sustiva at the same time as you stop taking other antiretrovirals with shorter half-lives, it's like being on Sustiva by itself for a while. This gives a survival advantage to any virus in your body with the mutation that makes it resistant to Sustiva. During that short time after stopping your drugs, much of your HIV could become completely resistant to Sustiva and become resistant to Viramune and Rescriptor, too.
If you plan to stop a regimen that includes Sustiva, it's probably safest to stop the Sustiva one or two weeks before stopping the other drugs in your combination. It may also be possible to switch from Sustiva to a drug with a shorter half-life for a while before stopping everything.
Most antiretrovirals have relatively short half-lives -- including most of the ones that are dosed once a day. But the half-life of Viramune, for example, is also long enough to require careful planning with your provider to avoid the development of resistance if you're stopping a regimen that includes that drug.
Figuring Out if Your HIV Is Drug-Resistant
Regular viral load testing is the quickest way to tell whether treatment is working. If your viral load doesn't reach very low or undetectable levels within a few months after you begin treatment, it's a sign that something's off. Similarly, if an undetectable viral load becomes detectable and continues to go up while you're still on treatment, it's a sign that your regimen isn't working properly.
Viral load tests can't tell why your regimen isn't working. A detectable or increasing viral load doesn't necessarily mean that drug-resistance has occurred. But it could mean that you're at risk of developing drug resistance because there's more HIV replication going on. It's important to find out what's happening.
Viral load tests can't tell whether your HIV is resistant to one drug or, perhaps, your whole regimen. They can't tell which drug or combination may be most effective for you in the future, either.
This is where drug resistance testing comes in.
There are two types of drug resistance tests. Genotype tests look for specific mutations in the genetic structure of your reverse transcriptase and protease enzymes that could cause drug resistance. Phenotype tests measure the sensitivity of your HIV to specific antiretrovirals.
If your regimen isn't working, genotype and phenotype tests can help you and your provider figure out which drug or drugs your virus is resistant to and which ones you're most likely to respond to. This information can help you put together a new regimen that's likely to be effective.
Resistance tests are recommended in many situations. The Department of Health and Human Services' Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents suggest that HIV drug resistance testing should be done:
- If you're switching regimens because your current regimen is failing;
- If your viral load doesn't drop significantly shortly after beginning treatment;
- Before starting treatment during acute (initial) HIV infection if the test is done within a few weeks after infection; and, possibly,
- Before starting treatment if you may have been infected with drug-resistant virus.
Avoiding HIV Drug Resistance
There are many ways that you can slow down the development of drug resistance:
- The more you know about antiretrovirals, the better prepared you'll be to make treatment choices that can help you avoid drug resistance.
- The first regimen you take may be your best chance to suppress HIV the most and prevent drug resistance from developing.
- It's also important to take your medications as prescribed. Missing doses, not taking the right number of pills, not taking them at the right time, or taking medication on an empty stomach if it's supposed to be taken with food, can cause viral load to increase and drug-resistant mutations to develop.
- A good relationship with your healthcare provider can help with all of this. Communicate honestly with your provider. Ask questions, talk about any problems you're having, and tell him or her everything you're taking -- including over-the counter medications, herbs, and any other legal or illegal drugs.
Taking these steps can help avoid drug resistance from getting a chance to develop and leave you more options in the future.
James Learned was Director of Treatment Education at AIDS Community Research Initiative of America (ACRIA) until June of this year. He writes for various community-based publications and conducts trainings on HIV and viral hepatitis treatment issues. E-mail: James_Learned@prodigy.net.
Letters & Numbers
When we read about mutations that cause resistance to HIV drugs or look at the results of a genotype test, mutations are listed as a letter followed by a number and then another letter. This way of describing a mutation may seem confusing, but it's really very straightforward.
HIV is made up of proteins, and proteins are made up of amino acids. A codon tells us which amino acid is found at a specific spot in a protein chain. The reverse transcriptase and protease enzymes are protein chains made up of codons. The amino acids in a protein chain are numbered starting at one end of the chain.
With reverse transcriptase, for example, the 184th amino acid in the protein chain is called position 184. A mutation in reverse transcriptase means that a different amino acid has replaced the one that would be located at that place in wild-type virus. Each mutation is given a specific name to tell it apart from other mutations.
The first letter in a mutation stands for the amino acid that's found at that position in wild-type virus. The number in the middle is the codon, where the mutation is located. And the final letter stands for the amino acid that's there instead of what we'd find in wild-type virus (the mutation).
- M184V is the mutation that makes HIV resistant to both Epivir and Emtriva. M184V tells us that there's a mutation at codon 184 in HIV's reverse transcriptase enzyme. At that position, the amino acid methionine (M) has been replaced by valine (V), another amino acid.
- K103N is the mutation that can cause resistance to all three non-nucleosides. K103N tells us that there's a mutation at codon 103 in the reverse transcriptase enzyme. At that position, the amino acid lysine (abbreviated as K) has been replaced by asparagine, another amino acid (abbreviated as N).
- D30N is the most common mutation in the protease enzyme that can cause resistance to the protease inhibitor Viracept (nelfinavir). This mutation alone doesn't cause cross-resistance to other protease inhibitors. D30N means that there's a mutation at codon 30 in the protease enzyme. At that position, aspartic acid (abbreviated as D) has been replaced by asparagine.