Resistance is a very important term for you to understand, because it will come up again and again when you discuss your HIV medicines with your health care team. Resistance means that your particular virus will not respond to certain HIV medicines, called antiviral drugs. Think anti (means against) and viral--put together, means against the virus. Health care providers will abbreviate this term to ARV (anti-retro-viral) drugs. An older term you may still hear, is HAART, or highly active anti-retroviral therapy, but this term has led to confusion in those who thought the word meant “heart”. So, if you have resistance, your virus may not respond to some HIV medications.
If you remember from an earlier chapter when I talked about viral load, HIV medicines (ARV medicines) are supposed to suppress the virus to undetectable levels (less than 48 or 50). If the medicines are unable to do this, and the virus is able to make more virus copies of itself, despite the medicine, you may have resistance.
Resistance is all about the HIV drugs. Before the HIV drugs came upon the scene, there was no resistance.
Resistance is dependent on the level of drug in your body, which exerts pressure on the virus, and “host factors”... Also, those with lower CD4 counts and higher viral loads, before starting the HIV medicine, are more likely to get resistance.
The reason you have resistance is because your particular virus has changed (or morphed, or mutated, whatever you want to call it) into a virus that is able to “get around” the medicines you are giving it. You can take these medicines until the cows come home, and they will never work. Here’s the kicker, however. You may even have resistance before you ever even start the HIV medicines.
How is this possible to get resistance if I’ve never even been on HIV medicine? you ask. Because, it depends on the particular virus that was given to you by the person who gave you your HIV infection. If the person who infected you with HIV had resistant HIV, you may have it, too. It’s very unfair, but true. Nowadays, HIV care providers are seeing more and more resistance in patients who have never before taken HIV medicines. Today, in the United States, nearly one out of four newly diagnosed HIV positive people will have drug resistance. This rate is increasing every year.
How do we know you have resistance? Before your first visit to the HIV clinic, your medical provider will test your particular virus for resistance. The resistance test that is done on newly diagnosed HIV positive patients is called a genotype test. There are two other types of tests, a phenotype test, which is used for those who have been on lots of different HIV drug regimens and/or have lots of genotype HIV mutations; and a Virco-type test. These last two tests are not used as much as the genotype test, so we will spend more time talking about the genotype test.
Genotype Test
All newly diagnosed HIV positive patients, including pregnant women, should have a genotype test done, immediately upon HIV diagnosis. If a long period then goes by without taking HIV medicines, like a year or so, another genotype should be done before you start the HIV medicine. Another test is needed just in case, during the year you did not take HIV medicine, you obtained another strain of HIV from another sex or needle-sharing partner (hopefully not, but this does happen, so please use condoms and don’t share drug needles).
The genotype test actually looks at the genetic make-up of your virus. If the virus is mutating, or changing, these changes can be detected. However, there must be enough mutated virus to measure. If the mutated virus makes up less than 20% of your total virus, it can’t be measured. Here is an example of a genotype test.
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| HIV-1 genotypic mutations detected and corresponding level of resistance.medscape.org |
A genotype mutation is reported as a letter, and a number, and another letter. For instance, a very common genotype mutation is the Epivir/Emtriva mutation, M184V. The M184 refers to the position of the amino acid and the V means that there is a mutation at that position.
The choice of medicine you start will be based on the results of this genotype test and your HIV medicine history. Some patients have heard of the very popular HIV drug called Atripla, a 3-drugs-in-one combination that is taken just one pill at night before going to bed.
Everyone loves this idea of just one pill to fight the virus. However, based on your genotype results, you may not be able to take this combination pill if you already have resistance to one or more of the drugs in the pill. The genotype test results are needed before you know if that particular pill can be used on your particular virus. Otherwise, you may waste a few months taking the Atripla, just to find out that this medicine is not working, and may never work. Also, consider the money cost of taking a drug that is not working. It’s like throwing good money away for no benefit.
In rare cases, you may know the HIV medication history of the patient that gave you HIV. This information can be also be used, along with your genotype results, to figure out which HIV medicines you should take.
Resistance is something that lasts for years, and no one knows if eventually it goes away. Also, sometimes you can have resistance but the genotype test won’t find the resistance. That’s why your provider must use the genotype results plus your past HIV medicine history to figure out what to start you on now. Here are two examples of how the genotype is used to figure out what HIV medicines you should take.
Example 1Vivian once took an HIV drug called Viracept. She took this drug on and off, for years, as part of a 3-drug “cocktail” to treat her HIV. Every month, she ran out of her medicines and half the time, she forgot to take her evening doses of medicines. She has now been off her cocktail for a year now, and comes into the clinic today wishing to “turn over a new leaf and take my medicine right.” Her CD4 count is 10 and her viral load is more than 2,000,0000. Her current genotype results show no resistance. She liked her old regimen and wants to restart the same drugs she took in the past. Do you think that Vivian can restart the Viracept and the other two HIV drugs she used to take? The medicines should work, since Vivian’s genotype doesn’t show resistance to any HIV medicine. Right? Wrong. Vivian’s medical provider may assume, based on Vivian’s history, that she does have resistance to the Viracept, even though the genotype doesn’t show the resistance. That’s because the virus mutations may only show up when Vivian is actually taking the drugs. Because Vivian only has a CD4 of 10, she doesn’t have time to play around waiting to see if the drugs she’s taking will work. So, her health care provider will most likely avoid two or even three of the past drugs Vivian use to take.
Example 2Lee once took the drug Viracept as part of a 3-drug cocktail, from 2001 to 2007. He was then thrown in jail for 9 months, “through no fault of my own,” he tells his doctor upon meeting him in the clinic the first time. Lee took his HIV medicine religiously, and never ran out of the medicines, even though he didn’t like having to take the medicine twice a day. Lee’s CD4 is 300 and his viral load is 80,000. He prefers to start a new HIV regimen that is taken just once a day. Lee’s current genotype shows that he has no resistance to any HIV drug. What should Lee’s medical provider do? Start Lee on new medicine or put Lee back on his old medicine? Does it matter? Yes, it does matter. What Lee’s doctor will probably do is restart the old HIV medicines Lee took in the past, see if Lee’s viral load becomes undetectable on the medicine (less than 48 or 50), and then change Lee to a once-a-day regimen. This is so his doctor can figure out if Lee really does not have resistance. This is nice to know in case his doctor wants to use the drug Viracept in the future. It’s good to have lots of options when it comes to HIV medicine.So, you can see from the above two examples, how important the genotype resistance test is.
Here is another instance when a genotype will be needed. Supposing you are already taking HIV medicines, and your CD4 has risen slightly, but you are unable to achieve an undetectable viral load. You have been on your 3-drug cocktail for 6 months now. If your HIV viral load is approximately 1000, your health care provider may order a genotype to figure out if you have resistance to the drugs you are taking. If your viral load is less than around 1000, a genotype will not be able to be done and you will just have to wait until either you become undetectable or your viral load goes up.
Please be honest with your medical provider--if you are not taking the medicines right, that’s the reason that the medicines aren’t working, not resistance.
The genotype test gives the best results when a person is actually taking the medicines. However, you can still get accurate genotype test results within 4 weeks of stopping your particular HIV medicines. If more than 4 weeks go by, your HIV virus may go back to what is called “wild-type” virus, the type of virus it once was before changing in response to low levels of medicine.
Notice I said low levels of medicine. That’s because high levels of medicine in your body are what is needed to keep the virus from mutating or changing. High levels of medication actually keep the virus suppressed so much that the virus can’t make more copies of itself. That’s what you want. Total suppression. And the only way to get this is by taking the medicine faithfully, every day--twice a day, if necessary--without missing doses.
Phenotype Testing
If you have lots of genotype mutations and have been on lots of HIV medicine in the past, your medical provider will probably want a phenotype test in addition to the genotype test. The phenotype test may be ordered along with the genotype, or a PhenoSense test, a combined genotype and phenotype, may be ordered.
While the genotype looks at genetic mutations, the phenotype test looks at the amount and type of HIV drug that is needed in order to stop the virus from multiplying. In other words, the test can measure the virus’s ability to multiply when exposed to different types and different levels of drug. Can your virus still multiply when exposed to more and more of a particular drug? Which drug will work better?
This test is similar to the “culture and sensitivity” test that your medical provider will order if you have a urinary tract infection. First, the lab person finds out which bacteria is causing your urinary infection, then he/she puts the bacteria in a culture dish, then puts different medicines and different concentrations of those medicines on top of the bacteria. Then, the lab person looks to see which medicine worked in eliminating the bacteria. Some drugs may not get rid of the bacteria at all (the bacteria is resistant), other drugs will work a little bit (intermediate resistance), and some drugs will be very likely to kill the particular bacteria the patient has in their urine (the bacteria is susceptible). The medical provider will give the patient the best drug for that particular infection.
The good thing about the phenotype test is that it can tell you if a drug will be partially effective against your virus. This is important, especially if you have taken lots of drugs in the past and have lots of resistance and limited options. You may want to take the drug that works a little bit, rather than not have that option on the table at all. On the other hand, the phenotype test will tell you if a particular drug will not work at all.
Another advantage of the phenotype is that it is useful for the new HIV drugs and for persons infected with rare types of HIV. (The genotype tells you what “type” of HIV you have). Like the genotype test, the test should be done while you are taking HIV medicines or within 4 weeks of stopping your medicine.
One interesting thing about the phenotype test is that your particular virus will be compared to the virus of other HIV positive people who have “wild-type” virus, or virus that has never been exposed to HIV medicine. This wild-type virus is susceptible to all the medications--there is no resistance.
Like the genotype, the phenotype can’t tell you very much if your resistant virus is less than 10 to 20% of your total virus, or if you have been off medications for more than one month or so. The phenotype is also more expensive than the genotype.
Virco-type Test
This is an interesting type of resistance testing that predicts your phenotype by first analyzing your virus’s genetic mutations (your genotype) and comparing those results to data they have gleaned from other HIV positive people in their genotype-phenotype data base.
What is Cross-Resistance?
Your medical provider may tell you that you have cross-resistance. Cross resistance means that not only do you have resistance to one drug in a class of drugs, but, because of that type of resistance, you will not be susceptible to other drugs in the same class. For instance, Viramune (nevirapine) and Sustiva (Efavirenz) are in the same class of drugs, called NNRTIs, or non-nucleoside reverse transcriptase inhibitors. (Whew, what a mouthful. It’s not important to remember the names of the different classes, but only to know that there are different classes of medicines and sometimes, if you are resistant to one drug in a certain class, you might be resistant to all the drugs in the class). If you have resistance to Nevirapine, you will probably have resistance to Sustiva and that takes this drug off the table in terms of medicines that you will be able to take to treat your virus. Not only that, there is another medicine in this class called Rescriptor, or Delavardine. No one uses this medicine much anymore, but if you have cross-resistance to one medicine in the class, you won’t be able to use this medicine either. You can see how this can be serious stuff, because you now have an entire class of medicines, that won’t work for you.
Your medical provider will know which drugs make it more likely that you will get cross-resistance. At any rate, the way to prevent cross-resistance, is to take your medicine without missing doses.
Figuring out which drug you should take is not easy. This decision should be made by you and your medical provider and this medical provider should, in nearly all cases, be an HIV specialist. In addition, some cases are so complex, that the skills of a clinical pharmacology HIV expert is needed.
Your medical provider may also use the internet resources of the Stanford HIV Drug Resistance Database and the Los Alamos National Laboratory HIV Drug Resistance Database to help choose the particular drug regimen which will be effective against your particular virus. These resources are constantly being evaluated and updated by HIV experts.
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