Drug Resistance 101

Everything you need to know about antiretroviral resistance, how it happens, and how to combat it.

The thought of any disease developing drug resistance is frightening. Earlier this year, the Centers for Disease Control and Prevention announced that the first antibiotic- resistant strain of gonorrhea had hit the United States. To be clear, this wasn’t the first time gonorrhea had grown resistant to a particular drug—many drugs no longer treat gonorrhea—but it marks the moment gonorrhea is becoming resistant to every drug currently available to treat it. Having a previously curable infectious disease become immune to any and all treatment options is a nightmare scenario.

HIV can also become drug resistant, but most people are able to use antiretroviral combination therapy for many years without ever developing such a resistance. Fortunately, if you do develop a resistance, numerous treatment options are still available to take your current medication’s place. So don’t panic or lose sleep; even drug resistant strains of HIV can be treated these days. But you do need to know the facts about resistance, how it develops, what the symptoms are, and how it’s treated.

What is Drug Resistance?

Drug resistance occurs when a disease develops a defense to the mode of attack that a medication is using to fight it. Imagine if you arm yourself with a gun to protect your home, and then burglars buy bulletproof vests. That’s resistance.

All organisms are constantly evolving to deal with the stressors in their environment, but whereas humans may appear unchanged over generations, organisms like viruses can change at a disturbingly rapid pace. Each HIV particle is actually short-lived, surviving only a couple of days. Unfortunately, the virus is very prolific during those 48 hours, and—after hijacking your T-cells, uses them to create billions of copies of itself in a given day. Because it’s reproducing so quickly, there’s a high probability of errors being made and then those errors being replicated. In fact, scientists believe in every reproduction cycle HIV makes at least one mistake.

When a person with HIV isn’t on treatment, these mutations rarely offer an advantage over the initial strain, so the first (sometimes called “wild”) strain of HIV typically wins out. But once you’re taking antiretroviral medications, things change. In that case, if one of the millions of errors a day turns out to cause a mutation in the virus that makes it more resistant to the drugs being used to kill it, that mutation gives the new strain a competitive advantage over the wild version, and soon more of the mutated strain are replicating and passing on their drug resistance. If another error makes it even more resistant to that drug, the level of resistance continues to build, and eventually the medication stops working.

Is Resistance That Common?

One of the reasons that HIV combination therapy uses three drugs today is so that even if one of the drugs is no longer working, the other two can. While strains of HIV that have developed resistance to two medications are found in about three percent of all new cases, strains that have become resistant to three drugs are much rarer, found in less than one percent (technically, 0.6 percent) of all new HIV cases, according to a 2012 study.

Even so, without the three medications working in tandem, your viral load can begin to climb. And you’re unlikely to realize it’s happening. According to the British HIV treatment and advocacy site I-Base, “Avoiding resistance is more important than increasing your CD4 count because it will let your treatment work for many years.”

Symptoms of Resistance

So how do you know if you have a drug resistant strain of HIV? The only way to know for sure is through testing. When you are first diagnosed with HIV, your doctor should check to see which strain you’ve got, as some strains are resistant to different drugs.

If you have been on treatment, reached undetectable levels, and continued to adhere to your medications—but your viral load rebounds anyway—you should be tested for drug resistance. You should also be tested before you switch medications, as you’ll need to know whether your strain of HIV has a resistance to one type of drug. The National Institutes of Health also recommend drug-resistance testing for all HIV-positive pregnant women, whether they are on medication or not (because drug resistant strains can be perinatally transmitted to a child).

Stopping Resistance

How do you keep HIV from developing a resistance to your medication? The risk of resistance increases when drug levels drop below a minimum active level. This usually only occurs if you miss doses or stop treatment. Getting on medication, adhering to your treatment as prescribed, not missing doses, and maintaining an undetectable viral load are your best defenses against developing resistance. As a 2005 study published in the Journal of Virology demonstrated, when your viral load is undetectable, HIV’s mutations appear to stop. While undetectable, the replication and errors that occur during the process are shut down.

Unfortunately, that doesn’t completely eliminate the risk of developing a resistance. This was the situation with one gay couple, in a case presented by Erika Castro of Switzerland’s Lausanne University Hospital, at the 2010 Conference on Retroviruses and Opportunistic Infections. One of the men was on therapy and undetectable with a non-resistant strain of HIV; the other had been on antiretrovirals for five years but still had a detectable viral load and a multi-drug resistant strain of HIV. The resistant strain was transmitted from the one partner to the other. This is a reminder that being HIV-positive—and even being undetectable and uninfectious—does not prevent you from getting another strain of the virus, including a strain more difficult to treat than the one you have.

Medication Matters

According to a 2012 report, the Centers for Disease Control and Prevention learned that roughly two out of every 10 new cases of HIV involve strains with at least partial resistance to one or more antiretroviral medication.

Some drugs have a higher risk of resistance and only need one mutation for the virus to gain complete resistance. This is particularly true with nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz, rilpivirine, and etravirine), integrase inhibitors (raltegravir), and some nucleoside analogues like 3TC and FTC. These drugs are also more vulnerable if used in combinations that aren’t effective in maintaining viral loads below 50 copies/ml.

When the virus develops a resistance, there is often cross-resistance to similar drugs in the same class. Cross-resistance occurs when a mutation that gives the virus an edge against one medication also gives the virus resistance to similar drugs, even if you’ve never taken them before. This is most common among drugs in the same class, so if you develop a resistance to one NNRTI (like rilpivirine), then another NNRTI (like efavirenz) is also unlikely to work.

Fortunately, some drugs offer more protection from HIV developing resistance. The the 48-week ODIN trial found that darunavir (a component of both Prezista and Prezcobix) has a high genetic barrier to HIV developing drug resistance. It stops the virus both from multiplying and mutating. Decreasing the rates of duplication and cutting down on the number of errors the virus makes reproducing, dramatically reduces the opportunity for drug resistant mutations to appear and replicate. While Prezcobix is less prone to drug resistance, it shouldn’t be taken by those who’ve developed drug resistance to darunavir.

The most important things to remember about drug resistance are to get testing before starting treatment, work with your doctors to determine the best medication for you, adhere to your treatment, and get/keep your viral load undetectable. And, importantly, if you do develop a resistance, talk to your doctor about switching medications. Just because you’ve developed a resistance to one drug—or even a whole class of drugs—doesn’t mean that other HIV meds won't work for you.

Remember, HIV strains with multiple drug-class resistances are rare and, so far, none have shown the kind of treatment-wide resistance that gonorrhea is developing to antibiotics. So don’t lose sleep over your drug resistant strain of HIV—just hit it with a different combination therapy.