The word “resistance” might conjure up images of protesters, government workers, or throngs of early voters. But HIV- positive people know all too well the fallout of a different kind of resistance: antiretroviral drug resistance.
Thankfully, the majority of those living with HIV will likely never face antiretroviral drug resistance. Although the risk of developing resistance increases over time, modern antiretroviral drugs are less vulnerable and have higher adherence rates — two factors that decrease the risks.
Still, we can’t ignore the fact that there’s been a globally documented expansion of HIV drug resistance, which the World Health Organization says has the potential to fuel an increase in new HIV diagnoses and deaths. So what is antiretroviral drug resistance and how can you fight it?
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 protect your house with a security system and then burglars learn how to hack into it. That’s resistance.
All organisms are constantly evolving to deal with the stressors in their environment, and viruses can change at a disturbingly rapid pace. HIV can create billions of copies of itself in a single day. In all of that replication, mistakes are occasionally made and passed along. Some of those mistakes create mutations that are helpful to the virus. Those versions become more common if they survive the medications you are taking.
As more of the mutated strain replicates, it passes on its drug resistance. If another error makes it even more resistant to that drug, the level of resistance continues to build. Eventually, the medication stops working.
How Common Is Drug Resistance?
Unfortunately, that’s a hard question to answer. A 2017 WHO report noted that, in some poor and under-resourced countries, nearly one in 10 people starting treatment are doing so while already showing resistance to one of two commonly prescribed first-line HIV drugs (efavirenz or nevirapine). Those rates don’t account for those newly diagnosed who show resistance to other HIV drugs, nor do they include those who’ve developed resistance to HIV drugs after starting treatment.
A 2016 meta-analysis published in the journal Infection, Genetics and Evolution reported transmitted drug resistance may be as high as 12 to 24 percent of new diagnoses in the U.S. But the International Antiviral Society – USA’s 2018 Updated HIV Drug Resistance Guidelines reports that “in resource-rich regions, the prevalence of transmitted drug resistance is about 10 percent.” The U.S. (as a whole) is considered “resource-rich,” so this lower number may apply. But both of these reports only address the kind of drug resistance that is transmitted with the HIV strain — rather than including those that develop while someone is on treatment.
Symptoms of Resistance
So how do you know if you have a drug-resistant strain of HIV? The only reliable method is testing. When you are first diagnosed with HIV, your doctor should check which strain you have since some strains are resistant to diff erent drugs. This genotypic-resistance testing should especially look for mutations impacting reverse transcriptase and protease inhibitors.
When Should I Be Tested?
If you’ve been off treatment for a while, if your viral load increases while you are on treatment (even if you remain undetectable), or if you are planning to switch medications, you should be tested for resistance. In addition, the National Institutes of Health also recommends drug-resistance testing for all pregnant women living with HIV, whether they are on medication or not, because drug-resistant strains can be perinatally transmitted to a child.
The risk of resistance increases when drug levels drop below a certain active level. This usually only occurs if you miss doses or stop treatment. Any interruption to your treatment plan can have long-term impacts, and WHO reports that those who experience treatment interruptions are three times more likely to develop resistance to efavirenz or nevirapine.
Your best defenses against developing resistance involve getting on medication, adhering to your treatment as prescribed (meaning: not missing doses, taking the medication at the recommended time of day and with — or without — food or other drugs as recommened), and maintaining an undetectable viral load.
Adherence has increased over time due to antiretroviral therapy medications becoming more tolerable (and now available in easy-to-take, single-tablet regimens). As the Infection, Genetics and Evolution report noted, “Most ART regimens used for first-line therapy are suffciently potent to completely block HIV-1 replication and have a genetic barrier to resistance high enough to maintain long-term virological suppression.”
Because gaps in treatment play a pivotal role in the development of drug resistance, WHO’s Global Action Plan on HIV Drug Resistance is encouraging people with HIV to take medications as prescribed, and doctors and service providers to keep poz people on treatment, increase viral load testing (to catch viral rebounds that happen as resistance is developing), and quickly facilitate switching to other medications when resistance is suspected.
When the virus develops a resistance, there is often cross-resistance to the whole drug class. Cross-resistance occurs when a mutation that gives the virus an edge against one medication also works against similar drugs, even if you’ve never taken them. If you develop a resistance to one NNRTI (like rilpivirine), then another NNRTI (like efavirenz) is also unlikely to work.
Do Particular Drugs Make a Difference?
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 analogs 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.
Fortunately, some drugs offer more protection against HIV developing resistance. For example, the 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.
What If I Develop Resistance?
Fortunately, if you do develop a resistance, numerous treatment options are still available to replace your current medication. Talk to your doctor about switching. 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.
HIV strains with multiple drug-class resistances are rare, but there’s also new hope for folks who have developed a resistance to most classes of antiretrovirals. Both ibalizumab (a monoclonal antibody)—a long-acting injectable already approved by the U.S. Food and Drug Administration — and fostemsavir (an attachment inhibitor, still in development) have been shown to ght multidrug-resistant HIV when added to a previously failing antiretroviral regimen. Each drug uses a novel attack on the virus, creating new classes of drugs in the process and giving people with HIV more ways to fight antiretroviral resistance.