A Primer on HIV Drug Resistance

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 — however, increased surveillance of global HIV drug resistance in recent years tells us more. And not all is good news. The WHO’s 2019 global report on HIV drug resistance showed that up to 26 percent of people in the world who are initiating HIV treatment are infected with a virus carrying resistance to first-line drugs (such as efavirenz). There’s also been a significant increase in resistance among infants born with HIV, now up to 69 percent globally.

In resource-rich countries like the U.S., due to factors like adherence and access to the latest medications, resistance rates are much lower, somewhere around 10 percent, according to most available data.

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 different 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 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.

Preventing Resistance

The risk of resistance increases when drug levels drop below a certain active level. This usually occurs only 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 than first-time users of these drugs.

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 recommended), 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). “Most ART regimens used for first-line therapy are sufficiently potent to completely block HIV-1 replication and have a genetic barrier to resistance high enough to maintain long-term virological suppression,” a report in the journal Infection, Genetics and Evolution noted.

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.

What's Cross-Resistance?

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 nonnucleoside reverse transcriptase inhibitor (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 NNRTIs (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 (marketed under the brand name Prezista and also a component of Prezcobix) has a high genetic barrier to the development of drug resistance. It not only stops the virus from multiplying and but cuts down on its ability to mutate, and therefore a resistant strain is unlikely to develop.

What If I Develop Resistance?

Fortunately, if you do develop 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. Two drugs that can combat resistance were recently approved by the Food and Drug Administration: the long-acting injectable ibalizumab (a monoclonal antibody, brand name Trogarzo) and fostemsavir (an attachment inhibitor, brand name Rukobia). Both have been shown to be effective in treating multidrug-resistant HIV when added to a previously failing antiretroviral regimen. Each drug is in a new class and uses a novel attack on the virus, giving people with HIV more ways to fight antiretroviral resistance.