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Resistance Mechanisms Leading to MDR HIV


Michael Sension, MD, provides insights on resistance mechanisms promoting MDR HIV.

Ryan Haumschild, PharmD, MS, MBA: If you could, give us an overview and then discuss how this smaller patient population is an important subset of the greater population of patients with HIV [human immunodeficiency virus].

Michael Sension, MD: It is true, to develop resistance, you have to have subtherapeutic levels of a drug. The vast majority of people I’ve seen who develop resistance through the years have a story to tell of why they didn’t take their medicines. I think I could write certainly a chapter, if not a whole book, on “Why I forgot to take my medicines, or why I didn’t take my medicines,” and they developed subtherapeutic levels of a drug, which led to resistance. But it’s not everybody who has that particular story. Some of my patients did exactly what they were told to do by their physicians. For example, for those who have had HIV or have been living with HIV for 30-plus years, the very first medication that came out was a single treatment that people often think of as AZT [azidothymidine, also called zidovudine]. When AZT first came out, it was the only drug people took, and some people took it. Then another nucleoside reverse transcriptase inhibitor became available, and they took that. They did sequential monotherapy, and they added an agent as their physician instructed them to, and they developed resistance as well because they never had a potent enough regimen to achieve virologic suppression.

So, there are adherence issues. There are sometimes drug-drug interactions that occur that lower drug exposure. Sometimes there are drug-food interactions where one needs to have a certain amount of food in the stomach for the drug to be properly absorbed. Sometimes a drug requires a normal acid environment in the stomach. If one is taking antacids due to whatever conditions they’re trying to treat, heartburn or reflux disease, it can interfere with the proper absorption. Occasionally, we see people with some malabsorption syndromes where they don’t absorb the medication properly. Then sometimes people miss doses because of safety issues, or tolerability issues with medications that are causing them to miss a dose. There are a variety of reasons that could lead to suboptimal levels of a drug. You can always blame the patient and say, “You didn’t take your medicines the appropriate way.”

Ryan Haumschild, PharmD, MS, MBA: I appreciate you demystifying that because I think it’s educational for everyone. Sometimes people think traditionally, as pharmacists and others, that if you don’t take your medications, you start to have trends of resistance. That might be true, but not for all. I think that was a great review. If you could, let’s take it another step further. I’d appreciate it if you could describe the heterogeneity of resistance seen in multidrug resistant HIV, and what are some of the different resistance mutations you may see in your unique patients? I know you hit on some earlier, but if you could, let’s talk about those mutations a bit more.

Michael Sension, MD: Most patients have a fairly unique history of the medications they’ve been on. Depending upon what medicines they started off taking, and if they had any degree of suboptimal levels of medication with those particular regimens they were on, they might develop specific resistance mutations. Some of the early drugs we used back in the 1980s and ’90s, as medications were being developed, had relatively low barriers to resistance. For example, the very first nucleoside reverse transcriptase inhibitors tended to go down different pathways of resistance. There were thymidine analogue mutations we would see that would sometimes differ depending upon the pathway to resistance of the thymidine analogues. We had then certain signature mutations that would evolve for certain medications.

When somebody was an HIV provider in the 1990s, they essentially had to be an expert at dealing with resistance and knowing what specific mutations might confer resistance to which drugs, and then what might cause cross-resistance. For example, some early medications that we still use today, 3TC or lamivudine, has a classic signature mutation, the 184V mutation. One of the very first NNRTI [non-nucleoside reverse transcriptase inhibitor] medications developed was efavirenz. That had a very classic 103N mutation associated with it. Another NNRTI developed about the same time in the 1990s was nevirapine, which had another signature mutation, Y181C, associated with it. Oftentimes when people developed resistance to one drug, they were then resistant to another drug that they’d never even been exposed to, so there were cross-resistance issues.

Transcript edited for clarity.

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