The Impact of Drug Resistance on Treatment Efficacy


Joseph Eron, MD, Daniel R. Kuritzkes, MD, and Monica Gandhi, MD, MPH, explore the ways in which drug-resistance mutations impact treatment efficacy.

Joseph Eron, MD: Dan, for people who aren’t in tune to resistance or mutations, remind us about how some resistance mutations are more important than others. Some are accessory. Can we keep all these things in our heads? Do we need our clinicians to do that? Is there a source?

Daniel R. Kuritzkes, MD: I can’t keep them all in my head anymore. There are too many of them and too many classes. Yes, you definitely need a source. There are some good reference sources. One is the Stanford University HIV drug-resistance database, which you can use to just go get information. You don’t have to register. You bring it up on your device, and you can enter the mutations that may have been reported back from a genotypic drug resistance test. Figure out what impact they have on susceptibility to whatever drug you’re interested in. The other resource is the IAS-USA [International Antiviral Society–USA], which continues to update its list of the most clinically significant drug-resistant mutations. Though its somewhat less comprehensive than the Stanford list, it’s useful for clinicians.

Monica Gandhi, MD, MPH: I want to add something because I have a very defined way that I teach fellows about resistance. We definitely use both of those tools, but I asked them to memorize the 6 TAMs [thymidine analog mutations]: 41, 67, 70, 210, 215, and 219. Then we know cumulatively that we’re going to get more reduced susceptibility if we have too many. I’ve also asked them to memorize M184V, K65R, and L74V. So I asked them to memorize 9 NRTI [nucleoside reverse transcriptase inhibitor] mutations. In the NNRTI [non-nucleoside reverse transcriptase inhibitor] class, I asked them to remember K103 and Y181C. Lastly, there’s E138, which is rilpivirine resistance.

I don’t ask them to memorize anything else, but we put on our phones the doravirine-associated mutations. That came out from the studies DRIVE-AHEAD, DRIVE-FORWARD, and DRIVE-SHIFT. We have 5 mutations. We all have a contact on our phone. You can call doravirine whenever you want, and we have these mutations listed. Then I asked them to have on their phone darunavir and the 11 darunavir-associated mutations. We know, especially with 3 or more, that we have trouble with darunavir. That’s my trick in case you can’t access a computer. That’s how we memorize.

Joseph Eron, MD: Yeah. That’s very clever.

Daniel R. Kuritzkes, MD: You’ll have to send me your link.

Monica Gandhi, MD, MPH: You’re going to have 2 contacts later today, doravirine and darunavir.

Joseph Eron, MD: That’s very helpful. To summarize, there are people out there who have limited treatment options. Sometimes it’s due to multidrug resistance, but that’s much less common. It’s not unimportant because there are people like that, and we need to know how to treat them. Then there are people who have limited treatment options. They may be highly treatment experienced, or at least highly prescription experienced, but they never consumed much of those pills. Those people are equally important. In some respects—as you pointed out, Monica—that population is contributing to the ongoing spread of the epidemic. Resistance is complicated, but there are ways to sort it out, and there are experts. One final thing is that if you’re not an expert and you have someone with multidrug resistance, there’s no shame in contacting someone who knows this field carefully.

Monica Gandhi, MD, MPH: I don’t think we know the prevalence of resistance as well globally. We have a better idea in the United States, but I was recently in Brazil, and they’re looking at the prevalence and resistance. Who knows? We need better surveillance for the rest of the world.

Joseph Eron, MD: That’s clearly important. Thank you for bringing that up. We know from things like COVID-19 and monkeypox that things that start in other places can certainly show up here.

Transcript Edited for Clarity

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