Virologic Resistance in HIV Infection

Joseph Eron, MD: Eric, are we seeing resistance? You talked about barrier to resistance with the different drugs, but resistance, emergence, altogether?

Eric Daar, MD: In our clinics, we have 2 populations. We have those people who started with sequential monotherapy or dual therapy; they’ve accumulated a lot of resistance. Most of those people, who are still with us now, became suppressed when darunavir and integrase inhibitors came out. In those who are starting therapy for the first time, resistance is very rare. Even in the clinical trials, we talk about boosted protease inhibitors [PIs]—no PI resistance. Dolutegravir-based regimens—no integrase or NUC resistance.

But then, we point fingers at other drugs, like elvitegravir and raltegravir, saying resistance does develop with them. But it’s in 3 people. So, in clinical practice, as we get better and better at selecting our patients for treatment and supporting them during treatment, that true virologic resistance is really going to be quite rare. We still have to look for it. Occasionally, we send for a resistance test. But I have to admit, it’s only done occasionally. Even in a big clinic, we rarely have to do it.

Joseph Eron, MD: Yes. Dan, you started out our whole conversation with the biology of how to select for new resistance. You have to have ongoing replication. Part of the reason why we’re so focused on viral loads of less than 50, 40, or 20 is for that reason, right? It’s not because we’re obsessed with numbers.

Daniel Kuritzkes, MD: Exactly. The way the virus replicates, it’s a really sloppy machine. It makes lots of mistakes. And so, if you let it make mistakes, some of those mistakes will inevitably be ones that generate a resistance mutation. Then the drug will become less and less effective. And if you use enough drugs, there may be too many mistakes for them to occur by chance. You prevent that from happening. The data are now really compelling. Somebody whose virus load is below the threshold of detection by any of the commercial assays has no ongoing virus replication. Therefore, he or she will not get resistant.

There really isn’t the phenomenon of a person breaking through late, after 3 or 4 years, because they’ve now developed resistance when they were always taking their medication and there was no replication. If you probe deeply enough, it’s always because somebody took a drug holiday. They were unable to continue to get their drug. They ran out of the drug. They got incarcerated and couldn’t get a hold of the drug. There are a variety of reasons that lead to virologic failure, with or without resistance. It’s not because resistance magically emerged.

Luckily, we don’t have to worry about it. And with the newer regimens, we don’t even worry about transmitted resistance any more. You need to do a resistance test before starting someone on treatment.

Joseph Eron, MD: You know, there’s really less and less rationale to be doing resistance testing before starting someone on therapy.

Transcript edited for clarity.