Foundations of ART Management in Heavily Treatment–Experienced Patients

Resistance testing has been and will continue to be a key part of the first steps of how we analyze what is happening in people with virologic failure. The current recommendation is that drug resistance testing be performed in those who are starting therapy for the first time to look for transmitted resistance as well as those who are experiencing virologic failure.¹

Ideally in this second group, resistance testing should be performed while patients are still taking their failing regimen. Once a patient is off therapy for ≥4 weeks, there is an increasing likelihood that resistant virus will not be detected by the test. The exception to this is noted in the most recent version of the Department of Health and Human Services ART guidelines and includes those who have experienced virologic failure on a regimen of long-acting cabotegravir and rilpivirine or who acquired HIV after receiving cabotegravir as pre-exposure prophylaxis. Since the half-life of long-acting injectable drugs is very long, those in this group should undergo resistance testing no matter how much time has elapsed since drug discontinuation.

In addition, resistance is cumulative, so any resistant virus that was present at any time is assumed to remain present in the given patient’s body. This concept of archived drug resistance is that the virus is always present, even if it is not detected by standard tests. In fact, it is estimated with the current genotypic tests that are commercially available, that a virus present at a frequency of <10% to 20% of the circulating virus population will not be detected.

That’s why we need to look at previous treatment history and all previous genotypic or phenotypic resistance tests. We also consider resistance that is inferred based on treatment history, such as when a person experienced virologic failure on a specific regimen. In this case, we suspect that the patient may have resistance to those drugs, even if it was not documented or detected by resistance testing.

The last important reminder is that we should not discontinue or interrupt therapy in people who are experiencing virologic failure. We have data showing that, with treatment interruption, CD4+ cell counts decline and HIV-1 RNA increases, and patients are at risk for clinical progression.

The level of failure will determine the type of resistance testing we should perform.¹ For most people experiencing early failure for whom we don't anticipate a complicated resistance pattern, genotypic resistance testing is preferred. If it turns out that a more complex drug resistance pattern is suspected (particularly to PIs), then both a genotypic and phenotypic test may be of value.

There are also commercially available assays that analyze proviral DNA for resistance mutations. This test is primarily used for people who have low levels of virus, too low to detect HIV-1 RNA in plasma. But these tests are imperfect, and they need to be interpreted with caution: All resistant virus that has been archived may not be picked up by these tests.