HIV Drug Resistance Declines in the Modern ART Era

A new 6-year analysis led by Quest Diagnostics, offers encouraging evidence that HIV drug resistance in the United States continues to fall in the era of modern antiretroviral therapy (ART). Published in Open Forum Infectious Diseases, the analysis evaluated more than 90,000 HIV plasma RNA sequences and over 25,000 proviral DNA sequences submitted to Quest between 2018 and 2024. Researchers examined resistance mutations across 4 major antiretroviral classes and found an overall 17% decline in drug resistance prevalence during the study period.¹

"We use next generation sequencing, we capture these minority resistance variants. So what really makes this study unique, is the scale and the correlation that we we noted the DNA trends mirrored RNA declines, and when we adjusted DNA sensitivity to match RNA, they really mirrored each other," Elizabeth Marlowe, PhD, D(ABMM), executive scientific director of infectious diseases for Quest Diagnostics, said. "So it really provides a nice population view of how resistance evolves in both active infection and latent reservoirs."

Marlowe was the senior author on the study and she notes the reduction was most notable in nucleoside and non-nucleoside reverse transcriptase inhibitor resistance, trends that she attributes to the widespread adoption of high-barrier, integrase-based therapies; improved tolerability and convenience of single-tablet regimens and long-acting injectables; and increased access to treatment and early diagnosis. As more patients maintain viral suppression and fewer develop new mutations, transmission of resistant strains also appears to be decreasing.

In a first-of-its-kind comparison, the study assessed population-level resistance trends using both plasma RNA (active virus) and proviral DNA (archived virus). Despite DNA testing detecting more minority variants, the two datasets closely mirrored each other, offering new insights into how archived resistance evolves and how DNA genotyping can help guide regimen changes in suppressed patients.

One mutation—integrase R263K—showed a small but notable rise as well as older adults.

"In the entity mutations, there's a particular mutation called the R263K, we saw a slight increase. We did see higher resistance, though, in older adults, those between the ages of 60 and 90 years of age, and that probably reflects sort of longer exposure to these earlier generation therapies," Marlowe said.

Overall, Marlow says the findings reflect meaningful progress in HIV care and underscore the critical role of laboratory-clinician partnerships in achieving long-term epidemic control.

Reference
1. Kagan R, Baxter J, Kim T, Marlowe E, HIV-1 Drug Resistance Trends in the Era of Modern Antiretrovirals: 2018–2024, Open Forum Infectious Diseases, Volume 12, Issue 8, August 2025, ofaf446, https://doi.org/10.1093/ofid/ofaf446