HIV-1 Drug Resistance Trends in the Era of Modern Antiretrovirals: 2018-2024

Abstract

Background: Antiretroviral drug resistance limits treatment options for people with human immunodeficiency virus (HIV) 1 and may reduce the effectiveness of preexposure prophylaxis. Novel treatment options with enhanced efficacy and more convenient formulations have become available from 2016 to 2021. Large-scale studies of trends in the prevalences of plasma RNA drug resistance mutations (DRMs) since 2018 are lacking, and there have been no systematic studies of trends in proviral DNA DRMs.

Methods: We retrospectively analyzed deidentified HIV-1 plasma RNA and proviral DNA sequences from specimens submitted to a reference laboratory between January 2018 and May 2024. We analyzed the annual prevalence of DRMs with a Stanford HIV Drug Resistance Database score of ≥30 for nucleoside and nonnucleoside reverse-transcriptase inhibitors (NRTIs and NNRTIs), protease inhibitors, and integrase strand transfer inhibitors (INSTIs).

Results: The prevalence of resistance declined for both RNA and DNA sequences. Single-class and dual-class NRTI + NNRTI resistance declined but was higher for DNA (NRTI + NNRTI, declined from 6.1% to 3.5% for RNA and from 12.1% to 7.8% for DNA). Rilpivirine DRMs remained low, with prevalences of 6.3% (RNA) and 10.2% (DNA) in 2024. The doravirine DRM prevalences in 2024 were 2% (RNA) and 2.9% (DNA). INSTI and dual-class NRTI + INSTI resistance also declined, but the prevalence of integrase DRM R263K increased.

Conclusions: Prevalence of NRTI and NNRTI resistance has declined, consistent with increased use of regimens with higher resistance barriers, improved tolerability, and more convenient dosing. Proviral DNA resistance trends were correlated with those for RNA. Continued advances in antiretroviral therapy efficacy, durability, and tolerability may lead to increased rates of virologic suppression and further reduce the incidence of archived resistance mutations in proviral DNA.

Keywords: HIV-1; drug resistance mutations; integrase; protease; reverse-transcriptase.

Figure 1.

Prevalence of resistance in human immunodeficiency virus (HIV) 1 plasma RNA and proviral DNA specimens from 2018 to 2024, including nucleoside reverse-transcriptase (RT) inhibitor, nonnucleoside RT inhibitor, protease inhibitor, and integrase strand transfer inhibitor drug resistance mutations (DRMs) with a Stanford HIV Drug Resistance Database score ≥30. RNA DRMs included plasma RNA DRMs detected by Sanger sequencing in all RNA sequences with a concurrent order for RT, protease and integrase genotypic resistance testing; DNA DRMs included those at the clinical minority variant (MV) cutoff of 10% and at an MV cutoff of 20% (Cochran-Armitage test for trends, P < .001 for RNA and DNA [both MV cutoffs]).

Figure 2.

Multiclass resistance by year and by age group. A, Dual-class resistance—nucleoside reverse-transcriptase (RT) inhibitor (NRTI) + nonnucleoside RT inhibitor (NNRTI) or NRTI + integrase strand transfer inhibitor (INSTI) resistance—for RNA and DNA sequences. DNA drug resistance mutations (DRMs) with a Stanford HIV Drug Resistance Database [HIVDB] score ≥30 were analyzed at the 10% clinical minority variant (MV) cutoff. RNA DRMs included all RNA sequences with a concurrent order for RT, protease, and integrase genotypic resistance testing (Cochran-Armitage test for trends, P < .001 for RNA and DNA). B, Dual- and triple-class resistance by patient age group for RNA and DNA specimens. DRMs with a Stanford HIVDB score ≥30 were tabulated for each category. A 10% MV cutoff was used for DNA sequences (Cochran-Mantel-Haenszel test for resistance category differences by age group, P < .004 for RNA and P < .001 for DNA; adjusted χ² by age group, P < .001 for both RNA and DNA).

Figure 3.

APOBEC-associated drug resistance mutations (DRMs) at 16 of 18 resistance-associated codons in the human immunodeficiency virus (HIV) 1 integrase, reverse-transcriptase (RT), and protease genes designated as APOBEC-context mutations in the Stanford HIV Drug Resistance Database [29]. DRMs include mutations in plasma RNA sequences and mutations in proviral DNA sequences with a minority variant (MV) cutoff of 10% or 20%. Only a single instance of APOBEC-associated protease mutation G48S was found in RNA and proviral DNA sequences. The D232N integrase APOBEC-associated mutation could not be evaluated for proviral DNA sequences, as it is identical to the reference sequence. D232N is found in 0.25% of RNA integrase sequences. Abbreviations: INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside RT inhibitor; NRTI, nucleoside RT inhibitor; PI, protease inhibitor.

Figure 4.

A, Doravirine and rilpivirine drug resistance mutation (DRM) prevalence in RNA and DNA sequences. B, Cabotegravir DRM prevalence in RNA and DNA sequences. Rilpivirine, doravirine, and cabotegravir DRMs with a Stanford HIV Drug Resistance Database score ≥30 were tabulated. A 10% minority variant cutoff was used for DNA sequences. Doravirine DRMs included V106A/M, Y188F/L, G190E/Q, L234I, F227C/I/L/V, M230L, Y318F; rilpivirine DRMs: L100I, K101E/P, Y181C//F/G/I/S/V, Y188L/F, G190E/Q, F227C, and M230I/L; cabotegravir DRMs, G118R, F121C, G140R, Q148H/K/R, N155H, and R263K.