Baseline HIV Resistance Testing Finds High Susceptibility to First-Line Therapy

A single-center retrospective study of 278 treatment-naive people with HIV-1 found that most viruses remained susceptible to guideline-recommended first-line antiretroviral therapy (ART), while a minority carried clinically relevant drug-resistance mutations. Genetic analysis of the protease and reverse transcriptase regions of the HIV-1 pol gene showed susceptibility rates of 99.6% for tenofovir disoproxil fumarate (TDF), 98.2% for emtricitabine or lamivudine (FTC/3TC) and 98.5% for doravirine (DOR). These findings support the continued effectiveness of current first-line regimens and the value of baseline genotypic resistance testing, although the study’s design and population limit how broadly the results can be generalized.

Participants were followed at one institution and had not received ART before enrollment. The group included 240 men, or 86.3%, and 38 women, or 13.7%. Median age was 42 years, with an interquartile range of 31–51 years, and there was no statistically significant difference in age between the sexes (p = 0.432). The median CD4 cell count was 381 cells/mm³, with an interquartile range of 280–468 cells/mm³. The investigators analyzed protease and reverse transcriptase sequences by Sanger sequencing, assigned HIV-1 subtypes with the REGA HIV-1 Subtyping Tool version 3.0, and interpreted drug-resistance mutations using version 9.7 of the Stanford HIV Drug Resistance Database.

Subtype B was the most prevalent viral subtype, detected in 34.0% of participants, followed by subtype A at 32.4% and subtype F at 16.2%. Protease-inhibitor-associated mutations were present in 51 patients, or 18.3%, including major drug-resistance mutations in 45 patients, or 16.2%. Nucleoside reverse transcriptase inhibitor-associated mutations were detected in 37 patients, or 13.3%, with major mutations in seven patients, or 2.5%. Non-nucleoside reverse transcriptase inhibitor-associated mutations occurred in 66 patients, or 23.7%, but most were polymorphic or accessory variants; clinically relevant NNRTI resistance mutations were found in only six patients, or 2.2%.

The most frequently observed mutations varied by drug class. Among protease-inhibitor mutations, M46L was most common; among NRTI mutations, it was S68G; among major NRTI mutations, it was M184V. The NNRTI-associated mutations most frequently detected were E138G, E138A and K103N. Susceptibility to alternative agents was also assessed. The study reported rates of 99.6% for ritonavir-boosted darunavir, 83.8% for ritonavir-boosted atazanavir and 78.4% for rilpivirine. The investigators characterized the frequency of clinically relevant protease-inhibitor resistance as higher than in some previous reports, whereas clinically relevant NRTI and NNRTI resistance remained uncommon.

The results distinguish the broad occurrence of mutations from their clinical importance. Although nearly one-quarter of participants had mutations associated with NNRTIs, most were classified as polymorphic or accessory variants rather than clinically relevant resistance. In contrast, major NRTI mutations were uncommon, and clinically relevant NNRTI mutations were identified in only 2.2% of the cohort. The high measured susceptibility of the viruses to TDF, FTC/3TC and DOR indicates that these agents retained activity against most viruses in this treatment-naive population. The authors concluded that current guideline-recommended first-line ART remained effective in the studied cohort and emphasized baseline genotypic resistance testing as an important component of care. Because the investigation was retrospective, centered on one clinic and restricted to protease and reverse transcriptase regions, it did not evaluate every possible resistance pathway or establish outcomes under treatment in a randomized comparison.

Subject of Research: Baseline HIV-1 drug-resistance mutations and antiretroviral susceptibility in 278 treatment-naive patients

Article Title: Investigation of Antiretroviral Therapy (ART) use and drug resistance characteristics in HIV-positive patients

Article References: Topal, Ş., Günal, Ö., Demir, T., Demirağ, M. D., Kara, A. Ş., Usanmaz, M., & Kılıç, S. S. (2026). Investigation of Antiretroviral Therapy (ART) use and drug resistance characteristics in HIV-positive patients. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14214-5

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14214-5

Keywords: HIV-1, antiretroviral therapy, drug resistance, genotypic testing, treatment-naive patients, reverse transcriptase, protease inhibitors, NRTI, NNRTI, Sanger sequencing, Investigation, Antiretroviral