Low-Abundance Drug-Resistant Viral Variants in Chronically HIV-Infected, Antiretroviral Treatment–Naive Patients Significantly Impact Treatment Outcomes

• Published in: The Journal of infectious diseases Vol. 199; no. 5; pp. 693 - 701
• Main Authors: Simen, Birgitte B., Simons, Jan Fredrik, Hullsiek, Katherine Huppler, Novak, Richard M., MacArthur, Rodger D., Baxter, John D., Huang, Chunli, Lubeski, Christine, Turenchalk, Gregory S., Braverman, Michael S., Desany, Brian, Rothberg, Jonathan M., Egholm, Michael
• Format: Journal Article
• Language: English
• Published: Oxford The University of Chicago Press 01.03.2009; University of Chicago Press; Oxford University Press
• Subjects: Adult; AIDS; Anti-HIV Agents - therapeutic use; Antiretrovirals; Biological and medical sciences; Chronic Disease; Disease Progression; DNA, Complementary - chemistry; Drug resistance; Drug Resistance, Viral; Female; Fundamental and applied biological sciences. Psychology; Genetic mutation; Genetic Variation; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - genetics; HIV/AIDS; Human immunodeficiency virus; Human viral diseases; Humans; Infectious diseases; Male; Medical sciences; Memory interference; Microbiology; Mutation; Reverse transcriptase inhibitors; RNA; RNA, Viral - genetics; Sequencing; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virology; Infection; Resistance; Immunopathology; Prognosis; Treatment; Microbiology; Viral disease; Antiviral; AIDS; Immune deficiency
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/596736

BackgroundMinor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important ObjectivesTo compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF) MethodsThe Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified ResultsMutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P<.001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, “NNRTI strategy”), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41–45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17–5.36]) ConclusionsUltra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants