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Monika Hermankova, BA; Stuart C. Ray, MD; Christian Ruff, BA; Monique Powell-Davis, BS; Roxann Ingersoll, BS; Richard T. D'Aquila, MD; Thomas C. Quinn, MD; Janet D. Siliciano, PhD; Robert F. Siliciano, MD,PhD; Deborah Persaud, MD

JAMA. 2001;286:196-207.

Context  The continued release of human immunodeficiency virus type 1 (HIV-1) into plasma at very low levels during highly active antiretroviral therapy (HAART) can be detected using specialized techniques, but the nature and significance of this low-level viremia, especially as related to acquisition of drug resistance mutations, are unclear.

Objective  To determine genetic resistance profiles of low-level plasma HIV-1 in patients with prolonged viral suppression (<50 copies/mL of plasma HIV-1 RNA) while receiving HAART.

Design and Setting  Cross-sectional study conducted at a US academic hospital from November 1999 to February 2001 using a novel method for amplification of low levels of viral genomes in plasma.

Patients  Eighteen HIV-1–infected patients (7 children and 11 adults), enrolled in a longitudinal study of HIV-1 reservoirs, who had suppression of viral replication while receiving protease inhibitor–containing combination therapy. Two patients (1 adult and 1 child) with less optimal suppression of viral replication were included to assess virus predominating when plasma HIV-1 RNA levels are low but detectable (<1000 copies/mL). Follow-up analyses were conducted in 3 patients.

Main Outcome Measure  Detection of drug resistance mutations in clones amplified from low-level plasma virus.

Results  Viral sequences were amplified from 8 of the 18 patients with simultaneous plasma HIV-1 measurements of less than 50 copies/mL and from 2 patients with 231 and 50 copies/mL. Clones from 3 treatment-naive patients with less than 50 copies/mL of plasma HIV-1 RNA showed continued release, for as long as 42 months, of wild-type drug-sensitive virus. The 7 patients with prior nonsuppressive therapy, with viral loads below 50 copies/mL and during "blips" to 231 and 64 copies/mL, had only resistance mutations consistent with pre-HAART therapy (although reverse transcriptase inhibitor mutations may have continued to occur). New HAART-related mutations were seen in a control patient with prior viral load levels of about 400 to 1000 copies/mL. For phylogenetic analysis, sequences were available for both resting CD4⁺ T cells and plasma HIV for 7 of 10 patients and showed patient-specific clustering of sequences and a close relationship between virus in the plasma and the latent reservoir.

Conclusions  Based on the samples that could be amplified, low-level viremia in children and adults receiving HAART with prolonged suppression of viremia to less than 50 copies/mL of HIV-1 RNA may result primarily from archival, pre-HAART virus, reflecting earlier treatment conditions, and does not appear to require development of new, HAART-selected mutations reflecting partial resistance to therapy. Low-level viremia below 50 copies/mL may represent less of a concern regarding impending drug failure of current HAART regimens. However, the archival drug-resistant virus may be relevant regarding future treatment strategies.

Author Affiliations: Departments of Medicine (Mss Hermankova and Powell-Davis, Mr Ruff, and Drs Ray, Quinn, J. Siliciano, and R. Siliciano) and Pediatrics (Dr Persaud), and the Institute of Genetics (Ms Ingersoll), Johns Hopkins University School of Medicine, Baltimore Md; Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston (Dr D'Aquila); National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md (Dr Quinn).

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