HIV-1 drug resistance profiles in children and adults with viral load of <50 copies/mL receiving combination therapy

Context The continued release of human immunodeficiency virus type 1 (HIV-1 ) into plasma at very low levels during highly active antiretroviral therap y (HAART) can be detected using specialized techniques, but the nature and significance of this low-level viremia, especially as related to acquisitio n 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 hospita l from November 1999 to February 2001 using a novel method for amplificatio n of low levels of viral genomes in plasma. Patients Eighteen HIV-1-infected patients (7 children and 11 adults), enrol led in a longitudinal study of HIV-1 reservoirs, who had suppression of vir al replication while receiving protease inhibitor-containing combination th erapy. Two patients (1 adult and 1 child) with less optimal suppression of viral replication were included to assess virus predominating when plasma H IV-1 RNA levels are low but detectable (<1000 copies/mL). Follow-up analyse s were conducted in 3 patients. Main Outcome Measure Detection of drug resistance mutations in clones ampli fied from low-level plasma virus. Results Viral sequences were amplified from 8 of the 18 patients with simul taneous plasma HIV-1 measurements of less than 50 copies/mL and from 2 pati ents 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 a s 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 duri ng "blips" to 231 and 64 copies/mL, had only resistance mutations consisten t with pre-HAART therapy (although reverse transcriptase inhibitor mutation s 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 plasm a 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 virem ia to less than 50 copies/mL of HIV-1 RNA may result primarily from archiva l, pre-HAART virus, reflecting earlier treatment conditions, and does not a ppear to require development of new, HAART-selected mutations reflecting pa rtial resistance to therapy. Low-level viremia below 50 copies/mL may repre sent less of a concern regarding impending drug failure of current HAART re gimens, However, the archival drug-resistant virus may be relevant regardin g future treatment strategies.