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


METHODS
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.


METHODS
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.


METHODS
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.
Hermankova
M
M
Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N Wolfe St, 256 Park Bldg, Baltimore, MD 21287, USA. dpers@welch.jhu.edu
Ray
S C
SC
Ruff
C
C
Powell-Davis
M
M
Ingersoll
R
R
D'Aquila
R T
RT
Quinn
T C
TC
Siliciano
J D
JD
Siliciano
R F
RF
Persaud
D
D
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004352:Drug Resistance, Microbial / Q000235:genetics*; D005260:Female; D015684:Gene Products, pol / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load; D014766:Viremia / Q000175:diagnosis / Q000503:physiopathology*
D019380:Anti-HIV Agents; D015684:Gene Products, pol; D012367:RNA, Viral; D054303:HIV Reverse Transcriptase; D016333:HIV Protease