title: Monitoring of HIV type 1 DNA load and drug resistance in peripheral blood mononuclear cells during suppressive antiretroviral therapy does not predict virologic failure.
abstract: Our objective was to determine whether monitoring HIV-1 DNA concentration or new resistance mutations in peripheral blood mononuclear cells (PBMCs) during effective antiretroviral therapy (ART) predicts virologic failure. A retrospective analysis used blood specimens and clinical data from three nevirapine containing arms of a four-arm, open-label, randomized trial comparing ART regimens in HIV-1-infected children who had failed mono- or dual-nucleoside therapy. Sensitive assays compared cell-associated HIV-1 DNA concentrations and nevirapine (NVP) and lamivudine (3TC) resistance mutations in children with plasma HIV-1 RNA <400 copies(c)/ml who did or did not experience subsequent virologic failure. Forty-six children were analyzed through the last available follow-up specimen, collected at 48 (n=16) or 96 (n=30) weeks of ART. Thirty-five (76%) had sustained viral suppression and 11 (24%) had plasma viral rebound to ≥ 400 c/ml (virologic failure detected at a median of 36 weeks). HIV-1 DNA levels at baseline, 24, 48, and 96 weeks of ART were similar in children who did vs. did not experience virologic failure (p=0.82). HIV-1 DNA levels did not increase prior to viral rebound. NVP resistance mutations were detected in 91% of subjects in the failure group vs. 3% in the suppressed group (p <0.0001). Among nine evaluable children, NVP mutations were first detected prior to virologic failure in two (22%), at viral rebound in five (56%), and after failure in two (22%) children. HIV-1 DNA concentrations did not predict virologic failure in this cohort. New drug resistance mutations were detected in the PBMCs of a minority of virologically suppressed children who subsequently failed ART.
authors.affiliation: Seattle Children's Hospital Research Institute, Seattle, Washington 98101, USA.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Beck
authors.forename: Minyoung
authors.initials: M
authors.lastname: Jang
authors.forename: Jennifer
authors.initials: J
authors.lastname: McKernan-Mullin
authors.forename: Marta
authors.initials: M
authors.lastname: Bull
authors.forename: Thor
authors.initials: T
authors.lastname: Wagner
authors.forename: Sharon
authors.initials: S
authors.lastname: Huang
authors.forename: Lin-Ye
authors.initials: LY
authors.lastname: Song
authors.forename: Sharon
authors.initials: S
authors.lastname: Nachman
authors.forename: Paul
authors.initials: P
authors.lastname: Krogstad
authors.forename: Susan H
authors.initials: SH
authors.lastname: Eshleman
authors.forename: Andrew
authors.initials: A
authors.lastname: Wiznia
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Frenkel
mesh_terms: D000293:Adolescent; D044966:Anti-Retroviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000097:blood* / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000821:virology*; D009154:Mutation; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4819-24
references.pmid: 12684537
references.citation: JAMA. 2008 Aug 6;300(5):555-70
references.pmid: 18677028
references.citation: J Acquir Immune Defic Syndr. 2005 Mar 1;38(3):268-76
references.pmid: 15735443
references.citation: PLoS Pathog. 2007 Aug 31;3(8):e122
references.pmid: 17784786
references.citation: AIDS. 2003 Mar 28;17(5):679-83
references.pmid: 12646790
references.citation: J Infect Dis. 2001 Jun 15;183(12):1732-8
references.pmid: 11372025
references.citation: AIDS Res Hum Retroviruses. 2000 Aug 10;16(12):1113-21
references.pmid: 10954886
references.citation: Nature. 1997 May 8;387(6629):188-91
references.pmid: 9144290
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10948-53
references.pmid: 11005867
references.citation: Math Biosci. 2009 Jan;217(1):77-87
references.pmid: 18977369
references.citation: J Virol. 2009 Oct;83(19):9731-42
references.pmid: 19605490
references.citation: N Engl J Med. 1997 Sep 11;337(11):725-33
references.pmid: 9287227
references.citation: Trends Mol Med. 2004 Nov;10(11):525-31
references.pmid: 15519278
references.citation: J Infect Dis. 2003 Jan 1;187(1):38-46
references.pmid: 12508144
references.citation: J Clin Microbiol. 1998 Feb;36(2):569-72
references.pmid: 9466779
references.citation: J Virol. 2005 Aug;79(15):9625-34
references.pmid: 16014925
references.citation: AIDS. 2002 Sep 27;16(14):1961-3
references.pmid: 12351958
references.citation: JAMA. 2001 Jul 11;286(2):171-9
references.pmid: 11448280
references.citation: J Infect Dis. 2003 Jan 1;187(1):144-8
references.pmid: 12508159
references.citation: J Virol. 2006 Jul;80(13):6441-57
references.pmid: 16775332
references.citation: J Infect Dis. 2004 Apr 15;189(8):1452-65
references.pmid: 15073683
references.citation: J Virol. 2005 Apr;79(8):5203-10
references.pmid: 15795303
references.citation: J Infect Dis. 2002 May 15;185(10):1409-16
references.pmid: 11992275
references.citation: J Infect Dis. 2004 Dec 1;190(11):1979-88
references.pmid: 15529263
references.citation: AIDS. 2002 Sep 27;16(14):1967-9
references.pmid: 12351960
references.citation: J Acquir Immune Defic Syndr. 2008 Aug 1;48(4):418-27
references.pmid: 18614915
references.citation: N Engl J Med. 1997 Sep 11;337(11):734-9
references.pmid: 9287228
references.citation: AIDS. 2001 Apr 13;15(6):665-73
references.pmid: 11371680
references.citation: Nat Med. 2009 Aug;15(8):893-900
references.pmid: 19543283
references.citation: J Virol. 2003 May;77(10):5721-30
references.pmid: 12719565
references.citation: Nat Med. 2003 Jun;9(6):727-8
references.pmid: 12754504
references.citation: J Infect Dis. 2006 Jun 15;193(12):1718-27
references.pmid: 16703516
references.citation: J Clin Microbiol. 2007 Apr;45(4):1288-97
references.pmid: 17314225
references.citation: J Acquir Immune Defic Syndr. 2009 Jul 1;51(3):283-9
references.pmid: 19398922
references.citation: N Engl J Med. 1999 Dec 16;341(25):1874-81
references.pmid: 10601506
references.citation: Ann Intern Med. 1998 Apr 15;128(8):613-20
references.pmid: 9537934
references.citation: N Engl J Med. 1999 May 27;340(21):1605-13
references.pmid: 10341272
references.citation: JAMA. 2001 Jul 11;286(2):196-207
references.pmid: 11448283
references.citation: Clin Infect Dis. 2002 Apr 1;34(7):991-1001
references.pmid: 11880966
references.citation: Nat Med. 1999 May;5(5):512-7
references.pmid: 10229227
references.citation: Virology. 1997 Sep 15;236(1):104-9
references.pmid: 9299622