title: Impact of HIV-1 replication on immunological evolution during long-term dual-boosted protease inhibitor therapy.
abstract: To explore CD4-cell and viral evolution in relation to different levels of HIV-1 replication, as observed during protease inhibitor (PI)-based antiretroviral therapy. Adult HIV-1 infected cohort patients, receiving historical salvage therapy with daily doses of saquinavir (2,000 mg), ritonavir (200 mg) and either lopinavir (800 mg) or atazanavir (300 mg) for >36 weeks were retrospectively analysed for highest detectable viral load up to week 96 and assigned to groups according to the viral load level: always <50 copies/ml (1), 50-199 copies/ml (2), 200-499 copies/ml (3) and ≥500 copies/ml (4). A total of 126 patients were evaluated; at baseline, median CD4-cell count was 204/mm(3), HIV-1 RNA was 5.13 Log10-copies/ml and duration of prior HIV-1 infection was 11.7 years. Patients were assigned by 43, 30, 7 and 20 % to groups 1-4. Median observation time was 136 weeks (range: 38-304); at weeks 48/96, the CD4-cell gains for groups 1-4 were +88/+209, +209/+349, +67/+300 and +114.5/+ 128, respectively. After fitting data in a linear fixed effect model, ascending CD4 slopes were continuously increasing for group 1, similarly for 2 and clearly decreasing for 3-4 (p = 0.0006). Of 25 individuals from group 4, patient number with major IAS-USA protease mutations increased from 5 to 10 before and after failing PI therapy, whereas minor mutations remained stable (n = 18). On double-boosted PI therapy, CD4-cell increases through week 96 were similar for patients at always undetectable or with detection of low viral load. Viral detection >200 copies/ml was associated with decreasing CD4-cell slopes and emergence of major mutations, supporting this as benchmark for virological failure definition on PI therapy.
authors.affiliation: Infectious Diseases Unit at Medical Department No. 2, Hospital of the Johann Wolfgang Goethe-University, Frankfurt, Germany. c.stephan@em.uni-frankfurt.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Stephan
authors.forename: Valentin
authors.initials: V
authors.lastname: Bartha
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: Nils
authors.initials: N
authors.lastname: von Hentig
authors.forename: Pavel
authors.initials: P
authors.lastname: Khaykin
authors.forename: Gaby
authors.initials: G
authors.lastname: Knecht
authors.forename: Peter
authors.initials: P
authors.lastname: Gute
authors.forename: Hans-Reinhard
authors.initials: HR
authors.lastname: Brodt
authors.forename: Martin
authors.initials: M
authors.lastname: Stürmer
authors.forename: Annemarie
authors.initials: A
authors.lastname: Berger
authors.forename: Markus
authors.initials: M
authors.lastname: Bickel
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D054298:Human Immunodeficiency Virus Proteins