title: Should viral load thresholds be lowered?: Revisiting the WHO definition for virologic failure in patients on antiretroviral therapy in resource-limited settings.
abstract: The World Health Organization (WHO) guidelines on antiretroviral therapy (ART) define treatment failure as 2 consecutive viral loads (VLs) ≥1000 copies/mL. There is, however, little evidence supporting 1000 copies as an optimal threshold to define treatment failure. Objective of this study was to assess the correlation of the WHO definition with the presence of drug-resistance mutations in patients who present with 2 consecutive unsuppressed VL in a resource-limited setting.In 10 nurse-led clinics in rural Lesotho children and adults on first-line ART for ≥6 months received a first routine VL. Those with plasma VL ≥80 copies/mL were enrolled in a prospective study, receiving enhanced adherence counseling (EAC) and a follow-up VL after 3 months. After a second unsuppressed VL genotypic resistance testing was performed. Viruses with major mutations against ≥2 drugs of the current regimen were classified as "resistant".A total of 1563 adults and 191 children received a first routine VL. Of the 138 adults and 53 children with unsuppressed VL (≥80 copies/mL), 165 (116 adults; 49 children) had a follow-up VL after EAC; 108 (74 adults; 34 children) remained unsuppressed and resistance testing was successful. Ninety of them fulfilled the WHO definition of treatment failure (both VL ≥1000 copies/mL); for another 18 both VL were unsuppressed but with <1000 copies/mL. The positive predictive value (PPV) for the WHO failure definition was 81.1% (73/90) for the presence of resistant virus. Among the 18 with VL levels between 80 and 1000 copies/mL, thereby classified as "non-failures", 17 (94.4%) harbored resistant viruses. Lowering the VL threshold from 1000 copies/mL to 80 copies/mL at both determinations had no negative influence on the PPV (83.3%; 90/108).The current WHO-definition misclassifies patients who harbor resistant virus at VL below 1000 c/mL as "nonfailing." Lowering the threshold to VL ≥80 copies/mL identifies a significantly higher number of patients with treatment-resistant virus and should be considered.
authors.affiliation: Medical Services and Diagnostic, Clinical Research Unit, Swiss Tropical and Public Health Institute University of Basel Molecular Virology, Department Biomedicine-Petersplatz, University of Basel, Basel, Switzerland SolidarMed, Swiss Organization for Health in Africa, Maseru, Lesotho SolidarMed, Swiss Organization for Health in Africa, Luzern, Switzerland Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Niklaus D
authors.initials: ND
authors.lastname: Labhardt
authors.forename: Joëlle
authors.initials: J
authors.lastname: Bader
authors.forename: Thabo Ishmael
authors.initials: TI
authors.lastname: Lejone
authors.forename: Isaac
authors.initials: I
authors.lastname: Ringera
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hobbins
authors.forename: Christiane
authors.initials: C
authors.lastname: Fritz
authors.forename: Jochen
authors.initials: J
authors.lastname: Ehmer
authors.forename: Bernard
authors.initials: B
authors.lastname: Cerutti
authors.forename: Daniel
authors.initials: D
authors.lastname: Puga
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral; D017408:Guidelines as Topic; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007927:Lesotho; D008875:Middle Aged; D012424:Rural Population; D019562:Viral Load / Q000187:drug effects*; D014944:World Health Organization
chemical_list: D019380:Anti-HIV Agents