title: Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy.
abstract: Considering that most patients who experience virological failure (VF) on lopinavir-based antiretroviral therapy (ART) fail due to poor adherence rather than resistance, an objective adherence measure could limit costs by rationalising the use of genotype antiretroviral resistance testing (GART) in countries with access to third-line ART. A cross-sectional study was conducted in a resource-limited setting at two large clinics in Kwazulu-Natal, South Africa, in patients experiencing VF (HIV-RNA > 1000 copies/mL) on lopinavir-based ART who had undergone GART. Associations between major protease inhibitor (PI) resistance mutations and random plasma lopinavir concentrations were explored. A total of 134 patients, including 31 children, were included in the analysis. The prevalence of patients with major PI resistance mutations was 20.9% (n = 28). A random lopinavir concentration above the recommended minimum trough of 1 µg/mL [adjusted odds ratio (aOR) = 5.81, 95% confidence interval (CI) 2.04-16.50; P = 0.001] and male sex (aOR = 3.19, 95% CI 1.22-8.33; P = 0.018) were predictive of the presence of at least one major PI resistance mutation. Random lopinavir concentrations of <1 µg/mL had a negative predictive value of 91% for major PI resistance mutations. Random lopinavir concentrations are strongly associated with the presence of major PI resistance mutations. Access to costly GART in patients experiencing VF on second-line ART could be restricted to patients with lopinavir concentrations above the recommended minimum trough of 1 µg/mL or, in areas where GART is unavailable, could be used as a criterion to empirically switch to third-line ART.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: richard.court@uct.ac.za.
authors.forename: Richard
authors.initials: R
authors.lastname: Court
authors.affiliation: Department of Virology, Nelson R. Mandela School of Medicine, University of Kwazulu-Natal, Durban, South Africa.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gordon
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Karen
authors.initials: K
authors.lastname: Cohen
authors.affiliation: Clinical Research Centre, University of Cape Town, Cape Town, South Africa.
authors.forename: Annemie
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Department of Infectious Diseases, Nelson R. Mandela School of Medicine, University of Kwazulu-Natal, Durban, South Africa.
authors.forename: Bernadett
authors.initials: B
authors.lastname: Gosnell
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D003937:Diagnosis, Differential; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D061466:Lopinavir / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D013019:South Africa; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D061466:Lopinavir
keywords: Antiretroviral resistance; HIV; Lopinavir pharmacokinetics; Protease inhibitor; Second-line antiretroviral therapy; Therapeutic drug monitoring