title: Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden.
abstract: BACKGROUND
  People with HIV-1 in low-income and middle-income countries increasingly need second-line regimens with boosted protease inhibitors. However, data are scarce for treatment response in patients with HIV-1 subtype C (HIV-1C), which is predominant in these regions. We aimed to examine factors associated with virological failure in patients in a standardised national health-care setting.
  
  
  METHODS
  We analysed data for participants in InfCare HIV, a prospective national cohort that includes more than 99% of people with HIV in Sweden. We extracted data for the cohort from the InfCare HIV database on Jan 14, 2015. Baseline was initiation of antiretroviral therapy. We used logistic regression to assess factors associated with primary virological failure (failure to suppress HIV-1 within 9 months) in patients with HIV-1B and HIV-1C and calculated odds ratios (OR) for failure. We also used Cox regression models to calculate hazard ratios (HR) for time-to-secondary virological failure (detectable viral load after initial virological suppression). We did homology-based molecular modelling to assess docking.
  
  
  RESULTS
  We included 1077 patients with HIV-1B and 596 with HIV-1C. In multivariate regression analysis, pre-therapy higher viral load (OR 1·82, 95% CI 1·49-2·21; p<0·0001), subtype C infection (1·75, 1·06-2·88; p=0·028), and boosted protease inhibitor-based regimens (1·55, 1·45-2·11; p=0·004) were associated with increased risk of primary virological failure. Individuals with HIV-1C who were given therapy with boosted protease inhibitors had earlier time-to-secondary virological failure than did those with HIV-1B given similar regimens (adjusted HR 1·92, 95% CI 1·30-2·83; p=0·002). Molecular modelling suggested lower affinity for protease inhibitors to HIV-1C protease than to HIV-1B.
  
  
  CONCLUSIONS
  Our findings suggest an increased risk of virological failure in patients with HIV-1C, especially in those on boosted protease inhibitor-based regimens. Future studies should further dissect the biochemical and viral mechanisms of resistance to protease inhibitors in patients with non-B subtypes of HIV-1, including clinical studies to assess the efficacy of boosted protease inhibitor-based regimens in low-income and middle income countries.
  
  
  BACKGROUND
  Karolinska Institutet Research Foundation, Swedish Research Council, Stockholm County Council, Swedish Physicians against AIDS, US National Institutes of Health, University of Missouri.
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; Department of Infectious Diseases, County Council of Gävleborg, Gävle, Sweden.
authors.forename: Amanda
authors.initials: A
authors.lastname: Häggblom
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Svedhem
authors.affiliation: Departments of Molecular Microbiology and Immunology, Christopher Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
authors.forename: Kamalendra
authors.initials: K
authors.lastname: Singh
authors.affiliation: Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sönnerborg
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. Electronic address: ujjwal.neogi@ki.se.
authors.forename: Ujjwal
authors.initials: U
authors.lastname: Neogi
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D011446:Prospective Studies; D019438:Ritonavir / Q000494:pharmacology / Q000627:therapeutic use; D013548:Sweden; D017211:Treatment Failure
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019438:Ritonavir