title: Interpretation of genotypic HIV-1 resistance to darunavir and virological response: validation of available systems and of a new score.
abstract: BACKGROUND
  There is not yet consensus on interpretation of genotypic HIV-1 resistance to darunavir (DRV). We validated existing rules and a newly derived score.
  
  
  METHODS
  Protease inhibitor (PI)-failing patients starting a DRV/ritonavir-based regimen, with available baseline resistance genotypes, were extracted from three Italian databases. Virological response (VR) was analysed between 4 and 32 follow-up weeks, defined as a drop from baseline HIV RNA of ≥2 log(10) or a value <50 copies/ml if the last measurement had been obtained at ≤12 weeks and as HIV RNA<50 copies/ml if it had been obtained at >12 weeks of follow-up. DRV/ritonavir resistance was interpreted by seven algorithms. A new weighted score (DRV-2009) was derived and validated, analysing associations of protease mutations with VR.
  
  
  RESULTS
  A total of 217 patients were analysed, with a mean (±sd) follow-up time of 17 (±9) weeks. At baseline, median HIV RNA was 4.26 log(10) copies/ml (IQR 3.11-5.03); VR was achieved in 135/217 (62%) patients. Adjusting for use of a new drug class, number of previous PIs experienced, CD4(+) T-cell count and HIV RNA, only the Rega DRV/ritonavir interpretation was significantly associated with VR (per increase in susceptibility category, OR 1.94, 95% CI 1.32-2.86; P<0.001). The DRV-2009 score V11I+L33F+R41K+I47V+2*I50V+2*I54M+K55R+D60E+L74P+L76V+N88D+2*L89V-L10I/V-I13V-G16E-G48V-F53I/L-I62V-I66F-V77I (<0 indicating susceptibility, 0-1 intermediate resistance and ≥2 resistance) correlated with VR in the derivation set (n=132, R=0.395; P<0.001). In the validation set (n=85), after adjusting for mutual interpretation and new use of enfuvirtide, DRV-2009 (P=0.017) and Rega (P=0.013) were both independently associated with VR.
  
  
  CONCLUSIONS
  In contrast to the other algorithms, both the DRV-2009 score and Rega interpretation showed a robust predictive capacity of VR to DRV/ritonavir-containing regimens.
authors.affiliation: Institute of Clinical Infectious Diseases, Catholic University, Rome, Italy. andrea.deluca@rm.unicatt.it
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
authors.forename: Simona
authors.initials: S
authors.lastname: Di Giambenedetto
authors.forename: Renato
authors.initials: R
authors.lastname: Maserati
authors.forename: Nicola
authors.initials: N
authors.lastname: Gianotti
authors.forename: Pasquale
authors.initials: P
authors.lastname: Narciso
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.forename: Mattia C F
authors.initials: MC
authors.lastname: Prosperi
authors.forename: Fausto
authors.initials: F
authors.lastname: Baldanti
authors.forename: Valeria
authors.initials: V
authors.lastname: Micheli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zazzi
authors.forename: Carlo F
authors.initials: CF
authors.lastname: Perno
authors.forename: Maria M
authors.initials: MM
authors.lastname: Santoro
mesh_terms: D000465:Algorithms; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D011237:Predictive Value of Tests; D019438:Ritonavir / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir