Human immunodeficiency virus 1 Targeted Locus (Loci)

Background. The clinical relevance of ultrasensitive HIV-1 genotypic resistance testing in antiretroviral treatment (ART)-experienced individuals remains unknown. Methods. This was a retrospective, multicentre, cohort study in ART-experienced, HIV-1-infected adults who initiated salvage ART including, at least, one ritonavir-boosted protease inhibitor, raltegravir or etravirine. Pre-salvage ART Sanger and 454 sequencing of plasma HIV-1 were used to generate separate genotypic sensitivity scores (GSS) using the HIVdb (v6.3.1), ANRS (v2012.09), and REGA (v9.1.0) algorithms. Virological failure was defined as 2 consecutive HIV-1 RNA levels = 200 copies/mL at least 12 weeks after non-interrupted salvage ART initiation. The ability of Sanger and 454-GSS to predict virological failure was assessed by Receiver Operating Characteristic (ROC) curves and survival analyses including multivariate Cox regression testing. (Clinicaltrials#: NCT01346878) Results. The study included 132 evaluable subjects; 28 (21%) developed virological failure. Using HIVdb, 454 sequencing predicted virological failure better than Sanger sequencing in the ROC curve analysis (area under the curve: 0.69 vs. 0.60, Delong's test p=0.029). Time to virological failure was shorter for subjects with 454-GSS<3 vs. 454-GSS=3 (Log-rank p=0.003), but not significantly different between Sanger-GSS<3 and =3. Factors independently associated with increased risk of virological failure in the multivariate Cox regression were a 454-GSS<3 (HR=4.4, 95 CI [1.4,14.0], p=0.013), baseline HIV-1 RNA levels =100,000 copies/mL (HR=2.7, 95 CI [0.9, 7.5], p=0.064), and the number of previous antiretrovirals received (HR=1.2 per additional drug, 95CI [1.0, 1.4], p<0.001). Equivalent findings were obtained with the ANRS and REGA algorithms. Conclusions. Ultrasensitive HIV-1 genotyping improves GSS-based predictions of virological outcomes of salvage ART relative to Sanger sequencing of plasma viruses. This may improve the clinical management of ART-experienced subjects living with HIV-1.