Improved Prediction of Salvage Antiretroviral Therapy Outcomes Using Ultrasensitive HIV-1 Drug Resistance Testing

• Published in: Clinical infectious diseases Vol. 59; no. 4; pp. 578 - 588
• Main Authors: Pou, Christian, Noguera-Julian, Marc, Pérez-Álvarez, Susana, García, Federico, Delgado, Rafael, Dalmau, David, Álvarez-Tejado, Miguel, Gonzalez, Dimitri, Sayada, Chalom, Chueca, Natalia, Pulido, Federico, Ibáñez, Laura, Rodríguez, Cristina, Casadellà, Maria, Santos, José R., Ruiz, Lidia, Clotet, Bonaventura, Paredes, Roger
• Format: Journal Article
• Language: English
• Published: Oxford OXFORD UNIVERSITY PRESS 15.08.2014; Oxford University Press
• Subjects: Adult; AIDS; Anti-Retroviral Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral drugs; Antiretroviral Therapy, Highly Active - methods; Antiretrovirals; Antiviral agents; Antivirals; Biological and medical sciences; Cohort Studies; Drug resistance; Drug Resistance, Viral; Female; Genotype & phenotype; Genotyping Techniques - methods; HIV; HIV 1; HIV Infections - diagnosis; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV/AIDS; Human immunodeficiency virus; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Male; Medical sciences; Microbial Sensitivity Tests - methods; Middle Aged; Pharmacology. Drug treatments; Prognosis; Retrospective Studies; RNA; Salvage Therapy - methods; Sequencing; T lymphocytes; Treatment Failure; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virology; Immunopathology; Antiretroviral agent; Treatment resistance; Prognosis; HIV-1 virus; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Chemotherapy; Treatment; Viral disease; Antiviral; Human immunodeficiency virus; Salvage treatment; Predictive factor; HIV-1; genotypic susceptibility score; antiretroviral drug resistance; salvage antiretroviral therapy; deep sequencing
• ISSN: 1058-4838; 1537-6591; 1537-6591
• DOI: 10.1093/cid/ciu287

Background. The clinical relevance of ultrasensitive human immunodeficiency virus type 1 (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 1 ritonavir-boosted protease inhibitor, raltegravir or etravirine. Presalvage ART Sanger and 454 sequencing of plasma HIV-1 were used to generate separate genotypic sensitivity scores (GSS) using the HIV db, ANRS, and REGA algorithms. Virological failure (VF) was defined as 2 consecutive HIV-1 RNA levels ≥200 copies/mL at least 12 weeks after salvage ART initiation, whereas subjects remained on the same ART. The ability of Sanger and 454-GSS to predict VF was assessed by receiver operating characteristic (ROC) curves and survival analyses. Results. The study included 132 evaluable subjects; 28 (21%) developed VF. Using HIVdb, 454 predicted VF better than Sanger sequencing in the ROC curve analysis (area under the curve: 0.69 vs 0.60, Delong test P = .029). Time to VF was shorter for subjects with 454-GSS < 3 vs 454-GSS ≥ 3 (Log-rank P = .003) but not significantly different between Sanger-GSS < 3 and ≥3. Factors independently associated with increased risk of VF in multivariate Cox regression were a 454-GSS < 3 (HR = 4.6, 95 CI, [1.5, 14.0], P = .007), and the number of previous antiretrovirals received (HR = 1.2 per additional drug, 95 CI, [1.1, 1.3], P= .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. This may improve the clinical management of ART-experienced subjects living with HIV-1. Clinical Trials Registration. NCT01346878.