Sensitive testing of plasma HIV-1 RNA and Sanger sequencing of cellular HIV-1 DNA for the detection of drug resistance prior to starting first-line antiretroviral therapy with etravirine or efavirenz

• Published in: Journal of antimicrobial chemotherapy Vol. 69; no. 4; pp. 1090 - 1097
• Main Authors: Geretti, Anna Maria, Conibear, Tim, Hill, Andrew, Johnson, Jeffrey A., Tambuyzer, Lotke, Thys, Kim, Vingerhoets, Johan, Van Delft, Yvon
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2014; Oxford Publishing Limited (England)
• Subjects: Adolescent; Adult; Aged; Anti-HIV Agents - therapeutic use; Antiretroviral drugs; Benzoxazines - therapeutic use; DNA, Viral - genetics; DNA, Viral - isolation & purification; Drug Resistance; Drug therapy; Europe; Female; Genotyping Techniques - methods; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - genetics; HIV-1 - isolation & purification; Human immunodeficiency virus 1; Humans; Israel; Male; Microbial Sensitivity Tests - methods; Middle Aged; Mutation; Polymorphism; Protease inhibitors; Pyridazines - therapeutic use; RNA, Viral - genetics; RNA, Viral - isolation & purification; Russia; Treatment Outcome; Young Adult; Europe; Israel; Russia; HIV; ART; genotyping
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkt474

Objectives This study investigated strategies that may increase the yield of drug resistance testing prior to starting antiretroviral therapy (ART), and whether transmitted and polymorphic resistance-associated mutations (RAMs) correlated with virological outcomes. Methods We carried out retrospective testing of baseline samples from patients entering the SENSE trial of first-line ART in Europe, Russia and Israel. Prior to randomization to etravirine or efavirenz plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), plasma samples underwent routine Sanger sequencing of HIV-1 RT and protease (plasmaSS) in order to exclude patients with transmitted RAMs. Retrospectively, Sanger sequencing was repeated with HIV-1 DNA from baseline peripheral blood mononuclear cells (PBMCSS); baseline plasma samples were retested by allele-specific PCR targeting seven RT RAMs (AS-PCR) and ultra-deep RT sequencing (UDS). Results By plasmaSS, 16/193 (8.3%) patients showed ≥1 transmitted RAM affecting the NRTIs (10/193, 5.2%), non-nucleoside reverse transcriptase inhibitors (4/193, 2.1%) or protease inhibitors (2/193, 1.0%). No additional RAMs were detected by AS-PCR (n = 152) and UDS (n = 24); PBMCSS (n = 91) yielded two additional samples with one RAM each. Over 48 weeks, 4/79 (5.1%) patients on etravirine and 7/78 (9.0%) on efavirenz experienced virological failure; none had baseline RAMs. Conversely, 11/79 (13.9%) patients randomized to etravirine had one polymorphic RAM from the etravirine score in baseline plasma (V90I, V106I or E138A), without any impact on virological outcomes. Conclusions The detection of resistance increased marginally with PBMC testing but did not increase with sensitive plasma testing. A careful consideration is required of the cost-effectiveness of different strategies for baseline HIV drug resistance testing.