17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

EVOLUTION OF REVERSE TRANSCRIPTASE CONNECTION DOMAIN MUTATIONS IN PATIENTS ON ANTIRETROVIRAL THERAPY

Antivir Ther. 2008; 13(Suppl. 3):A47 (abstract no. 42)

V von Wyl¹, P Bürgisser², S Yerly³, J Böni⁴, T Klimkait⁵, R Kouyos¹, B Ledergerber¹, H Günthard¹ and the Swiss HIV Cohort Study (SHCS)
¹Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland ²Division of Immunology, University Hospital Lausanne, Switzerland; ³Central Laboratory of Virology, University Hospital Geneva, Switzerland; ⁴Institute for Medical Microbiology, University of Basel, Switzerland; ⁵National Center for Retroviruses, University of Zurich, Switzerland

BACKGROUND: Many resistance testing assays do not cover genomic regions beyond currently known International AIDS Society USA (IAS-USA) drug resistance mutations. Yet, there is mounting evidence for mutations in the connection domain (CD) or the RNase H domain of the reverse transcriptase to confer resistance against non-nucleoside reverse transcriptase inhibitors (NNRTI) or nucleoside reverse transcriptase inhibitor (NRTI). We aimed to investigate the evolution of the CD mutations 312Q, 335C, 335D, 348I, 360I, 360V, 365I, 369I, 371V, 376S and 399D in the context of IAS-USA mutations.

METHODS: Reverse transcriptase sequences spanning the first 400 codons were retrieved. Dependencies between IAS-USA and CD mutations were investigated with cluster analysis and Bayesian networks (http://bcourse.cs.helsinki.fi).

RESULTS: In total, 1,213 sequences were obtained: 415 (34%) from therapy-naïve and 798 (66%) from therapy-experienced patients. Of the latter, 665 had ever failed virologically on thymidine analogues. Frequencies of the following CD mutations were significantly increased among treatment-experienced compared with treatment-naïve patients: 348I (11% versus 1%), 360V (4% versus 1%), 365I (5% versus 2%), and 371V (26% versus 19%). Conversely, the frequency of 335D was decreased (11% versus 24%). Dendrograms of mutation patterns from treated patients revealed clustering of mutations from thymidine analogue mutation (TAM)1 or TAM2 pathways, respectively. No CD mutations clustered with TAMs, but the occurrence of N348I was tightly associated with M184V: of 79 tests positive for N348I, M184V was not detected in only seven (9%), although it is likely to be present as a minor species based on treatment history. Bayesian network analyses confirmed a shared pathway for M184V and N348I not directly linked to TAMs, but network structures were inconclusive regarding direction of dependency. Interestingly, patients on first-line therapy containing zidovudine and lamivudine with genotypic tests indicating the presence of both M184V and N348I were found to have been exposed to treatment for longer periods (median 1,000 days; interquartile range [IQR] 334–1426.5; n=12) than those with the M184V mutation alone (median 298.5 days; IQR 181–685; n=18; Wilcoxon P=0.034), suggesting that the emergence of N348I is preceded by M184V.

CONCLUSIONS: The CD mutation N348I does not seem to emerge in the absence of M184V, and contrary to earlier reports was not associated with TAMs. Thus, at this point sequencing of the CD does not seem mandatory.

2008-06-10
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