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EMERGENCE OF INTEGRASE RESISTANCE MUTATIONS DURING INITIAL THERAPY WITH TDF/FTC/DTG
Jennifer A. Fulcher1, Yushen Du1, Ren Sun1, Raphael J. Landovitz2
1Univ of California Los Angeles, Los Angeles, CA, USA,2UCLA Cntr for Clinical AIDS Rsr & Educ, Los Angeles, CA, USA
Dolutegravir (DTG) with two NRTIs has emerged as a preferred regimen for initial treatment of HIV-infected individuals due to high efficacy, tolerability, and previously unreported INI drug resistance when used as initial therapy. We present genotypic information during a period of virologic failure in a 46 year old treatment naive man who initiated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus DTG with a high viral load.
Longitudinal patient samples (3 time points) covering an eight day period of increasing viral load were used for deep sequencing analysis of integrase (IN) genotypes. Plasma RNA was isolated and reverse transcribed, then target regions of IN pre-amplified using nested PCR. Paired end sequencing was performed using Illumina HiSeq 2000. Population sequencing was performed by standard clinical genotype assay (Quest Diagnostics) at the start of antiretroviral therapy and time of virologic inflection.
The patient was treated with TDF/FTC plus DTG as initial therapy (HIV RNA 1,970,000 copies/ml and CD4 78 cells/mm3) Population sequencing showed no clinically significant resistance mutations in reverse transcriptase (RT) or protease (PR). Baseline IN genotype was not performed. HIV RNA initially decreased to 2,770 copies/ml after two weeks, but then increased to 15,700 copies/ml and plasma samples were collected serially over an eight day period. Deep sequencing of these samples generated a mean of 2,483,155 reads covering the region IN amino acids 142-165. The initial time point showed no significant IN mutations, however the next two time points showed rapid evolution of mutations as shown in Figure, notably the emergence of Q148K. Population sequencing corresponding to the middle time point showed RT mutations M184V and V118I and confirmed IN mutation G163E.
Rapid emergence of known integrase inhibitor resistance mutations during failure of virologic suppression suggest that INI resistance may have contributed to failure on the initial regimen in this case. To our knowledge, this is the first description of potential DTG-resistance in a treatment naive individual.