Emergent drug resistance with integrase strand transfer inhibitor-based regimens

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Objectives:To estimate the incidence of and risk factors for emergent resistance to integrase strand transfer inhibitor (INSTI) and nucleoside(-tide) reverse transcriptase inhibitors (NRTI) in HIV-1-infected adults receiving an INSTI and two NRTIs.Design:Retrospective cohort study.Methods:Persons aged at least 19 years were included if they received their first prescription for raltegravir, elvitegravir or dolutegravir in British Columbia, Canada in 2012–2014 and were followed to 31 December 2015. Emergent resistance was defined as new mutations conferring intermediate-high level NRTI or INSTI resistance (score ≥30, Stanford HIV Drug Resistance Algorithm v.7.0.1). First-year resistance rates and 95% confidence intervals (95% CI) were estimated for ‘any’ (INSTI or NRTI) resistance using Poisson regression. The relationship between any emergent resistance and explanatory variables was modeled by Cox proportional hazards.Results:There were 270 raltegravir, 323 elvitegravir and 392 dolutegravir-treated persons who were predominantly male (77%), antiretroviral therapy (ART)-experienced (81%), with low prevalence of preexisting drug resistance (16%). INSTI and NRTI resistance emerged in both ART-experienced and ART-naive persons (including dolutegravir-treated ART-naive), with no statistically significant differences in ‘any’ resistance rates (95% CI) between INSTIs: raltegravir 3.80 (1.90, 7.60), elvitegravir 2.37 (1.06, 5.27) and dolutegravir 1.48 (0.62, 3.55)/100 person-years. The strongest factors associated with emergent resistance were CD4+ less than 200 cells/μl, adjusted hazard ratio (95% CI) 10.46 (4.67, 23.41) and less than 80% adherence to the INSTI regimen hazard ratio 2.52 (1.11, 5.71).Conclusion:Incident drug resistance rates were low with ‘real-world’ use of INSTI-based regimens. However, incomplete ART adherence and low CD4+ cell count were associated with increased resistance rates regardless of which INSTI was prescribed. Provide adherence support and monitor for drug resistance.

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