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. 2019 Feb 12;6(3):ofz060.
doi: 10.1093/ofid/ofz060. eCollection 2019 Mar.

Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis

Kimia Kamelian  1   2 , Katherine J Lepik  1   3 , William Chau  1 , Benita Yip  1 , Wendy W Zhang  1   2 , Viviane Dias Lima  1   2 , Marjorie A Robbins  1 , Conan Woods  1 , Andrea Olmstead  1   2 , Jeffrey B Joy  1   2 , Rolando Barrios  1   4 , P Richard Harrigan  2
Affiliations

Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis

Kimia Kamelian et al. Open Forum Infect Dis. .

Abstract

Background: Integrase strand transfer inhibitors (INSTIs) are highly efficacious and well tolerated antiretrovirals with fewer adverse side-effects relative to other classes of antiretrovirals. The use of INSTIs raltegravir, elvitegravir, and dolutegravir has increased dramatically over recent years. However, there is limited information about the evolution and prevalence of INSTI resistance mutations in clinical human immunodeficiency virus populations.

Methods: Human immunodeficiency virus-1-positive individuals ≥19 years were included if they received ≥1 dispensed prescription of antiretroviral therapy (ART) in British Columbia between 2009 and 2016 (N = 9358). Physician-ordered drug resistance tests were analyzed and protease inhibitor (PI), reverse-transcriptase inhibitor (RT), and INSTI resistance were defined as having ≥1 sample with a combined, cumulative score ≥30 by Stanford HIV Drug Resistance Algorithm version 7.0.1.

Results: Although most ART-treated individuals were tested for PI and RT resistance, INSTI resistance testing lagged behind the uptake of INSTIs among INSTI-treated individuals (11% in 2009; 34% in 2016). The prevalence of INSTI resistance was relatively low, but it increased from 1 to 7 per 1000 ART-treated individuals between 2009 and 2016 (P < .0001, R2 = 0.98). Integrase strand transfer inhibitor resistance mutations increased at integrase codons 66, 97, 140, 148, 155, and 263.

Conclusions: The prevalence of INSTI resistance remains low compared with PI and RT resistance in ART-treated populations but is expanding with increased INSTI use.

Keywords: HIV integrase strand transfer inhibitor; dolutegravir; drug resistance; elvitegravir; raltegravir.

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Figures

Figure 1.
Figure 1.
Antiretroviral therapy (ART) and drug resistance testing. All active ART-treated individuals tested and not tested for protease inhibitor and reverse-transcriptase inhibitor (PI-RT) resistance and active integrase strand transfer inhibitor (INSTI)-treated individuals tested and not tested for INSTI resistance as of December 31st of each year from 2009 to 2016 are indicated. Individuals contributed to the count of PI-RT or INSTI tested in the first year that a PI-RT or INSTI resistance test was performed, and this tested status was automatically carried forward to each subsequent year the individual was treated with ART in the Drug Treatment Program. ART-treated ever PI-RT tested, ART-treated individuals ever tested for PI-RT resistance; ART-treated never PI-RT tested, ART-treated individuals never tested for PI-RT resistance; ART-treated ever INSTI tested, ART-treated individuals ever tested for INSTI resistance; ART-treated never INSTI tested, ART-treated individuals never tested for INSTI resistance.
Figure 2.
Figure 2.
Prevalence of protease inhibitor and reverse-transcriptase inhibitor (PI-RT) and integrase strand transfer inhibitor (INSTI) drug resistance. The annual prevalence of PI-RT and INSTI drug resistance per 1000 antiretroviral therapy (ART)-treated individuals between 2009 and 2016 within the Drug Treatment Program is shown. The trend shows a decrease in the prevalence of PI-RT resistance from 337 per 1000 ART-treated individuals in 2009 to 285 per 1000 ART-treated individuals in 2016 (P < .0001, R2 = 0.98); the trend shows an increase in the prevalence of INSTI resistance from 1 per 1000 ART-treated individuals in 2009 to 7 per 1000 ART-treated individuals in 2016 (P < .0001, R2 = 0.98).
Figure 3.
Figure 3.
Prevalence of mutations conferring integrase strand transfer inhibitor (INSTI) resistance within newly identified INSTI-resistant individuals. The prevalence of INSTI resistance mutations in INSTI-resistant individuals within the Drug Treatment Program (DTP) between 2009 and 2016 is shown. An individual’s INSTI mutation contributed to the mutation count in the first year it was detected and automatically carried forward to all subsequent years the individual received antiretroviral therapy in the DTP. A person with mutations in 3 separate codons (eg, 92, 95, and 97) in a year will contribute 3 counts for that year, whereas a person with mutations in multiple positions within a codon only contributes a count of 1 for that codon (eg, mutations in positons 155H and 155S will only be counted once under 155H/S/T). The “Other Mutations” category represents the sum of mutation counts from 118R, 121Y, 145S, 146P, 147G, 151A/L, 153F/Y, 230R, 51Y, and 95K. NOTE: Certain specific positions associated with INSTI resistance increased in prevalence over the time period.
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