Antiretroviral therapy (ART) regimens comprising an integrase strand transfer inhibitor (INSTI) and two nucleoside(-tide) reverse transcriptase inhibitors (NRTI) have demonstrated safety and efficacy in clinical trials and are currently first-line or alternative first-line therapy options in many healthcare settings [1–4]. Clinical trials of raltegravir, elvitegravir and dolutegravir-based regimens in treatment-naive and treatment-experienced patients have shown low rates of emergent drug resistance [5–13]. Patient outcomes in a ‘real-world’ clinical setting may differ from clinical trial results because of greater diversity in the patient population and clinical practices . To date, there is limited information regarding the emergence of drug resistance during treatment with INSTI-based regimens in standard clinical practice, particularly for the newer agents in this class, elvitegravir and dolutegravir. This study was motivated by a safety signal that identified a cluster of cases with treatment-emergent drug resistance associated with INSTI-based ART following a rapid upswing in INSTI prescribing in British Columbia (BC), Canada between 2012 and 2014 .
The objectives of this retrospective cohort study were to estimate the incidence of emergent integrase and reverse transcriptase drug resistance mutations in adults treated with INSTI-based regimens prescribed during standard clinical practice and to identify potential risk factors associated with emergent drug resistance.
Study design and setting
The study cohort was drawn from HIV-1-infected persons in the province of British Columbia, Canada who received antiretroviral medications, plasma viral load (pVL) monitoring and drug resistance testing through centralized, publicly funded programs administered by the BC Centre for Excellence in HIV/AIDS (BC-CfE). Details of these programs have been described elsewhere [16,17]. Persons treated with one INSTI and two NRTIs were included if they were at least 19 years of age at the time of their first prescription for raltegravir, elvitegravir or dolutegravir, had an INSTI start date between 01 January 2012 and 31 December 2014 and had at least one genotypic test for protease/reverse transcriptase (Pr-RT) resistance before INSTI start. Consistent with monitoring guidelines at the time, integrase resistance testing was not routinely conducted in the absence of INSTI exposure and was therefore not required for inclusion [1,4]. Persons were excluded if they initiated the INSTI outside British Columbia or during a clinical trial, if follow-up duration was 30 days or less, or if pVL was not measured between INSTI start and end of follow-up. Persons could contribute data for more than one INSTI.
ART prescribing, laboratory monitoring and requests for drug resistance testing were managed by each person's healthcare provider. Baseline clinical and demographic variables, ART dispensing and laboratory data were abstracted from BC-CfE databases. Ethical approval was obtained from the University of BC, Providence Healthcare Research Ethics Board.
Follow-up and censoring
Two end-of-follow-up dates were used to align with study objectives. For calculation of first-year drug resistance rates and virologic outcomes, the end date was 12 months after INSTI start, to provide equal follow-up opportunity for all INSTIs. For the analysis of risk factors associated with emergent resistance, follow-up continued to the end of available data, 31 December 2015, to maximize observed drug resistance events. For both analyses, follow-up was censored on the date of the last pVL measured prior to removal of the INSTI from the regimen, patient relocation outside of British Columbia, death or end-of-follow-up date, whichever was earliest.
The current study included both ART-experienced and ART-naive persons; therefore, virologic outcomes during the first year of INSTI therapy considered both achieving and maintaining virologic suppression. Persons were classified as either ‘suppressed’, achieving pVL less than 50 copies/ml within 6 months and/or maintaining pVL less than 50 copies/ml following virologic suppression (ignoring isolated blips <200 copies/ml), or ‘not suppressed’, failing to achieve pVL less than 50 copies/ml within 6 months or having pVL rebound more than 200 copies/ml or at least two consecutive pVL 50–200 copies/ml. Persons who were ‘not suppressed’ were further categorized as having or not having emergent drug resistance.
Baseline resistance was defined as cumulative mutations in pre-INSTI pVL samples resulting in intermediate or high-level resistance (total score ≥30, Stanford HIV Drug Resistance Algorithm v.7.0.1; Stanford University, Stanford, California, USA) [18,19] to at least one drug in the INSTI, NRTI, nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor drug classes. Persons with ‘susceptible’ virus had a pre-INSTI score less than 30 for all drug classes. Persons without prior integrase resistance testing were presumed to have INSTI-susceptible virus, based on the low prevalence of integrase resistance in British Columbia . Emergent drug resistance was defined as a combination of new mutations in a post-INSTI sample with Stanford score of at least 30 for at least one INSTI or NRTI drug. For persons with preexisting drug resistance (i.e. baseline score at least 30), emergent resistance constituted new mutations resulting in a score increase of more than 10.
For each INSTI, crude incidence rates of emergent integrase, reverse transcriptase and ‘any’ (integrase or reverse transcriptase) resistance during the first year of follow-up were calculated as the number of persons with emergent resistance divided by the cumulative person-years INSTI exposure, expressed as resistance rate per 100 person-years. Poisson regression was used to calculate 95% confidence intervals (95% CI) and P values.
Persons were categorized by INSTI drug. Those contributing data for more than one INSTI had baseline variables updated prior to each INSTI exposure. Raltegravir was available throughout the study period. Elvitegravir became available in 2013, coformulated with cobicistat, tenofovir disoproxil fumarate and emtricitabine. Dolutegravir became available as a single ingredient tablet in 2014 and coformulated with abacavir and lamivudine in 2015. The NRTIs dispensed with the initial INSTI prescription were categorized as either abacavir–lamivudine or tenofovir disoproxil fumarate-lamivudine/emtricitabine.
Baseline pVL and CD4+ values were measured within 6 months prior to INSTI start. Missing values were imputed from prior and subsequent measurements (methods described in Supplemental Table S1, http://links.lww.com/QAD/B84). First-year INSTI regimen adherence was estimated from dispensing records, calculated as days-supply of ART divided by follow-up days, expressed as a percentage . For ART-experienced persons, prior adherence was also calculated during the 12 months preceding INSTI start.
HIV pVL measurements were performed by the Virology Laboratory at St Paul's Hospital (Vancouver, British Columbia, Canada) using the COBAS TaqMan assay (Roche Diagnostics, Indianapolis, Indiana, USA). The BC-CfE Research Laboratory (Vancouver, British Columbia, Canada) performed Pr-RT and integrase genotypic drug resistance tests on physician-requested samples. Detailed methods have been published elsewhere [22,23]. In brief, from 2012 onwards, HIV RNA was extracted from plasma by automated methodologies, amplified by nested PCR, sequenced by ABI 3730 DNA analyzer (Life Technologies, Burlington, Ontario, Canada), with subsequent sequence analysis by RECall .
The genotypic sensitivity score (GSS) was calculated for each INSTI-based regimen as a means of quantifying the number of active drugs [18,22]. Each antiretroviral was assigned a GSS value based on cumulative, preexisting drug resistance mutations. Drugs with a Stanford drug resistance score less than 30 received a GSS value of 1.0, intermediate resistance (score 30–59) GSS value 0.5 and high-level resistance (score ≥60) GSS value 0. Regimen GSS was the sum of individual drug scores [18,22].
Other clinical and demographic variables at the time of INSTI start included age, biological sex, hepatitis C antibody status (positive or negative/unknown), ART history and HIV subtype (B or non-B).
Clinical and demographic variables were summarized by descriptive statistics and tested for statistically significant associations with emergent resistance in bivariate analyses using Pearson's chi-squared or Fisher's exact tests for categorical and Wicoxon rank sum for continuous variables. Kaplan–Meier plots were used to estimate the probability of developing emergent drug resistance over time, stratified by each categorical, explanatory variable, with differences between category levels identified by log-rank test.
The relationship between any emergent resistance and explanatory variables was modeled by Cox proportional hazards, with the hazard ratio being the measure of this association. To account for the inclusion of persons who contributed data for more than one INSTI, the model used the robust sandwich covariance matrix estimate for clustered data structure . Candidate variables showing a significant association with drug resistance were tested in the multivariable model. A stepwise, backward selection method was used to select covariates based on maximum likelihood P values (statistical significance of the covariate) and Akaike Information Criterion (goodness-of-fit statistic) . Compliance with the proportional hazards assumption was checked by visual inspection of Kaplan–Meier curves and by the weighted residuals score test . Statistical analyses were performed using SAS v9.4 (Cary, North Carolina, USA) and R v.3.2.2 (Vienna, Austria).
Between 1 January 2012 and 31 December 2014, 1379 persons initiated raltegravir, elvitegravir or dolutegravir through the BC-CfE Drug Treatment Program. After excluding persons who had a background regimen other than two NRTIs (n = 332), lacked baseline drug resistance testing (n = 68) or who had no baseline pVL or less than 30 days follow-up (n = 51), the final cohort included 928 unique individuals, 57 (6.1%) of whom contributed data for two INSTIs. There were a total of 985 distinct INSTI-person records: 270 raltegravir, 323 elvitegravir and 392 dolutegravir-treated persons.
Baseline clinical and demographic characteristics are summarized in Table 1. Additional variables for the treatment-experienced subset are shown in Supplemental Table S2, http://links.lww.com/QAD/B84. The three INSTI treatment groups were similar at baseline, being predominantly HIV subtype B, male, ART-experienced but INSTI-naive, with a low prevalence of preexisting drug resistance. The proportion of persons with prior INSTI exposure increased according to the chronological availability of these drugs: raltegravir 1.9%, elvitegravir 8.7% and dolutegravir 20.9%, with a corresponding increase in the proportion with prior integrase resistance testing (12.2, 21.4 and 25.8%, respectively).
Among ART-experienced persons, approximately half had switched from a boosted protease inhibitor to the INSTI-based regimen, with an antiretroviral adverse drug reaction being the most common reason for regimen change (Supplemental Table S2, http://links.lww.com/QAD/B84). Nearly half of the treatment-experienced persons in the elvitegravir group had less than 80% adherence to their previous ART regimen, whereas only 20% of ART-experienced persons in the raltegravir and dolutegravir groups had prior ART adherence less than 80%.
The selection of NRTI backbone was influenced by antiretroviral coformulated products. Elvitegravir–cobicistat was available exclusively in combination with tenofovir disoproxil fumarate-emtricitabine, and a high proportion of dolutegravir-treated persons received abacavir–lamivudine in anticipation of a single tablet formulation. Regardless of regimen composition, 95% of persons in all treatment groups received a regimen comprising three fully active drugs (GSS = 3.0).
Follow-up and monitoring
Median (25–75th percentile, Q1–Q3) follow-up time to 31 December 2015 was 1.6 (1.0–2.5) years for raltegravir, 1.3 (0.9–1.8) years for elvitegravir and 1.2 (1.0–1.4) years for dolutegravir. Within the first year of treatment, all treatment groups had similar follow-up and monitoring (Table 2), with the majority of persons completing 12 months observation with a median of four pVL measurements.
Virologic outcomes, first year
A higher proportion of dolutegravir-treated persons achieved and/or maintained study-defined virologic suppression during the first year (83% dolutegravir, 74% raltegravir and 77% elvitegravir, Table 2). In all INSTI groups, the most common reasons for a classification of ‘not suppressed’ were not achieving pVL less than 50 copies/ml within 6 months, or having pVL rebound more than 200 copies/ml following initial suppression, with less than 10% experiencing consecutive pVL blips less than 200 copies/ml. Of those classified as ‘not suppressed without resistance’, 60% of persons with a pVL more than 200 copies/ml had both integrase and Pr-RT drug resistance testing to confirm the absence of new mutations.
First-year rates of emergent integrase resistance mutations were similar for all INSTIs at approximately one case per 100 person-years exposure (Table 2). Overall drug resistance rates were numerically lowest for dolutegravir-treated (1.48/100 person-years) and highest for raltegravir-treated (3.80/100 person-years), due to more emergent reverse transcriptase mutations in the raltegravir group. However, there were no statistically significant differences between INSTIs in either the proportions or rates of emergent resistance mutations during the first year.
Drug resistance mutations
During the entire follow-up period, 27 persons developed emergent reverse transcriptase and/or integrase drug resistance mutations: 14 of 270 (5.2%) raltegravir, eight of 323 (2.5%) elvitegravir and five of 392 (1.3%) dolutegravir. Deidentified cases and mutations are summarized in Table 3. Of the 14 persons with newly detected INSTI resistance, ten of 14 (71%) had documented absence of preexisting integrase mutations, and the remainder were INSTI-naive.
Among raltegravir-treated persons, the most commonly selected integrase mutations were N155H and Q148H/R in conjunction with G140A/S. In the elvitegravir group, two people developed T66A/I, with other integrase mutations including S147G, E92Q and P145S. Three dolutegravir-treated persons acquired new integrase mutations. One ART-naive person (Table 3, case 23) initially achieved pVL less than 50 copies/ml but subsequently developed emergent T66I associated with virologic rebound of 65 000 copies/ml. Two ART-experienced persons developed R263K mutations in conjunction with emergent M184I. Case 24 had virologic rebound following a period of pVL suppression, and Case 25 had a slowly declining pVL following treatment restart, with emergent resistance after 7 months.
The most common emergent reverse transcriptase mutation was M184V/I, which was observed in all three INSTI treatment groups in both ART-naive and ART-experienced persons. Newly detected K65R and K70R were also observed with raltegravir-based regimens.
Characteristics associated with emergent drug resistance
In bivariate analyses (Supplemental Table S3(a), http://links.lww.com/QAD/B84), persons who developed drug resistance were significantly more likely to be female, have a pre-INSTI pVL more than 100 000 copies/ml or CD4+ cell count less than 200 cells/μl or have less than 80% adherence to the INSTI regimen compared with persons without emergent resistance. No statistically significant associations were observed between emergent drug resistance and age, hepatitis C antibody status, HIV subtype, ART experience, prior INSTI exposure, preexisting drug resistance, regimen GSS or NRTI backbone. The proportion of persons receiving a tenofovir disoproxil fumarate-emtricitabine/lamivudine versus an abacavir–lamivudine NRTI backbone differed considerably between INSTI groups due to the available drug coformulations. We therefore also stratified the cohort by INSTI-NRTI combination (Supplemental Table S4, http://links.lww.com/QAD/B84). Due to the small numbers in each treatment subgroup, no statistically significant differences or potential patterns could be identified in the proportion of persons developing drug resistance associated with tenofovir-containing versus abacavir-containing backbones.
In the subset of ART-experienced persons (Supplemental Table S3(b), http://links.lww.com/QAD/B84), those who developed resistance were more likely to have had less than 80% adherence to their previous ART regimen. Neither switching from a protease inhibitor-based regimen nor switching because of an adverse drug reaction was significantly associated with emergent resistance.
In univariable Cox proportional hazards models (Table 4), female sex, pre-INSTI pVL more than 100 000 copies/ml, CD4+ less than 200 cells/μl and INSTI adherence less than 80% were associated with increased rates of emergent drug resistance. Dolutegravir (but not elvitegravir) had a protective effect against emergent resistance versus raltegravir. Kaplan–Meier curves estimating the probability of experiencing emergent resistance over time are shown for the two variables with the strongest association with drug resistance: CD4+ (Fig. 1a) and INSTI adherence (Fig. 1b).
The best-fit, multivariable model retained baseline 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, adjusted hazard ratio 2.52 (1.11, 5.71). INSTI was not included in the final model because this variable had a P value more than 0.2 and did not improve the model fit.
In this cohort of 928 distinct persons, who contributed data for 985 records of INSTI-based ART prescribed during standard clinical practice, we noted low rates of clinically important, new drug resistance mutations during the first year of treatment. Emergent integrase and/or reverse transcriptase mutations were observed with raltegravir, elvitegravir and dolutegravir in both ART-naive and treatment-experienced persons. First-year integrase resistance rates were approximately 1/100 person-years exposure for all three INSTIs. Although the dolutegravir-treated group had a lower rate of any emergent resistance (1.48/100 person years versus 2.37 for elvitegravir and 3.80 for raltegravir), these differences were not statistically significant. In the multivariable, Cox proportional hazards model, having CD4+ less than 200 cells/μl and less than 80% adherence to the INSTI regimen were the strongest factors associated with emergent resistance, whereas the choice of INSTI drug was not statistically significant and excluded from the model.
For raltegravir and elvitegravir, the proportion of persons with emergent integrase mutations was similar to the 48-week outcomes of randomized clinical trials, namely less than 1–2% for treatment-naive [5–9] and 1–5% for ART-experienced persons [11–13]. Emergent reverse transcriptase mutations at 48 weeks ranged from less than 1 to 3% in these clinical trials, similar to our observations. The integrase mutations associated with elvitegravir and raltegravir were also consistent with those described in the literature .
The 48-week outcomes of dolutegravir, phase III clinical trials published to date have detected neither integrase nor reverse transcriptase mutations in ART-naive persons receiving dolutegravir and two NRTIs [8–10]. In contrast, we observed one case each of emergent integrase (T66I) and reverse transcriptase (M184V) mutations in ART-naive persons who initiated dolutegravir-based regimens (cases 23 and 27). At least one other postmarketing case of dolutegravir-associated resistance (emergent Q148K with M184V) in an ART-naive person has been reported in the literature .
There is currently limited, published information regarding treatment-experienced persons switching to or restarting dolutegravir 50 mg daily and two NRTIs. In the STRIIVING study, virologically suppressed patients were switched from protease inhibitor, NNRTI or INSTI-based ART to dolutegravir-abacavir–lamivudine and, at weeks 24 and 48, none of the 275 persons in the early dolutegravir-switch arm had developed drug resistance [30,31]. In contrast, 3/334 treatment-experienced, INSTI-naive persons in our community-based cohort developed emergent integrase (R263K) and/or reverse transcriptase (M184I) mutations within 1 year after starting dolutegravir-based regimens. The R263K mutation has been identified in other treatment-experienced individuals failing dolutegravir-based ART .
Risk factors for emergent drug resistance during INSTI-based therapy were consistent with those reported for other ART regimens. Low CD4+ cell count has been associated with increased risk for drug resistance in a variety of healthcare settings [21,32–34]. In the context of British Columbia's universal healthcare system, in which prompt initiation of ART is recommended regardless of CD4+ cell count, and antiretroviral drugs are supplied free of charge to patients , CD4+ less than 200 cells/μl might be a proxy measure for limited engagement in care. There was a strong association between baseline CD4+ less than 200 cells/μl and having baseline pVL more than 100 000 copies/ml, female sex, less than 80% adherence to the INSTI regimen and, for ART-experienced persons, less than 80% adherence to the previous ART regimen.
Incomplete ART adherence has also been associated with increased risk for drug resistance [21,33]. Adherence estimates based on prescription fill quantities measure doses dispensed, not doses ingested, and may overestimate true medication use . ART prescription refill compliance less than 95% has previously been associated with increased risk for drug resistance . In this study, we observed emergent drug resistance in several persons with apparent at least 95% ART prescription fill history; however, more than half these individuals had a high pVL (>10 000 copies/ml) at the time of emergent drug resistance, suggestive of treatment interruption or inconsistent antiretroviral use despite drug availability. We selected a threshold of less than 80% refill compliance to represent suboptimal ART adherence, to improve the specificity of identifying persons with incomplete ART usage. Our observed association between less than 80% INSTI prescription fill history and increased rates of emergent resistance affirms the importance of daily ingestion of INSTI-based regimens but does not imply a specific threshold for the proportion of missed doses associated with developing drug resistance.
The association between GSS less than 3 and emergent resistance could not be adequately evaluated because most persons received regimens with three fully active antiretroviral drugs. Of note, cases 12 and 19 had preexisting M184V and thymidine analog mutations that compromised the NRTI backbone, and they developed additional drug resistance after switching from a protease inhibitor-based to a raltegravir or elvitegravir-based regimen. Case 1 was previously treated with a protease inhibitor-containing four drug regimen and likely had unrecognized, archived NRTI resistance in addition to new integrase mutations after a switch to raltegravir-based ART. These three cases echo the findings of the raltegravir SWITCHMRK study, which noted increased risk for integrase resistance when persons with preexisting NRTI mutations switched from protease inhibitor-based to INSTI-based ART .
The current study's results must be interpreted in the context of several limitations. Given the overall low rates of drug resistance, the sample size may have been insufficient to detect statistically significant differences between INSTIs or INSTI-NRTI combinations. Drug resistance testing was only performed if requested by the patient's physician; therefore, some preexisting or emergent mutations may have been undetected. Study results may not be generalizable to persons age less than 19 years, those with HIV-1 subtypes other than clade B, those taking INSTI-based regimens with fewer than three fully active drugs, or in healthcare settings in which pVL and drug resistance testing are not readily available.
In conclusion, raltegravir, elvitegravir and dolutegravir-based regimens were associated with overall low rates of emergent drug resistance during ‘real-world’ use; however, emergent integrase and reverse transcriptase mutations were detected in association with all three INSTIs, in both ART-naive and ART-experienced persons. Having a CD4+ cell count less than 200 cells/μl at the time of INSTI start and incomplete adherence (<80%) to the INSTI regimen were associated with approximately 10 times and 2.5 times increase in drug resistance rates, respectively. As for all ART regimens, regular pVL monitoring and adherence support are recommended for persons receiving INSTI-based ART, with prompt drug resistance testing if virologic suppression is not achieved or maintained.
We acknowledge with thanks the technical and administrative support provided by Rachel McGovern, Conan Woods, Ana Ulloa, Angie Semple and BC-CfE staff. K.J.L., P.R.H., J.T., L.A., S.G., J.S.G.M. and R.B. conceived and designed the study. M.R. and W.Z. performed the laboratory analysis. B.Y., L.W., and V.D.L. prepared and analyzed the data. K.J.L. drafted the article and all authors reviewed it.
This research was supported by Genome Canada (142HIV), CIHR, Genome British Columbia and Genome Quebec funding to P.R.H. and J.S.G.M.
Conflicts of interest
P.R.H. is supported by CIHR/GSK Research Chair in Clinical Virology. He has received grants from, served as an ad-hoc advisor to, or spoke at various events sponsored by Abbott, Merck, Virco and Gilead and served as a consultant for ViiV Healthcare, and Gilead. V.D.L. is supported by two grants from the Canadian Institutes of Heath Research (CIHR; MOP-125948; PJT-148595), by a Scholar Award from the Michael Smith Foundation for Health Research (no. 5199) and by a New Investigator award from CIHR (no. 288880). S.G. has received honoraria for attending Advisory Board meetings by Gilead, ViiV and Janssen. J.S.G.M.'s research is supported by grants, paid to his institution, from the British Columbia Ministry of Health, the US National Institutes of Health (R01DA036307), UN AIDS and MAC AIDS funds. Limited, unrestricted institutional grants have been provided by Abbvie, Gilead Sciences, J&J, Merck, and ViiV Healthcare. He has served on Advisory Boards for Teva, Gilead Sciences and InnaVirVax. R.B. has received speaker's fees from Gilead Sciences and Merck. For the remaining authors, none were declared.
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