The integrase strand transfer inhibitors (INSTIs) raltegravir, elvitegravir, and dolutegravir are widely used in first-line and alternative antiretroviral therapy (ART) [1,2]. Postmarketing observational studies have documented a 3–14% incidence of adverse drug reactions (ADRs) leading to INSTI discontinuation [3–11], compared to 1–4% ADR-related discontinuations in clinical trials [12–17]. INSTI ADR rates have varied between real-world cohorts, and few studies have compared all three INSTIs [8–11].
The increasing selection of ART alternatives permits treatment individualization, and antiretroviral tolerability remains an important consideration for both initial ART selection and subsequent regimen changes [1,18,19]. Understanding the possible differences in ADR profiles between INSTIs can better inform personalized ART selection.
The purpose of this retrospective cohort study was to characterize the incidence and type of INSTI ADRs resulting in INSTI discontinuation within the first 2 years of treatment. The main objective was to compare ADR rates in raltegravir, elvitegravir, and dolutegravir-treated persons, adjusted for confounders. For persons with an ADR, additional objectives were to describe and compare ADR symptoms between INSTIs, characterize ADRs associated with early (first year) and late (second year) discontinuations, and describe subsequent ART decisions following the INSTI ADR, with particular interest in the tolerability of switches between INSTIs.
Study design and setting
The study cohort included HIV-1-infected persons in British Columbia, Canada, who received ART through the publicly-funded British Columbia Centre for Excellence in HIV/AIDS (BC-CfE) Drug Treatment Program (DTP) . Persons aged at least 19 years were included if they received their first prescription for raltegravir, elvitegravir co-formulated with cobicistat (elvitegravir-cobicistat), or dolutegravir between 1 January 2012 and 31 December 2014, and were excluded if the INSTI was initiated during a clinical trial or outside British Columbia. Both ART-experienced and naive persons were included, and individuals could contribute data for more than one INSTI. Baseline demographic and clinical variables, ART dispensing, and pharmacovigilance data were abstracted from BC-CfE databases. Ethical approval was obtained from the University of British Columbia, Providence Healthcare Research Ethics Board.
Follow-up and censoring
Adverse drug reaction data collection continued until 31 December 2016, providing at least 2 years follow-up opportunity. Persons were followed until they experienced an INSTI ADR resulting in INSTI discontinuation, or were censored at the earliest occurrence of INSTI discontinuation for other reason, patient relocation outside British Columbia, death, or 24 months after INSTI start. Changes to INSTI tablet formulation or dose were not considered discontinuations.
For each person, INSTI treatment status at 24 months was summarized as ongoing, stopped due to INSTI ADR, stopped for other reason, or person deceased, moved, or lost to follow-up.
Primary outcome: adverse drug reaction
The primary outcome was any INSTI ADR resulting in INSTI discontinuation. ADR reports were abstracted from the BC-CfE Pharmacovigilance database. This longitudinal, population-based surveillance program collects clinician-reported antiretroviral ADRs through a system integrated with ART prescribing, and maintains individual ADR histories for DTP participants . ADR attribution to specific antiretrovirals is recorded as documented by the clinician.
To apply consistent ADR evaluation criteria, a causality review of INSTI ADR reports was undertaken by study co-authors who were not involved in Pharmacovigilance data collection. De-identified ADR records, blinded to INSTI drug, cobicistat, and year were independently reviewed by two HIV clinic pharmacists (J.T., L.A.). Reviewers applied WHO causality assessment criteria  to classify each ADR as ‘possibly’ (WHO categories ‘possible’ or higher) or ‘unlikely’ causally associated with the INSTI exposure. Discordant assessments were resolved by consensus.
Adverse drug reaction reports were qualified as events in this study if the reporter implicated the INSTI, and if the ADR resulted in INSTI discontinuation within 2 years after start. ADR reports were censored as nonevents if causality was unclassifiable due to insufficient information, or if the ADR was assessed as ‘unlikely’ to be associated with the INSTI.
For those with ADR-related INSTI discontinuation, occurrence of ART interruption (defined as clinician-documented interruption and/or plasma viral load rebound >1000 copies/ml at the time of ADR report) and next ART regimen were summarized descriptively. Post-ADR re-exposure to the same INSTI and switches to a different INSTI were assessed for tolerability up to May 2017. Other reasons for stopping the INSTIs were summarized according to predefined categories in the DTP database.
Exposure and confounder variables
The main exposure variable was INSTI drug. Baseline variables that could potentially influence ADR occurrence or reporting were summarized by descriptive statistics and considered as adjustment variables in the confounder model. These included age, biological sex, hepatitis C antibody status, and prior ART exposure at the time of INSTI start. Plasma viral load and CD4+ cell count values were measured within 6 months prior to INSTI start, with missing values imputed (methods described elsewhere ). For treatment-experienced persons, the reasons for switching to the INSTI, and antiretroviral ADR history were also recorded.
Antiretrovirals prescribed concurrently with the INSTI were categorized as either two nucleoside (-tide) reverse transcriptase inhibitors (NtRTIs): tenofovir disoproxil fumarate-emtricitabine/lamivudine, or abacavir-lamivudine, or as ‘other antiretroviral combination.’ To account for the possible confounding effect of simultaneous, multiple antiretroviral changes on ADR assessment, it was also noted whether or not the INSTI regimen included at least one other new antiretroviral. The pharmacokinetic enhancer cobicistat was only available in co-formulation with elvitegravir during the study period, and was not counted as a new antiretroviral in elvitegravir-containing regimens.
To adjust for the potential influence of INSTI availability on ART prescribing and ADR-related therapy changes, persons were classified according to INSTI start-time period, based on INSTI availability: Period 1 (raltegravir) 1 January 2012 to 30 April 2013, period 2 (raltegravir, elvitegravir-cobicistat) 1 May 2013 to 31 December 2013, and period 3 (raltegravir, elvitegravir-cobicistat, dolutegravir) 1 January 2014 to 31 December 2014.
Baseline clinical and demographic variables were summarized by descriptive statistics and compared across INSTI categories using Pearson's chi-square or Fisher's exact test for categorical, and Kruskal–Wallis test for continuous variables.
For each INSTI, ADRs were summarized by symptom detail and symptom class. Multiple symptoms within a class were counted once per class, per person. ADR symptom classes were compared across INSTIs for all ADRs and for late (second year) ADRs using Pearson's chi-square or Fisher's exact test.
Crude INSTI ADR rates and 95% confidence intervals (95% CIs, Poisson method) were calculated per 100 person-years follow-up. Median (25th–75th percentile, Q1-Q3) follow-up time and time to INSTI ADR were calculated to censor date, and to date of ADR-related INSTI discontinuation, respectively. Time from INSTI start to ADR-related discontinuation was plotted by the Kaplan–Meier method, with the log-rank test used to test for a statistically significant difference (P < 0.05) between INSTIs. Poisson regression was used to explore associations between baseline variables and INSTI ADR rates.
Cox proportional-hazards regression was used to estimate the hazard ratio for ADR-related INSTI discontinuation. To allow comparison among all three INSTIs, both raltegravir and dolutegravir were assigned as the INSTI reference category. The robust sandwich covariance matrix estimate for clustered data structure was used to account for persons who contributed data for more than one INSTI . Potential confounder variables were included in the full model and sequentially removed using a change-in-estimate strategy, whereby variables were removed if their exclusion resulted in a maximum change of less than 5% in the estimated INSTI coefficients in the reduced model [25,26]. Age and sex were included in the model a priori. Covariates were tested for co-linearity. Fulfillment of the proportional hazards assumption was assessed by visual inspection of Kaplan–Meier plots and by the weighted residuals score test . Statistical analyses were performed using SAS v9.4 (Cary, North Carolina, USA) and R v.3.3.2 (Vienna, Austria).
There were 1522 new INSTI starts between 1 January 2012 and 31 December 2014. After excluding INSTIs initiated in clinical trials or outside British Columbia (n = 58), 1344 persons contributed 1464 unique person-INSTI exposures: 551 raltegravir, 394 elvitegravir-cobicistat, 519 dolutegravir. There were 110 persons who contributed data for two INSTIs and five persons for three INSTIs.
Baseline characteristics at INSTI start are summarized in Table 1. Overall, participants were predominantly male (79%) and ART-experienced (85%). There were more females and ART-naive persons in the elvitegravir-cobicistat group, more Hepatitis C coinfection in the raltegravir group, and more virologically suppressed ART switches in the dolutegravir group. Among ART-experienced persons, more than half had previously experienced an antiretroviral ADR, but few (<5%) had prior INSTI-related ADRs.
Within each INSTI category, baseline clinical and demographic characteristics were stable across time periods (data not shown). The proportion of persons with prior INSTI exposure increased according to the chronological introduction of each drug (Table 1). Few raltegravir-treated persons were INSTI-experienced, whereas nearly one-third of dolutegravir-treated persons had previously taken a different INSTI. Among the 1248 ART-experienced persons, 552 (44%) switched from protease inhibitor-based ART, and 362 (29%) from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART (Supplemental Table S1, http://links.lww.com/QAD/B235). A total of 187 (15%) switched from a different INSTI, predominantly raltegravir changing to dolutegravir or elvitegravir-cobicistat. The most commonly stated reason for switching to the INSTI was an ADR to the previous regimen (approximately one-third of cases). ART simplification accounted for a high proportion of switches to dolutegravir and elvitegravir-cobicistat.
The majority (>98%) of persons received standard INSTI doses of raltegravir 400 mg twice daily, elvitegravir 150 mg daily, or dolutegravir 50 mg daily. Three raltegravir and 16 dolutegravir-treated persons received higher doses to overcome drug interactions or INSTI resistance (Supplemental Table S2, http://links.lww.com/QAD/B235).
At INSTI start, concurrent ART was most commonly two NtRTIs (76%, Table 1). Most (80%) ‘other’ ART combinations included a protease inhibitor (Supplemental Table S3, http://links.lww.com/QAD/B235). A higher proportion of raltegravir-treated persons received a background regimen other than two NtRTIs. Elvitegravir was available exclusively in combination with cobicistat, tenofovir disoproxil fumarate, and emtricitabine; therefore no elvitegravir-treated persons received an abacavir-lamivudine backbone. Other antiretroviral combinations with elvitegravir-cobicistat included addition of abacavir or a protease inhibitor (boosted by cobicistat in the combination tablet). During follow-up, the co-prescribed antiretrovirals were changed in 130 (8.9%) persons. The most common changes were switches between tenofovir disoproxil fumarate and abacavir (Supplemental Table S4, http://links.lww.com/QAD/B235). Tenofovir alafenamide was not available during the study period.
Follow-up and censoring
Median follow-up for all INSTIs was 24 months (Table 2), with a cumulative follow-up of 2377 person-years INSTI exposure. In all groups, the majority of persons remained on the INSTI at the end of the 2-year follow-up, with retention highest for dolutegravir (81%) and lowest for raltegravir (58%). More raltegravir-treated persons discontinued treatment for non-ADR reasons (Table 2), with regimen simplification being the most common reason (Supplemental Table S5, http://links.lww.com/QAD/B235). There were also more deaths in the raltegravir group, but none were associated with INSTI ADRs.
Adverse drug reactions
Among 1464 person-INSTI exposures, there were 107 ADR reports implicating the INSTI. After excluding nine ADRs that did not result in INSTI discontinuation and one unclassifiable ADR, the remaining 97 ADR reports underwent blinded causality assessment. Eight reports were evaluated as unlikely related to the INSTI, leaving 89 study-defined ADR events. Reasons for assessment as ‘unlikely’ included the following: symptom onset preceded INSTI start, symptoms did not improve following INSTI discontinuation, symptoms did not recur with INSTI restart, and/or other, more plausible causes of the symptoms were identified.
Adverse drug reaction incidence was highest for elvitegravir-cobicistat-treated persons, with 38 of 394 (9.6%) having an ADR-related discontinuation compared to dolutegravir 27 of 519 (5.2%) or raltegravir 24 of 551 (4.4%) (Table 2). Unadjusted ADR rates (95% CI) were also higher for elvitegravir-cobicistat [5.94 (4.32, 8.16) per 100 person-years] than for raltegravir [2.91 (1.95, 4.35)] or dolutegravir [2.96 (2.03, 4.31)]. Most ADRs occurred in persons who received standard INSTI doses (88/89, 99%), and who remained on the same co-prescribed antiretrovirals throughout follow-up (87/89, 98%). For the two persons who changed co-prescribed antiretrovirals, the INSTI ADR was not temporally associated with the other antiretroviral alterations.
As displayed in Fig. 1a, the higher incidence of elvitegravir-cobicistat ADRs was driven by a significantly higher proportion of persons with gastrointestinal ADRs (nausea, vomiting, diarrhea) 5.3% and general symptoms (fatigue, malaise) 1.3%. Central nervous system (CNS) symptoms such as sleep disturbances and headache were reported with all three INSTIs, and, although a higher proportion of dolutegravir-treated persons experienced a CNS ADR (3.5%, compared to elvitegravir-cobicistat 2.8% and raltegravir 1.6%), there was no statistically significant difference in CNS symptoms between INSTIs. Most CNS ADRs occurred in persons who received standard INSTI doses, with one case of sleep disturbance in a person treated with dolutegravir 50 mg twice daily. Details of all ADR symptoms are summarized in Supplemental Table S6-a (http://links.lww.com/QAD/B235), and the 11/89 (12%) ADRs designated as ‘severe’ reactions by the reporter are summarized in Table S6-b.
Symptoms associated with late ADR-related INSTI discontinuation (Fig. 1b) were similar to the overall pattern, with significantly more gastrointestinal complaints in the elvitegravir-cobicistat group. Although time of symptom onset was not consistently documented, several cases of late ADRs did specify long-standing, suspected side effects prior to INSTI discontinuation.
The median time to ADR-related INSTI discontinuation was 3 to 4 months (Table 2). As depicted in the Kaplan–Meier plot (Fig. 2) and Table 2, ADR-related discontinuations were reported throughout the 2-year follow-up period, but the majority (81%) occurred within the first year. Second-year INSTI discontinuations due to ADR were disproportionately higher in the elvitegravir-cobicistat group and accounted for (12/17, 70%) of late ADRs.
In bivariate analyses, only INSTI drug and a prior history of antiretroviral ADR were significantly associated with INSTI ADR (Supplemental Table S7, http://links.lww.com/QAD/B235). In the adjusted Cox regression model (Table 3), the hazard ratio (95% CI) for elvitegravir-cobicistat versus dolutegravir ADR was 2.24 [(1.13, 4.44), P = 0.020]; however, there were no statistically significant differences in the ADR HR for either dolutegravir or elvitegravir-cobicistat versus raltegravir. A sensitivity analysis limited to period 3, when all three INSTIs were available, provided a similar result: adjusted ADR HR for elvitegravir-cobicistat versus dolutegravir 2.01 [(1.02, 3.98), P = 0.044].
Following ADR-related INSTI discontinuation, 22 of 89 (25%) of persons had documented ART interruption of several days to months, half of whom had virologic rebound above 1000 copies/ml. Whether directly switching to another regimen or re-starting ART after a period of interruption, 33 (37%) persons reverted to their previous ART regimen, 26 (29%) switched to a different INSTI, and 27 (30%) switched to a different non-INSTI regimen.
Selection of the subsequent ART regimen appeared to be influenced by the available antiretrovirals at the time of discontinuation. Only three of 20 (15%) of persons who stopped raltegravir or elvitegravir-cobicistat due to ADRs in periods 1 and 2 had a different INSTI in their next regimen, whereas 23 of 69 (33%) of persons with an ADR-related stop in period 3 switched to another INSTI, predominantly dolutegravir. Examination of the timing of ADR-related INSTI discontinuations did not reveal any clustering of either early or late ADRs around the market release of the newer drugs (Supplemental Fig. S1, http://links.lww.com/QAD/B235). Most persons (70%) with a late INSTI ADR had started the INSTI in period 3, when all three INSTIs were available, and therefore had the opportunity to switch between INSTIs at any time.
There was no apparent relationship between the tolerability of one INSTI and subsequent tolerability of another INSTI. Among the 187 persons who had switched from a prior, tolerated, INSTI regimen to a new (study cohort) INSTI, 17 of 187 (9.1%) subsequently discontinued the new INSTI because of an ADR. The majority 15 of 17 (88%) of these ADRs occurred in persons who switched from raltegravir to either elvitegravir-cobicistat or dolutegravir for simplification. Conversely, among the persons with a study-defined INSTI ADR, 21 of 26 (78%) of those who switched to a different INSTI tolerated the new regimen (predominantly elvitegravir-cobicistat to dolutegravir switches). Two persons in the study cohort experienced more than one INSTI ADR: one developed a rash with both raltegravir and dolutegravir, and the other experienced elvitegravir-cobicistat related renal effects and dolutegravir CNS symptoms. Among the 89 ADR events, 10 persons (11%) eventually re-started the same INSTI due to patient or prescriber preference relative to other ART options.
The large cohort of 1344 persons included 1464 unique person-INSTI exposures to raltegravir, elvitegravir-cobicistat, and dolutegravir, with a total of 2377 person-years follow-up. After adjustment for potential confounders, the ADR rate for elvitegravir-cobicistat was approximately twice that of dolutegravir (hazard ratio 2.24, 95% CI 1.13, 4.44); however, there were no statistically significant differences between elvitegravir-cobicistat or dolutegravir versus raltegravir.
Other observational studies have reported INSTI ADR rates (proportions) as 5.7–7.6/100 person-years (3.6–5.8%) for raltegravir [7–11], 4.4–10.3/100 person-years (3.4–12.3%) for elvitegravir-cobicistat [6–11], and 3.8–13.9/100 person-years (2.5–13.7%) for dolutegravir [3,4,6–11]. Our study's findings are consistent with other cohorts, but at the lower end of the range for raltegravir 2.91/100 person-years (4.4%), and dolutegravir 2.96/100 person-years (5.2%), and at the higher end of the range for elvitegravir-cobicistat 5.94/100 person-years (9.6%).
In our cohort, the higher incidence of ADR-related discontinuation for elvitegravir-cobicistat was largely due to gastrointestinal symptoms. To date, one other study with a comparably high incidence of elvitegravir-cobicistat ADRs documented a high proportion of renal events, and noted these were likely attributable to tenofovir . In the present study, renal ADRs which the reporter attributed to tenofovir did not qualify as study events unless elvitegravir-cobicistat was also specifically implicated, thus there were few elvitegravir-cobicistat renal ADRs in our cohort (2/394, 0.5%). The observation of a higher proportion of ADR-related discontinuations in the second year of elvitegravir-cobicistat treatment could not be explained by the available data, and was neither due to the occurrence of unexpected symptoms, nor influenced by the availability of newer drugs. Although we observed a higher occurrence of CNS ADRs with dolutegravir relative to other INSTIs, this difference was not statistically significant, and the 3.5% incidence of dolutegravir-related CNS effects was lower than the more than 5% incidence reported by others [3,8]. There have been recent reports of weight gain associated with INSTIs [28,29]. In this cohort, there were only two INSTI discontinuations due to weight gain (one elvitegravir-cobicistat, one dolutegravir; Supplemental Table S6a, http://links.lww.com/QAD/B235).
Taken together with the work of others, this study affirms that all INSTIs are generally well tolerated, although side-effect profiles differ between drugs. Persons who experience ADRs with one INSTI may tolerate an alternative drug in this class; however, the converse is also true, and switching from one INSTI to another may result in new side effects. In this cohort, approximately one-third of persons with an INSTI ADR had switched to the INSTI to simplify or modernize the ART regimen. This included regimen changes from twice daily raltegravir to once-daily elvitegravir-cobicistat or dolutegravir, and switches from older drugs such as atazanavir or efavirenz to an INSTI. A high proportion of these persons subsequently switched back to their previous ART regimen following the INSTI ADR. Although ADR rates were not significantly higher in persons who switched to the INSTI for the purpose of ART simplification versus other reasons for regimen change (Supplemental Table S7, http://links.lww.com/QAD/B235), these findings serve as a reminder that ART changes for the purpose of modernization or simplification may not necessarily improve quality of life , and may result in ADRs to the new regimen. Approximately one-quarter of persons experiencing an INSTI ADR had a period of ART interruption associated with the event, which underscores the clinically important consequences of ART tolerability on adherence .
Comparisons of older and newer drugs can be confounded by shorter follow-up times for newer agents and changing prescribing patterns over time. Strengths of our study included providing equal, 2-year follow-up opportunity for all INSTIs, adjusting for time periods defined by INSTI availability, and excluding ADRs identified as unlikely associated with the INSTI in an independent, blinded causality review. In British Columbia, all antiretrovirals are centrally dispensed at no charge to patients; therefore ADR-related ART changes were not influenced by drug cost constraints. This population-based INSTI cohort included prescriptions from 345 physicians, reducing the influence of individual prescribing preferences. The availability of longitudinal pharmacovigilance data permitted adjustment for prior ADR history, which was found to have a significant association with subsequent ADR-related INSTI discontinuation.
The study's results must be interpreted in the context of its limitations. The application of a causality assessment tool permits consistent classification, but cannot prove the relationship between drug exposure and suspected ADR . Observed ADR rates might differ in other healthcare settings or patient populations. These results cannot be generalized to children and adolescents. This study only analyzed ADRs that resulted in INSTI discontinuation, which might underestimate overall ADR rates. Persons with clinically important ADRs might be unable to switch to a different regimen if their therapeutic choices are limited by drug resistance or other contraindications. Although this analysis attempted to adjust for patient demographics and the differences in prior ART exposure and co-prescribed antiretrovirals, the inability to completely adjust for both known and unmeasured confounders may have influenced the observed ADR-related INSTI discontinuations.
In conclusion, the present study affirms that raltegravir, elvitegravir-cobicistat, and dolutegravir are generally well tolerated when prescribed in routine clinical practice. Consideration of potential differences in INSTI side-effect profiles can inform individualization of ART.
We acknowledge with thanks the technical support provided by Conrado Franco Villalobos, Angie Semple and BC-CfE staff. K.J.L., J.T., L.A., R.B., S.G., and J.S.G.M. conceived and designed the study. A.U., J.T., and L.A. conducted the ADR causality assessment. B.Y., L.W., and V.D.L. prepared and analyzed the data. K.J.L. drafted the manuscript and all authors reviewed it.
Conflicts of interest
Source of funding: V.D.L. is supported by a grant from the Canadian Institutes of Health Research (CIHR, PJT-148595), by a Scholar Award from the Michael Smith Foundation for Health Research (#5199), and by a New Investigator award from CIHR (#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), and 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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