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Adverse drug reactions associated with integrase strand transfer inhibitors (INSTI) in clinical practice: post-marketing experience with raltegravir, elvitegravir-cobicistat and dolutegravir
Abstract Content:
Background: The integrase strand transfer
inhibitors (INSTI) raltegravir, elvitegravir with pharmacokinetic booster
cobicistat (elvitegravir-cobicistat) and dolutegravir have demonstrated safety
and efficacy in clinical trials. This post-marketing,
observational study describes and compares the incidence and type of INSTI adverse
drug reactions (ADRs) reported during routine clinical use in British Columbia
(BC) Canada.
Methods: HIV-1-infected persons age ≥19 years were included if their first prescription for raltegravir, elvitegravir-cobicistat or dolutegravir was dispensed between 01-Jan-2012 and 31-Aug-2014 through the BC Centre for Excellence in HIV/AIDS (BC-CfE) Drug Treatment Program. Patients could contribute data for more than one INSTI. All patients had ≥4 months follow-up opportunity until 31-Dec-2014. Clinical and demographic variables and ADR reports were abstracted from BC-CfE databases and summarized by descriptive statistics. The primary outcome was any ADR resulting in therapy discontinuation. ADR incidence density rates and 95% confidence intervals (CI95) were estimated by Poisson regression, adjusted for covariates. Adjusted relative ADR rates (RR) were calculated using raltegravir as the reference.
Results: The cohort included 1044 INSTI-treated patients, 75 (7.2%) of whom contributed data for ≥2 INSTIs, providing 1122 distinct patient-INSTI records: 522 raltegravir-treated, 301 elvitegravir-cobicistat-treated and 299 dolutegravir-treated patients. Table 1 summarizes patient and INSTI regimen characteristics.
[Table 1: Patient and Treatment Characteristics]
For each INSTI, the proportion of patients with an ADR leading to discontinuation was: Raltegravir 24/522 (4.60%), elvitegravir-cobicistat 26/301 (8.64%) and dolutegravir 9/299 (3.01%). As shown in Figure 1, the most commonly reported ADR symptoms were: Central nervous system (sleep disturbance, nightmares, headache), gastrointestinal tract (nausea, diarrhea, gastrointestinal discomfort) and general fatigue/ malaise. No serious ADRs (grade IV severity or leading to hospitalization) were reported.
[Figure 1]
After controlling for under-dispersion using robust Poisson regression and adjusting for sex, antiretroviral treatment experience and hepatitis C co-infection, adjusted ADR rates (CI95) per 100 person-years were: Raltegravir 1.88 (0.72-4.93), elvitegravir-cobicistat 5.76 (2.14-15.49), and dolutegravir 3.34 (1.19-9.40). The adjusted RR (CI95) of ADR relative to raltegravir was 3.06 (2.97-3.14) for elvitegravir-cobicistat and 1.78 (1.65-1.91) for dolutegravir.
Conclusions: All INSTI were generally well tolerated. The newer INSTIs elvitegravir-cobicistat and dolutegravir had shorter follow-up times than raltegravir, but had relatively higher rates of ADRs resulting in therapy discontinuation. Follow-up of this cohort is ongoing.
Methods: HIV-1-infected persons age ≥19 years were included if their first prescription for raltegravir, elvitegravir-cobicistat or dolutegravir was dispensed between 01-Jan-2012 and 31-Aug-2014 through the BC Centre for Excellence in HIV/AIDS (BC-CfE) Drug Treatment Program. Patients could contribute data for more than one INSTI. All patients had ≥4 months follow-up opportunity until 31-Dec-2014. Clinical and demographic variables and ADR reports were abstracted from BC-CfE databases and summarized by descriptive statistics. The primary outcome was any ADR resulting in therapy discontinuation. ADR incidence density rates and 95% confidence intervals (CI95) were estimated by Poisson regression, adjusted for covariates. Adjusted relative ADR rates (RR) were calculated using raltegravir as the reference.
Results: The cohort included 1044 INSTI-treated patients, 75 (7.2%) of whom contributed data for ≥2 INSTIs, providing 1122 distinct patient-INSTI records: 522 raltegravir-treated, 301 elvitegravir-cobicistat-treated and 299 dolutegravir-treated patients. Table 1 summarizes patient and INSTI regimen characteristics.
| Variable | Raltegravir N=522 | Elvitegravir-Cobicistat
N=301 | Dolutegravir N=299 | |
| Age, median (IQR) yr | 50 (43,56) | 43 (34, 50) | 49 (41,55) | |
| Sex n(%): male female | 420 (80%) 102 (20%) | 225 (75%) 76 (25%) | 237 (79%) 62 (21%) | |
| CD4, median (IQR) cells/microL | 440 (230, 650) | 470 (280, 650) | 550 (380, 760) | |
| Suppressed viral load <50 copies/mL n(%) | 288 (55%) | 126 (42%) | 201 (67%) | |
| Hepatitis C co-infection n(%) | 239 (46%) | 106 (35%) | 74 (25%) | |
| Previous ART, n(%): treatment naïve treatment experienced | 66 (13%) 456 (87%) | 67 (22%) 234 (78%) | 37 (12%) 262 (88%) | |
| Concurrent ARVs: 2 NRTI: TDF+3TC/FTC 2 NRTI: ABC+3TC Other ARV combination | 185 (36%) 111 (21%) 226 (43%) | 263 (87%) 0 ( 0%) 38 (13%) | 61 (20%) 179 (60%) 59 (20%) | |
| INSTI treatment duration: median (IQR) yr cumulative person-yr exposure | 1.15 (0.56, 1.79) 635 person-yr | 0.75 (0.44, 1.13) 233 person-yr | 0.50 (0.38, 0.63) 150 person-yr | |
| Abbreviations: IQR: interquartile range, ARV: antiretroviral, ART: ARV therapy, INSTI: integrase strand transfer inhibitor, ABC: abacavir, 3TC: lamivudine, FTC: emtricitabine, TDF: tenofovir, NRTI: Nucleoside (nucleotide) Reverse Transcriptase Inhibitor | ||||
For each INSTI, the proportion of patients with an ADR leading to discontinuation was: Raltegravir 24/522 (4.60%), elvitegravir-cobicistat 26/301 (8.64%) and dolutegravir 9/299 (3.01%). As shown in Figure 1, the most commonly reported ADR symptoms were: Central nervous system (sleep disturbance, nightmares, headache), gastrointestinal tract (nausea, diarrhea, gastrointestinal discomfort) and general fatigue/ malaise. No serious ADRs (grade IV severity or leading to hospitalization) were reported.
[Figure 1]
After controlling for under-dispersion using robust Poisson regression and adjusting for sex, antiretroviral treatment experience and hepatitis C co-infection, adjusted ADR rates (CI95) per 100 person-years were: Raltegravir 1.88 (0.72-4.93), elvitegravir-cobicistat 5.76 (2.14-15.49), and dolutegravir 3.34 (1.19-9.40). The adjusted RR (CI95) of ADR relative to raltegravir was 3.06 (2.97-3.14) for elvitegravir-cobicistat and 1.78 (1.65-1.91) for dolutegravir.
Conclusions: All INSTI were generally well tolerated. The newer INSTIs elvitegravir-cobicistat and dolutegravir had shorter follow-up times than raltegravir, but had relatively higher rates of ADRs resulting in therapy discontinuation. Follow-up of this cohort is ongoing.