Adverse drug reactions associated with integrase strand transfer inhibitors (INSTI) in clinical practice: post-marketing experience with raltegravir, elvitegravir-cobicistat and dolutegravir

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.

Age, median (IQR) yr50 (43,56)43 (34, 50)49 (41,55)
Sex n(%):

420 (80%)
102 (20%)

225 (75%)
76 (25%)

237 (79%)
62 (21%)
CD4, median (IQR) cells/microL440 (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:
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
[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
[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.

K.J. Lepik1,2, A. Nohpal1, B. Yip1, K.J. Toy2, L. Akagi1,2, J.S.G. Montaner1, S. Guillemi1, R. Hogg1, R. Barrios1
1BC Centre for Excellence in HIV/ AIDS, Vancouver, Canada, 2St Paul's Hospital, Pharmacy, Vancouver, Canada