Intolerance of Dolutegravir-Containing Combination Antiretroviral Therapy Regimens in Real-Life Clinical Practice

CONCISE COMMUNICATION

Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice

Mark G.J. de Boera, Guido E.L. van den Berkb, Natasja van Holtena, Josephine E. Oryszcynb, Willemien Doramaa, Daoud ait Mohab and Kees Brinkmanb

Objective: Dolutegravir (DGV) is one of the preferred antiretroviral agents in first-line combination antiretroviral therapy (cART). Though considered to be a well tolerated drug, we aimed to determine the actual rate, timing and detailed motivation of stopping DGV in a real-life clinical setting. Design: A cohort study including all patients who started DGV in two HIV treatment centers in The Netherlands. Methods: All cART-naı¨ve and cART-experienced patients who had started DGV were identified from the institutional HIV databases. Clinical data, including motivation and timing of discontinuation of DGV, were extracted from the patient files. Factors that potentially influenced discontinuation of DGV were compared between patients who stopped or continued DGV by multivariate and Kaplan–Meier analyses. Results: In total, 556 patients were included, of whom 102 (18.4%) were cART-naı¨ve at initiation of DGV. Median follow-up time was 225 days. Overall, in 85 patients (15.3%), DGV was stopped. In 76 patients (13.7%), this was due to intolerability. Insomnia and sleep disturbance (5.6%), gastrointestinal complaints (4.3%) and neuropsychiatric symptoms such as anxiety, psychosis and depression (4.3%) were the predominant reasons for switching DGV. In regimens that included abacavir, DGV was switched more frequently (adjusted relative risk 1.92, 95% confidence interval 1.09– 3.38, P log-rank 0.01). No virologic failures were observed. Conclusion: A relatively high rate of preliminary discontinuation of DGV due to intolerability was detected in our patient population. In particular, DGV was stopped more frequently if the regimen included abacavir. Multiple factors may explain these unexpected postmarketing observations, which warrant further investigation. Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.

AIDS 2016, 30:2831–2834

Keywords: dolutegravir, integrase inhibitor, side effects, toxicity

aDepartment of Infectious Diseases, Leiden University Medical Center, Leiden, and bDepartment of Internal Medicine, OLVG, Amsterdam, The Netherlands. Correspondence to Kees Brinkman, MD, PhD, Department of Infectious Diseases, OLVG, Oosterpark 9, 1091 AC Amsterdam, The Netherlands. E-mail: [email protected] Received: 2 July 2016; revised: 13 September 2016; accepted: 13 September 2016.

DOI:10.1097/QAD.0000000000001279

Table 1. Reported adverse reactions leading to discontinuation of Introduction and study objective a dolutegravir .

At present, integrase inhibitors are considered first-choice Adverse drug reaction n (%) drugs as one of the components of combination antiretroviral therapy (cART) [1]. Dolutegravir (DGV) Sleep disturbance, insomnia 31 (5.6) Gastrointestinal complaints 21 (3.8) is available in a combination tablet with abacavir and Joint, tendon and/or muscle pain 11 (2.0) lamivudine (Triumeq; ViiV Healthcare UK Ltd, Brent- Psychological/psychiatric symptomsb 14 (2.5) ford, UK) and as a 50-mg single drug tablet (Tivicay; ViiV Neurologic symptoms 10 (1.8) Healthcare UK Ltd), registered for treatment of both General malaise (headache and severe fatigue) 24 (4.3) Respiratory tract complaints 5 (0.9) experienced and cART-naı¨ve patients. Because of its Other 9 (1.6) reported favorable efficacy and safety profile, DGV rapidly gained increasing popularity among medical aNumbers and percentages do not add up to total because multiple negative side effects were diagnosed or reported in 31 (39%) patients teams providing care for individuals living with HIV. who stopped dolutegravir for this/these reason(s); in 11 (14%) patients DGV has a limited risk of interaction with comedication more than two negative side effects were reported. and, in several randomized controlled trials, the frequency bIncluding depression, anxiety, agitation, emotional instability and of reported severe side effects that caused discontinuation one case of psychosis. of DGV at week 48 was reported to be low, that is not exceeding 2–3% [2–4]. Because we observed an discontinuing DGV because of neuropsychiatric symp- unexpectedly high rate of patients who stopped DGV toms only. Consequently, in these survival analyses, and switched to a different cARTregimen, we conducted patients who stopped DGV for other reasons were a study investigating the frequency, timing and detailed censored at the time point of discontinuation. motivation of stopping DGV-containing cART in two hospitals in The Netherlands. Results Methods A total of 556 patients (LUMC, n ¼ 169; OLVG, n ¼ 387) taking DGV were included during the period of study. In the Leiden University Medical Center (LUMC) and The median age was 48 years (range 19–85 years), and the the OLVG Medical Center (OLVG), Amsterdam, The male-to-female ratio was 7.18. The majority (66.3%) of Netherlands, all cART-naı¨ve and cART-experienced the cohort consisted of men who have sex with men, individuals who were prescribed DGV between August whereas only a minority were known (ex)intravenous 2014 and March 2016 were identified from the drug users (2.2%). At initiation of DGV, 102 (18.4%) institutional HIV databases. These contain a complete patients were cART-naı¨ve. Triumeq was used by 319 list of all HIVþ patients in care for any period of time. (57.4%), DGV in any combination with abacavir by 356 Data about patient characteristics, previous cART,time of (64.0%), DGV in combination with tenofovir by 165 initiation and stopping DGV, and motivation for not (29.7%) and DGV in combination with a boosted continuing DGV were obtained from the electronic protease inhibitor (atazanavir or darunavir) by 59 (10.6%) patient files. Follow-up time was defined as the day of patients. Prior to the use of abacavir, all patients were initiation of DGV-containing cART until either the day checked for the absence of an HLA-B57 haplotype. Non- of discontinuation of DGV,the end of the study period or nucloside reverse transcriptase inhibitor combinations the day a patient was last spoken with if lost to follow-up. with DGV were rare [n ¼ 7 (1.3%)]. In both centers, standard follow-up after start or switch of cART consisted of outpatient visits at 4, 12, 24 and 48 Overall, in 85 (15.3%) patients, the DGV regimen was weeks, but patient-tailored deviations from this schedule stopped. This was reported to be due to adverse drug and telephone consultations in between visit dates were reactions in 76 (13.7%) patients. Median follow-up time regular practice. Treatment monitoring is usually was 225 days (interquartile range 133–296 days). If DGV intensified in case of suspicion of a relevant side effect was stopped, this occurred after a median use of 73 days, of cART. Reported drug-related side effects were range 5–327 days. Within 48 weeks after initiation, 81 categorized as shown in Table 1. Variables with potential out of 85 patients (95%) had stopped taking DGV. influence on continuation or discontinuation of DGV were compared between patients who stopped and The frequencies of reported adverse reactions are listed in continued DGV.Pearson’s chi-square test, Student’s t-test Table 1. Practically all reported side effects subsided, once or the Mann–Whitney U-test were performed for DGV was stopped. univariate analyses of bivariate and continuous data, respectively. Kaplan–Meier analyses and multivariate In Table 2, the analysis for risk factors for DGV logistic regression analyses were performed to adjust for continuation is shown. Age was not associated with follow-up time and confounding variables. In addition, a discontinuation of DGV (P ¼ 0.93). Twelve out of 68 subanalysis was performed with the endpoint of women stopped DGV (17.6%) compared with 73 out of

Table 2. Risk factors for discontinuation of dolutegravir since start or switch to a dolutegravir-containing regimen.

DGV stopped due to drug related toxicity/side effects, N (%)

a Variable Yes No RR (95% CI) P value Adjusted RR P value

Total 76 480 Age, mean (years) 47.8 47.9 0.93 Sex (male) 66 (86.8) 422 (87.9) 0.92 (0.50–1.70) 0.79 cART-naive 18 (17.6) 84 (17.5) 1.38 (0.85–2.24) 0.20 CD4þ T-cell count at start 628 627 0.97 of DGV, mean (cells/ml) Regimen Triumeq 52 (16.3) 267 1.61 (1.02–2.53) 0.04 1.69 (1.00–2.84) 0.049 ABC-containing cART 58 (16.3) 298 1.81 (1.10–2.99) 0.016 1.92 (1.09–3.38) 0.02 TDF-containing cART 17 (10.3) 148 0.68 (0.41–1.14) 0.13 PI-containing cART 2 (3.4) 57 0.23 (0.06–0.90) 0.015 0.20 (0.05–0.86) 0.03 Previous cART included Atripla 22 (11.5) 169 0.77 (0.49–1.24) 0.29 Center OLVG (vs. LUMC) 55 (14.2) 332 1.14 (0.72–1.83) 0.57

95% CI, 95% conﬁdence interval; cART, combination antiretroviral therapy; DGV, dolutegravir; LUMC, Leiden University Medical Center; OLVG, OLVG Medical Center RR, relative risk; ABC, abacavir; TDF, tenofovir disoproxil; PI, protease inhibitor. Manufacturers of Atripula: Bristol-Myers Squibb and Gilead Sciences Ltd. aAdjusted RR for sex, age and naı¨ve for cART, yes or no.

415 men (15%) (P ¼ 0.56). Of cART-naı¨ve patients, 19 neuropsychological or psychiatric (sleeping disturbances, (18.6%) stopped DGV compared with 66 (14.5%) of insomnia, mood alterations, anxiety and psychosis) and cART-experienced patients (P ¼ 0.30). Abacavir-con- gastrointestinal in nature. Both types of side effects have taining regimens were used by 356 (64%) patients and been reported in the registrational studies as well, though at were stopped in 58 cases (16.3%) due to adverse drug a much lower frequency. Because especially the neurop- reactions [adjusted relative risk (RR) 1.92, 95% sychological events have not been reported in studies with conﬁdence interval (95% CI) 1.09–3.38, P ¼ 0.02]. raltegravir, it seems unlikely to consider these events as class The proportion of patients on DGV cART with and effects of integrase strand transfer inhibitor (INSTI). Thus without abacavir over time is depicted in Fig. 1. far, the occurrence of unexpected neuropsychiatric side Combinations that contained both DGV and a protease effects of DGV was only reported in a small case series [6]. inhibitor were associated with a lower incidence of Gastrointestinal events were described in patients on discontinuation due to adverse drug reactions (adjusted RR 0.20, 95% CI 0.05–0.86, P ¼ 0.03). 1.00 cAT regimen with dolutegeavir but not bacavir In the subanalysis for DGV discontinuation due to 0.90 neuropsychiatric side effects (including insomnia, 0.80 psychological/psychiatric symptoms and other neuro- cAT regimen with dolutegeavir and abacavir logic side effects), the adjusted RR for discontinuation of 0.70 DGV associated with use of abacavir was 2.34 (95% CI 1.10–5.00). 0.60 0.50 All reported RRs above are adjusted for age, sex and cART-naı¨ve (yes or no). No virologic failures 0.40 were observed. 0.30

Proportion of patients on DGV 0.20

Discussion 0.10 P-logrank = 0.01 In this multicenter, postmarketing observational study, in a 0.00 ‘real life’ clinical setting of DGV use in cART, we found 0 60 120 180 240 300 360 420 480 540 that, in general, DGV was tolerated very well by most Total days on DGV containing regimen patients, but it was stopped at a much higher rate than reported in randomized controlled trials [5]. In nearly 90% Fig. 1. Proportion of patients on dolutegravir-containing of situations, the reason for interruption of DGV was drug combination antiretroviral therapy with or without abacavir. intolerability. The most frequently reported events were Small vertical lines indicate censored cases.

elvitegravir, but always in combination with a booster Acknowledgements (either ritonavir or cobicistat) [7]. Role of individual authors: M.d.B and K.B. designed and The constitution of the cART regimen significantly organized the study; G.v.d.B., N.v.H., J.O., W.D. and influenced the risk of switching to a non-DGV-containing D.A.M. collected and monitored the data; analyses were cART. Although DGV was interrupted also without performed by M.d.B. and K.B. All authors contributed to abacavir, the risk for discontinuation of DGV was the writing of the final manuscript. significantly higher when abacavir was included in the combination. Because the type of adverse events was Note: Part of this study was presented at CROI 2016 distributed similarly between abacavir users compared with (poster 948). nonabacavir users, and most of these effects have not been reported for abacavir alone, we considered that there might be an interaction between the drugs, leading to more Conflicts of interest treatment interruption. Interestingly, both drugs are There are no conflicts of interest. metabolized via hepatic glucuronidation by UDP-glucur- onosyltransferase [8,9]. To our knowledge, the potential interaction between DGV and abacavir mediated by this common degradation pathway has not been studied. References

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