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Increased dolutegravir peak concentrations in people living with HIV aged 60 and over and analysis of sleep quality and cognition
 
 
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CID May 16 2018 - Emilie R. Elliot1, Xinzhu Wang2, Suveer Singh2,4, Bryony Simmons2, Jaime H Vera3, Robert F Miller5, Colin Fitzpatrick3, Graeme Moyle4, Myra McClure2, Marta Boffito1,2 1St. Stephen's AIDS Trust–Chelsea and Westminster Hospital, London, UK, 2Imperial College, London, UK, 3Brighton and Sussex Med School, Brighton, UK, 4Chelsea and Westminster Hospital, London, UK, 5Mortimer Market Centre, Institute for Global Health, University College London, UK, "By 2015, one in three people accessing HIV care in the UK [1] and almost half in the US were aged 50 and over [2]. With advancing age, several physiological changes affect drug pharmacokinetics (PK) and pharmacodynamics (PD) [3]. A high prevalence of sleep disturbances is already described in the HIV population, even in the cART era, (30-73% versus 10-20% in the general population [21, 22]) and it is strongly associated with poorer disease outcomes, cognitive impairment and HIV-associated dementia [21, 23]
 
It is, therefore, important to characterise the role of aging on DTG PK/PD, especially with regards to central nervous system (CNS) toxicity and sleep disturbances. Overall, whilst sleep impairment rates (PSQI>5) at baseline, matched that historically reported in the HIV literature (44-51%), scores were only just in the lower range of abnormal (≤7)."
 
Abstract
 
Background

 
Demographic data show an increasingly aging HIV population worldwide. Recent concerns over dolutegravir-related neuropsychiatric toxicity have emerged, particularly amongst older HIV patients. We describe the pharmacokinetics (PK) of dolutegravir (DTG) 50mg once daily in people living with HIV (PLWH) aged 60 and older. Additionally, to address the call for prospective neuropsychiatric toxicodynamic data, we evaluate changes in sleep quality and cognitive function after switching to abacavir (ABC)/lamivudine (3TC)/DTG, over 6 months in this population.
 
Methods
 
PLWH aged≥60years with HIV-RNA<50copies/mL on any non-DTG based antiretroviral combination were switched to ABC/3TC/DTG. On day 28, 24-hour PK sampling was undertaken. Steady-state PK parameters were compared to a published historical control population aged≤50years. Six validated sleep questionnaires and neurocognitive (Cogstate®) testing were administered pre-switch and over 180 days (NCT02509195).
 
Results
 
Forty-three participants were enrolled; 40 completed the PK phase. Overall, five discontinued (two due adverse events, both sleep related, 4.6%). DTG maximum concentration (Cmax) was significantly higher in patients≥60 versus controls (GM 4246ng/mL versus 3402ng/mL, p=0.005). In those who completed day 180 (n=38), sleep impairment was higher at day 28 (PSQI median global score 5.0 versus 6.0 p=0.02) but not at day 90 or 180. Insomnia, daytime function, fatigue test scores did not change statistically over time.
 
Conclusion
 
DTG Cmax was significantly higher in older PLWH. Our data provides clinicians with key information on the safety of prescribing DTG in older PLWH.
 
INTRODUCTION
 
By 2015, one in three people accessing HIV care in the UK [1] and almost half in the US were aged 50 and over [2]. With advancing age, several physiological changes affect drug pharmacokinetics (PK) and pharmacodynamics (PD) [3].
 
The integrase inhibitor (InSTI) dolutegravir (DTG) is now the drug of choice for many HIV providers, thanks to high efficacy firmly demonstrated in trials and retained activity against some InSTI-resistant HIV-1 phenotypes [4]. Its low potential for drug-interactions is also an advantage in managing older people living with HIV (PLWH) [5]. DTG is a recommended key drug in major HIV guidelines and is a strong candidate to become first option in the WHO antiretroviral guidelines [6, 7].
 
In pre-marketing trials, DTG demonstrated favorable safety and tolerability profiles, with a <2% discontinuation rate secondary to any adverse events (AEs), comparable to raltegravir and superior to efavirenz [8, 9]. However, contrasting real-life data reveal unexpectedly higher rates (7-15%, median time 72 days) [10-14], most commonly due to insomnia/sleep disturbances and other neuropsychiatric (NP) AEs (up to 8%), regardless of prior neuropsychiatric history, thereby implicating a potentially neurotoxic effect of DTG [14-18]. Comparison studies suggest that NP-AEs are commoner with DTG than other InSTIs [11, 12, 16]. Interestingly, in several reports, DTG discontinuation was significantly higher in PLWH>60 years old [13, 16, 19], a group under-represented in licensing trials. This prompted a call in the literature for prospective studies evaluating DTG-associated AEs, including PK, sleep architecture analysis and neuropsychological testing, particularly in special populations [20].
 
A high prevalence of sleep disturbances is already described in the HIV population, even in the cART era, (30-73% versus 10-20% in the general population [21, 22]) and it is strongly associated with poorer disease outcomes, cognitive impairment and HIV-associated dementia [21, 23].
 
It is, therefore, important to characterise the role of aging on DTG PK/PD, especially with regards to central nervous system (CNS) toxicity and sleep disturbances. The primary objectives of this study were to describe the steady state PK of DTG 50 mg once daily (OD) in PLWH≥60 years and compare them to a published younger population (from the SINGLE trial [9]). The secondary objectives were to evaluate, in detail, changes in sleep and cognition over six months following a switch from non-DTG-based cART to abacavir (ABC), lamivudine (3TC) and DTG, as a fixed dose combination (FDC) tablet.
 
We hypothesised that age-related changes in drug PK might impact DTG, except its metabolism since it is mainly by UDP-glucuronosyltransferase-1A1 (UGT1A1) and no evidence supports age-related glucuronidation changes [24]. We also expected a reverse-association between sleep/cognition changes and PK parameters, particularly at the high end of the therapeutic range (or higher).
 
METHODS
 
Participants

 
Written informed consent was obtained from male and female PLWH, stable on cART, aged≥60 years with a body mass index (BMI) 18-35 kg/m2. The protocol required that approximately 70% of subjects be ≥65 years (to ensure a variable age range). Eligibility criteria included plasma HIV-RNA<50 copies/mL at screening and no history of treatment failure or documented significant drug resistance on viral genotyping. With ABC use, a negative HLA-B*5701 allele result was required and participants were screened for cardiovascular (CV) risk using the QRISK2 calculator [6, 25] (eligible if 10-year risk of CV event was <20% or if risk factors were well controlled with medication/lifestyle measures). Participants were excluded if they had: significant acute/chronic illnesses; abnormal physical examination, ECG or laboratory determinations or use of known interacting drugs/remedies. No patients had preceding Primary Sleep Disorder diagnoses. The study was approved by the London Central Research Ethics Committee and the Medicines and Healthcare products Regulatory Agency (MHRA) and ran in accordance with Good Clinical Practice and the Declaration of Helsinki (NCT02509195).
 
Study design
 
This was a four-centre, 180-day (excluding screening and follow-up), open-label, prospective PK/PD study. After screening, eligible subjects were switched to ABC/3TC/DTG 600/300/50 mg FDC (Triumeq®) on day 1, one pill OD, orally, in the morning with or without breakfast for the study period, except on day 28. On D28, subjects underwent intensive DTG PK determinations, having fasted for six hours pre-dose and four hours post-dose to match the SINGLE PK sub-study circumstances [9]. Blood samples were collected pre-dose, 1, 2, 3, 4, 8, 12 and 24 hours post-dose. Study medications safety was evaluated using the National Institute of Allergy and Infectious Diseases Division of AIDS (NIAID2004). Medication compliance was assessed through direct questioning and pill count.
 
Collection and quantification of plasma dolutegravir
 
Whole blood samples were collected at each time-point on D28, from an indwelling venous catheter, into 6 mL spray-coated EDTA tubes, Following centrifugation, plasma was aliquoted equally into three 2.0mL tubes (Sarstedt, Germany) and stored at -80oC. Samples were then shipped on dry ice to the Jefferiss Trust Laboratory (Imperial College London). DTG plasma concentrations were determined using ultra-performance liquid chromatography (UPLC) coupled with UV detection [26].
 
The assay calibration range was 0.25-10 mcg/ml, intra-assay variability 3.3%-6.1% and inter-assay variability 4.5%-5.7%. Overall accuracy was between 90.7% and 97.7% for three different quality control sample concentrations. The laboratory adheres to the ARV International Inter-laboratory Quality Control Program [27].
 
Pharmacokinetic and statistical analysis
 
A sample size of 40 subjects was calculated to provide at least 80% power to detect DTG PK parameter changes in older people against 16 controls. The calculated parameters were plasma concentration measured 24 hours after the observed dose (C24), maximum observed plasma concentration (Cmax), area-under-the-plasma-concentration-curve from 0 to 24 hours (AUC0–24) and half-life (t1/2). All PK parameters were calculated using actual blood sampling time and non-compartmental modelling techniques (WinNonlin-Phoenix, version 7.0). Descriptive statistics, including geometric mean (GM), 95% confidence interval (CI) and percentage coefficient of variation (CV%=100*standard deviation/mean) were calculated for DTG PK parameters at all time-points on D28, and compared to those obtained from the SINGLE PK sub-study control HIV population (≤50 years, n =16) [9] using non-parametric Mann-Whitney U test.
 
Sleep and cognitive data collection
 
Six published and validated self-reported paper questionnaires (table1) [28-33], recording different aspects of sleep, were administered to participants at baseline and on days 28, 90 and 180 in order to provide a comprehensive description of sleep quantity, quality and impact on daytime function, wakefulness, mental status and general wellbeing before and after medication switch. Answers to each question were coded as per questionnaire protocols (supplementary material) and entered into Excel for scoring.
 
Neurocognitive testing was carried out on D1 and D180 using the validated, widely used Cogstate® computerised assessment software [34], which evaluates a range of cognitive functions through eight domains: detection (DET)/identification (IDN) (speed of performance); card learning (OCL), one back memory (OBM)/two back memory (TWOB) (accuracy of performance); Groton Maze learning (GML), Groton Maze recall (GMR), and set-shifting (SETS) (number of errors made on testing). Participants completed a mock practice at screening to minimise learning effect.
 
Sleep and cognitive data analysis
 
Sleep baseline characteristics and outcome measures at each time-point were descriptively summarised using medians, interquartile ranges (IQR), and proportions. Composite scores for sleep questionnaires were calculated and interpreted as per questionnaire protocols and cut-offs (table 1). Neurocognitive scores were analysed using Cogstate® recommendations [35]. Changes in cognitive scores were calculated for each subject for each domain (baseline-D180), and were standardised according to the within-subject standard deviation (WSD). The score sign was reversed where appropriate so positive values represent improvement for all domains. A composite score for the change from baseline was calculated by averaging the standardised change scores across all Cogstate® tasks for each individual.
 
As data was not normally distributed, non-parametric tests were used for analysis. Changes in sleep and cognitive scores from baseline to each time-point were tested for significance using the Wilcoxon sign-rank test. Spearman's correlation examined correlations between outcomes and DTG PK parameters.
 
As efavirenz use is associated with NP-AEs, especially sleep disturbances [6], a sub-analysis was conducted using the Mann-Whitney test to compare individuals who switched from an efavirenz-based regimen to those who didn't, thereby preventing efavirenz removal from potentially masking DTG effects.
 
Internal consistency was evaluated for outcomes with multiple domains using Cronbach's α and corrected component-total Spearman's rho (rs) correlationsα (≥.70 and rs ≥.30 indicated adequate internal consistency). Correlation between different sleep questionnaires was evaluated at baseline to determine the level of agreement.
 
Statistical analyses were performed using Stata (version 14.1) and GraphPad Prism (version 7.03). In the analyses, p-values, uncorrected and corrected for multiple comparisons, were calculated; p<0.05 was deemed significant.
 
RESULTS
 
Study population

 
Fifty-three subjects were screened; 43 enrolled and received at least one study drug dose. Three/43 participants withdrew before D28 and could not be included in the PK analysis (two moved abroad and one experienced fatigue and photosensitivity attributed to the study drugs). Forty participants completed the PK phase and 38 attended the final study visit (D180). One participant withdrew secondary to insomnia/vivid dreams (resolved by switching to tenofovir/emtricitabine/raltegravir) and the other withdrew for job relocation; both were included in D28 PK and PD analyses. Subject and control characteristics are summarised in table 2.
 
Dolutegravir plasma pharmacokinetics
 
Figure 1 demonstrates GM DTG concentration-time curves for the observed and control populations. Steady-state PK parameters are summarised in table 3.
 
There were no differences in DTG AUC0-24, C24 or t1/2 between the two populations. However, Cmax (approximately two hours post-dose in both groups) was significantly higher in subjects≥60 years old (GM 4246 versus 3402 ng/mL, p=0.005).
 
Sleep questionnaire results at baseline and follow up
 
Detailed response rates and median (IQR) scores per questionnaire, domain and time-point are in the supplementary file, table A and figure B.
 
• Overall sleep impairment: Pittsburgh Sleep Quality Index (PSQI) [28]
 
Median global PSQI score was higher at D28 versus baseline (5.0 versus 6.0, p=0.02 adjusted for multiple testing) but at no other time-points. No domain achieved statistical significance individually.
 
Internal consistency was acceptable for the global score (α=0.72). Corrected component-total correlations ranged from 0.19 (daytime dysfunction) to 0.66 (quality).
 
• Insomnia: Insomnia Severity Index (ISI) [29]
 
Median (IQR) global ISI scores remained stable (range 5-6.5); four individuals developed moderate insomnia over time (ISI 14-21; not significant) and one subject's severe insomnia (ISI>21) improved whilst another's developed by D28 leading to discontinuation (described above). • Daytime sleepiness: Epworth Sleepiness Scale (ESS) [30]
 
At baseline, 29% individuals were considered 'sleepy' (ESS>10) compared with 24% at D180 (not significant).
 
• Daytime function: Functional Outcomes of Sleep Questionnaire (FOSQ) [31]
 
Median (IQR) global FOSQ remained stable from baseline to day D180 (range 18.01-18.81/20) with a generally good level of daytime function across the cohort.
 
• Fatigue severity: Fatigue Severity Scale (FSS) [32]
 
At baseline, four/39 (10%) individuals reported having fatigue; this was 20% on D180 (not significant).
 
• Risks for possessing a sleep disorder: Sleep Disorder Questionnaire (SDQ) [33]
 
No participants met the diagnostic criteria at baseline for any of the four sleep disorders tested and no significant change in scores was observed over time.
 
• Correlation between sleep measures
 
There was a significant correlation between all sleep measures evaluated by more than one questionnaire across all scores at baseline (.37r<.83; p<.05).
 
• Sleep scores by efavirenz status
 
Seventeen/40 (43%) subjects switched from an efavirenz-based combination. At baseline, some measurements appeared worse in individuals who did not switch from efavirenz. No significant difference was observed between groups in overall score changes at each time-point compared to baseline for all questionnaires except ISI, which improved over 180 days in participants without efavirenz in their previous regimen and worsened in those with (p=0.02); however this did not remain after adjustment for multiple comparisons (p>0.05) (supplementary file, table C).
 
• Relationship between sleep scores and PK parameters
 
There was no correlation between DTG PK parameters and D180 sleep scores or intra-subject change in global scores over 180 days (delta test scores) (figure 2; supplementary file, tables D and E). To rule out an effect dependent on a drug level threshold, the Mann-Whitney test was used to compare delta test scores in subjects with Cmax above the upper quartile (Q4) to those below (Q1-3). There were no differences (0.62< p-value<1.0); nor with 95th centile Cmax used as threshold (0.13< p-value<0.73). Similarly, there was no difference in Cmax between D180 test score or delta test score low and high quartile groups for all sleep questionnaires ((0.31≤p-value≤0.66 and 0.63< p-value<1.0).
 
Changes in cognitive scores (table 4)
 
Between baseline and D180, no change in global cognitive composite scores and individual domain scores was observed over time except GML (executive function) where a significant improvement from baseline to D180 was seen (median change (IQR) 0.32 (0-0.74), unadjusted p=0.002).
 
There was no correlation between C24 and AUC0-24 and D180 cognitive function or delta cognitive scores (individual domains and global composite scores; p=0.07). Unexpectedly, higher Cmax was associated with improvements in global cognitive function (r=0.39, p=0.02; figure 2). The improvement in median (IQR) delta score was higher in those with a Cmax>upper 95%CI than in those below (p=0.0195).
 
Clinical safety and efficacy
 
Two/43 (4.6%) participants discontinued the study secondary to AEs (described above). In the remaining subjects, there were no virological failures or grade 3 or 4 toxicity following treatment initiation. The studied FDC was well tolerated.
 
DISCUSSION
 
We characterized the steady-state PK of DTG 50 mg OD in an aging HIV population, mostly over 65 years, the age associated with potential changes in drug PK [24]. Compared to the younger control group, Cmax was significantly higher (25%) in those ≥60, indicating increased DTG absorption. Whilst the net effect of age-related physiological intestinal changes (e.g. reduction in pH, gastrointestinal motility etc.) on the absorption of most drugs is thought to be minimal [3], our findings could be explained by age-related alterations in expression of active DTG efflux transporters, such P-gP (P-glycoprotein) and BCRP (breast cancer resistance protein), across epithelial cells in the gastrointestinal tract [3, 24, 36]; however further research is required. There were no differences in DTG C24, AUC0-24 or t1/2 between the two groups, supporting a lack of age-associated effect on the main DTG metabolic pathway (UGT1A1).
 
To address the call for prospective PD data [20, 37], we also describe the first post-marketing analysis of sleep and cognition-related PD changes, over 180 days following a switch to ABC/3TC/DTG. DTG-related NP-AEs (including insomnia) are an emerging concern [14-18] and older age has been described as an independent risk factor [13, 16, 19]. In our study, two participants discontinued DTG because of NP-AEs (4.6%), which is consistent with published cohorts (1.7-8%). However, when investigating sleep quality and Cogstate status in those who continued the drug, we only observed a small increase in PSQI scores at D28, which resolved by D90, and a non-significant trend towards an increase in FSS score. Other scores remained stable or improved following the introduction of DTG. Whilst the one subject who withdrew secondary to NP-AEs had elevated levels of DTG, we did not find any association between DTG PK parameters and changes in sleep scores in the remaining subjects over time, which is in keeping with observations from Riva [38] and Hoffman [39]. There were also no changes in sleep scores in subjects with very high drug concentrations in whom, surprisingly, cognition improved significantly. These interesting findings suggest that the mechanisms of DTG-related neurotoxicity are likely to be more complex than a simple linear or threshold-defined PK relationship and may relate to a combination of factors, including pharmacogenetic, immune and/or functional predispositions.
 
Of interest, Yagura et al found that DTG C24h (≥1.06 μg/mL) correlated with CNS side effects in younger Japanese PLWH. No significant difference in DTG concentration was, however, observed with individual symptoms or insomnia. The researchers subsequently reported a weak association with UGT1A1*6 and UGT1A1*28 alleles [40].
 
Capetti et al. found DTG-related sleep disorders resolved in some patients switching to morning dosing (0.9% versus 3.5%) [19]. In our study, subjects were dosed in the morning to allow for steady state PK measurements; this could partially explain the absence of new sleep disturbances, although others researchers report unchanged rates with morning dosing [20, 40]. Our subject population was a group of only mildly sleep-disturbed individuals from baseline, which may also partially explain the lack of positive findings in those who completed the study. Overall, whilst sleep impairment rates (PSQI>5) at baseline, matched that historically reported in the HIV literature (44-51%), scores were only just in the lower range of abnormal (≤7). Additionally, the prevalence of subjects with moderate insomnia (ISI) in our cohort (7-21%) is below that previously reported in PLWH [21].
 
Controlling for a switch from efavirenz did not change the lack of positive results, likely due to the fact that efavirenz subjects in our study were those who do not experience sleep disturbances on it.
 
There are limitations to our study. Our subjects were predominantly male, thereby not fully representative of real life cohorts. DTG NP-AEs are thought to be higher in women, but this is an independent risk factor. Importantly, our study was not powered to detect changes in sleep quality but for the ability to detect PK differences between younger and older PLWH, PD results should therefore be interpreted with caution (although our numbers mirrored previous HIV sleep studies [21] and consistency across sleep tools (measuring the same effect) suggest that results are accurate). Furthermore, the use of self-reported questionnaires may compromise intra- and inter-subject consistency and lead to recall bias. The effect of suggestion may also introduce bias as was proposed by the authors of the SINGLE trial (efavirenz versus DTG) [9] to explain higher rates of DTG-related sleep disturbances. Although validated in the general population, our sleep questionnaires are not validated in aging PLWH. However, a good correlation between direction changes, reflects good inter-questionnaire reliability. Finally, the use of historical controls is a limitation, which should be addressed in future studies with a larger and active control arm.
 
The strengths of our study lie in its prospective and controlled design, investigating a special population growing in size and in need of data to tailor HIV treatment appropriately. Additionally, we are the first group to characterise detailed sleep and cognitive data in PLWH following Triumeq® introduction and to explore the DTG PK/PD relationship in aging PLWH. The use of multiple questionnaires allowed a more comprehensive evaluation of sleep and its effects than previously reported.
 
In conclusion, we showed a significantly higher DTG Cmax in PLWH≥60 versus younger subjects. The discontinuation rate was similar to previous real-life reports but the Cmax increase was not associated with sleep or cognitive decline over six months. This data informs physicians and patients on the safety and tolerability of DTG in older patients, particularly following the early period where careful monitoring remains recommended [11]. __

 
 
 
 
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