Effective antiretroviral therapy has reduced mortality significantly; thus, increasing life expectancy of people living with HIV (PLWH) closer to the general population . At the end of 2016, more than 40% of active patients in the Swiss HIV Cohort Study (SHCS) were over the age of 50 years . Mathematical models informed by data from United States, Italian, and Dutch HIV cohorts have projected that 40% of the HIV population will be greater than 60 years in 2030 [3,4]. As older PLWH are usually underrepresented in clinical trials , the impact of aging on the pharmacokinetics of antiretroviral drugs (ARVs) and related need for a dose adjustment are unclear.
Advanced age is characterized by anatomical, physiological and biological changes that have the potential to alter drug pharmacokinetics [6,7]. A major characteristic is the decreased hepatic and renal clearance and hence declined drug elimination with advanced age . Available, studies suggest that the concentrations of raltegravir and efavirenz are not significantly altered in PLWH 45–79 years and more than 60 years whereas protease inhibitors were shown to be mostly increased [8–10]. Finally, dolutegravir maximal concentrations were increased by 25% in PLWH at least 60 years .
A major limitation for most of these studies is the inclusion of individuals below 65 years. Although age of 50 years has been commonly accepted in the HIV field to define an ‘elderly’ [12,13], the WHO recommends 65 years as an age-cut-off . A pharmacological or clinical definition of an ‘elderly’ remains challenging because the aging process is not uniform across the population .
Therefore, a knowledge gap currently exists about the impact of older age on ARV pharmacokinetics and there is a lack of real-life data on aging PLWH. Polymorbidity and polymedication are poorly accounted for in-treatment guidelines, which are largely elaborated for single diseases . However, the elderly might be more susceptible to drug toxicity including ARVs than younger people. Additionally, data from other therapeutic areas suggest that age should be considered when prescribing in the elderly as they may require lower doses to achieve therapeutic efficacy and to avoid adverse events [17–19].
This work aims to compare boosted darunavir, dolutegravir and lamivudine plasma exposures between aging (≥65 years) and younger (<65 years) PLWH involved in two observational studies to better document pharmacokinetics of ARVs in this growing vulnerable population.
Study design and participants
Full pharmacokinetic investigations
These investigations were performed using a prospective and observational design and included PLWH enrolled in the SHCS and followed up in the centers of Lausanne and Basel. Male and female PLWH were eligible if they were aged 55 years or older and treated with a boosted darunavir or dolutegravir-containing regimen. Exclusion criteria were the coadministration of inhibiting or inducing comedications as well as the presence of severe comorbidities [i.e. cirrhosis (Child-Pugh score C), heart failure (NYHA 3–4), advanced kidney impairment (KDOQI 4–5)]. Participants arrived in the clinic in the morning of the full pharmacokinetic investigation and took their ARV treatment in front of the study nurse. Serial blood samples were collected at steady state, at the following time-points: t = 0 (just before the drug intake) and 30 min, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h after the drug intake.
All study participants gave written informed consent before entering the study. The study protocol was reviewed and approved by the Ethics Committee of Vaud and northwest/central Switzerland (CER-VD 2018–00369) and registered in ClinicalTrials.gov (NCT03515772).
Single point measurements
Single point measurements for therapeutic drug monitoring (TDM) of boosted darunavir and dolutegravir were collected in the framework of SHCS follow-up visits for PLWH attending the HIV clinics in Lausanne and Basel. One week before their biannual cohort visit, PLWH received a reminding letter with a form to fill out all their current medications and date/time of the last drug intake. Clinical nurses collected the forms, performed and documented blood sampling. TDM concentrations were measured at unselected times after the last drug intake.
Plasma concentration determination
All plasma level measurements were performed at the Laboratory of Clinical Pharmacology of the University Hospital of Lausanne. Blood samples were collected and centrifuged in EDTA-containing tubes. Plasma were aliquoted and shipped frozen (Basel samples) and were stored at −80 °C until analysis by several liquid chromatography tandem mass spectrometry (LC-MS/MS) methodologies, reported in refs. [20–22]. LC-MS/MS assay for plasma determination of elvitegravir and rilpivirine was adapted to include dolutegravir . Lamivudine plasma concentrations were only measured in PLWH participating in the full pharmacokinetic study.
Concentration–time profiles of boosted darunavir, dolutegravir and lamivudine, the most prescribed ARV drugs in the full pharmacokinetic study were plotted to visually compare drug disposition between aging and younger PLWH. Single point concentrations of boosted darunavir and dolutegravir, obtained during TDM and representing mostly younger PLWH, were overlaid to show the effect of aging on pharmacokinetics and to visualize interpatient variability more adequately.
Plasma pharmacokinetic parameters were calculated noncompartmentally using data from the pharmacokinetic study with rich sampling and the PKNCA package in R . The area under the concentration–time curve over a dosing interval (from 0 to τ, AUC0-τ) was calculated using the linear-up log-down method. Peak concentration (Cmax) and time to peak plasma concentration (tmax) were directly retrieved from the R output. Half-life (t1/2) was calculated as ln(2)/λz with λz being the elimination rate constant; apparent clearance (CL/F) as dose/AUC0-τ; and apparent volume (V/F) as (CL/F)/λz. Pharmacokinetic parameters were reported as median and range.
Nineteen PLWH (17 men) with a median age of 64 years (range 56–80 years) participated in the full pharmacokinetic investigations and contributed to 97, 107 and 127 boosted darunavir (n = 9 PLWH), dolutegravir (n = 10 PLWH), and lamivudine (n = 12 PLWH) plasma concentrations, respectively. Darunavir was boosted either with 100 mg of ritonavir (n = 7 PLWH) or with 150 mg of cobicistat (n = 2 PLWH). Boosted darunavir dose varied between participants: 600 mg once daily (one PLWH), 800 mg once daily (two PLWH), 1200 mg once daily (four PLWH) and 600 mg twice daily (two PLWH). Dolutegravir dosage was always 50 mg once daily. Lamivudine dosage was 300 mg once daily except one individual receiving 150 mg once daily. Overall, boosted darunavir, dolutegravir and lamivudine plasma concentrations ranged from 12 to 10 652, 623–6445 and 51–3546 ng/ml, respectively.
In addition, 804 PLWH with a median age of 52 (range 20–86) contributed to the single point TDM measurements, thus adding 244 boosted darunavir and 560 dolutegravir plasma concentrations for visual inspection of data.
No distinct separation was observed between boosted darunavir, dolutegravir and lamivudine plasma concentrations of aging (≥65 years) and younger (<65 years) PLWH (Fig. 1). Although a high variability in boosted darunavir pharmacokinetic parameters was noticed in both age groups, boosted darunavir clearance was 40% lower in elderly compared with younger PLWH. Dolutegravir and lamivudine CL/F were similar between age groups (differences of 13% and 11% for dolutegravir and lamivudine, respectively). Thus, dolutegravir and lamivudine exposures were respectively only 5% and 11% higher in aging PLWH compared with younger individuals. Overall, median boosted darunavir, dolutegravir and lamivudine t1/2 were 148%, 45% and 32% higher in elderly than in younger PLWH (Table 1).
Advanced age does not affect boosted darunavir, dolutegravir, and lamivudine pharmacokinetics to a clinically significant extent.
For the first time, our clinical study evaluated boosted darunavir concentration–time profiles in PLWH at least 65 years. Boosted darunavir exposure tend to be higher in aging PLWH based on visual inspection, as clearance was decreased by 40%. This observation is in line with other drugs being predominantly metabolized by CYP3A in the liver, such as simvastatin , midazolam  and triazolam . In contrast to our results, two population pharmacokinetic analyses of sparse sampling data did not show any significant influence of age on darunavir/ritonavir disposition, but the studied population was skewed towards younger PLWH in both studies [27,28]. Nevertheless, in our study, median clearance values of both investigated age groups were in the range of values reported from compartmental analysis varying from 11 to 20 l/h [27,28]. Between-individual variability of boosted darunavir pharmacokinetics was generally high for all analysed parameters, especially for t1/2, which varied from 4.4 to 44.4 h in aging PLWH. In the individual with the highest observed t1/2, darunavir elimination appeared to be altered with plasma concentrations being relatively stable between 12 and 24 h, but no explanation was found. Median t1/2 in the younger group was similar to that reported in population pharmacokinetic analyses  whereas median t1/2 in aging PLWH is close to the value reported by the manufacturer . Finally, boosted darunavir V/F differed between the two age groups, but variability was also noticed in the literature with values varying from 120 to 1200 l [27,28]. Despite the large observed variability of boosted darunavir pharmacokinetics, aging did not alter pharmacokinetics to a clinically significant extent.
Dolutegravir pharmacokinetic parameters were similar to those reported by the manufacturer  and to a clinical study investigating dolutegravir exposure in PLWH aged 60–79 years . There was no difference in pharmacokinetic parameters except for t1/2, which was 18 h in aging compared with 12.4 h in younger PLWH. Nevertheless, this difference should lead to minor clinical consequences as dolutegravir is usually administered once daily. Between-subject variability was also comparable to population pharmacokinetic analysis of sparse sampling data ranging from 23 to 32% [31–33]. Those models demonstrated a counterintuitive 10% increase in dolutegravir clearance between the age of 40 and 65 years [31,32], which does not result in clinically significant changes considering dolutegravir overall variability.
Our lamivudine pharmacokinetic values are in good accordance with previously published population pharmacokinetic models [34,35]. Clearance distribution is close to that reported by Moore et al. and t1/2 (median: 7.2 h, range: 4.2–9.2 h) is similar to the value of 5–7 h reported in the summary of product characteristics . Lamivudine is mainly cleared by renal elimination and reduced glomerular filtration rate with advanced age could guide clinicians to adjust lamivudine dosage in the elderly. However, our study suggests only a marginal impact of age on lamivudine pharmacokinetics (median clearance of 21.3 and 18.9 l/h in younger and aging PLWH, respectively).
The main limitation of this study is the relatively small number of full pharmacokinetic investigations. However, the comparison with a cohort of younger PLWH allows to demonstrate a lack of significant effect of aging on the pharmacokinetics of ARVs when considering elderly PLWH without severe comorbidities. Furthermore, this study fills the knowledge gap in real-life clinical pharmacokinetic data of ARVs in aging PLWH, which are essential for safe prescribing in this population.
In conclusion, boosted darunavir exposure was highly variable but modestly increased in aging PLWH. Dolutegravir and lamivudine exposure was minimally affected by age. Nevertheless, there is still a need for studies to allow a better understanding of ARV pharmacokinetics in this vulnerable growing population.
This work was supported by two Swiss National grants (Grant number 324730–165956 (Lausanne) and 324730–166204 (Basel), the OPO Foundation and the Isaac Dreyfus Foundation (Basel).
The authors would like to thank the study nurses (Ms Silke Purschke and Vanessa Grassedonio) from the Clinical Trial Unit at the University Hospital Basel for conducting the full PK clinical investigations. In addition, the authors would like to thank the study nurses from the HIV clinics in Lausanne (Alexandra Mitouassiwou-Samba, Deolinda Alves, Rachel Ribeiro, Valerie Sormani, Vreneli Waelti Da Costa) and Basel (Kerstin Asal, Rebekka Plattner, Vreni Werder, Reinhild Harant, Irena Ferati) for collecting blood samples and providing information on drug intake and blood sampling for the interpretation of single point measurements.
Author contributions: Study design and documentation to support the clinical study: P.C., F.S., T.B., C.M. Recruitment of participants: P.C., M.S., M.C., M.B., C.M. Laboratory work: P.C., S.A.S; L.A.D. Analysis and interpretation of data: P.C. and M.G. Manuscript draft: P.C. Critical review and approval of manuscript: all authors.
Members of the Swiss HIV Cohort Study: Anagnostopoulos A, Battegay M, Bernasconi E, Böni J, Braun DL, Bucher HC, Calmy A, Cavassini M, Ciuffi A, Dollenmaier G, Egger M, Elzi L, Fehr J, Fellay J, Furrer H, Fux CA, Günthard HF (President of the SHCS), Haerry D (deputy of ‘Positive Council’), Hasse B, Hirsch HH, Hoffmann M, Hösli I, Huber M, Kahlert CR (Chairman of the Mother & Child Substudy), Kaiser L, Keiser O, Klimkait T, Kouyos RD, Kovari H, Ledergerber B, Martinetti G, Martinez de Tejada B, Marzolini C, Metzner KJ, Müller N, Nicca D, Paioni P, Pantaleo G, Perreau M, Rauch A (Chairman of the Scientific Board), Rudin C, Scherrer AU (Head of Data Centre), Schmid P, Speck R, Stöckle M (Chairman of the Clinical and Laboratory Committee), Tarr P, Trkola A, Vernazza P, Wandeler G, Weber R, Yerly S.
Conflicts of interest
P.C., F.S., M.G., S.A.S., M.B., T.B., L.A.D. declare no conflicts of interest.
M.S. received honoraria for his institution from Janssen-Cilag, ViiV Healthcare for advisory board. M.C.'s institution received research grants from Gilead and Viiv and gave expert opinion to Abbvie, Gilead, MSD, Viiv and Sandoz. M.C. received travel grants from Gilead. C.M. received a research grant from Gilead and speaker honoraria for her institution from MSD.
1. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies
. Lancet HIV
2. Swiss HIV Cohort Study. Available at: http://www.shcs.ch/
. [Accessed 7 August 2017]
3. Smit M, Brinkman K, Geerlings S, Smit C, Thyagarajan K, Sighem A, et al. Future challenges for clinical care of an ageing population infected with HIV: a modelling study
. Lancet Infect Dis
4. Smit M, Cassidy R, Cozzi-Lepri A, Quiros-Roldan E, Girardi E, Mammone A, et al. Projections of noncommunicable disease and healthcare costs among HIV-positive persons in Italy and the U.S.A.: a modelling study
. PloS One
5. Watts G. Why the exclusion of older people from clinical research must stop
6. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications
. Br J Clin Pharmacol
7. Stader F, Siccardi M, Battegay M, Kinvig H, Penny MA, Marzolini C. Repository describing an aging population to inform physiologically based pharmacokinetic models considering anatomical, physiological, and biological age-dependent changes
. Clin Pharmacokinet
8. Calza L, Colangeli V, Magistrelli E, Bussini L, Conti M, Ramazzotti E, et al. Plasma trough concentrations of darunavir/ritonavir and raltegravir in older patients with HIV-1 infection
. HIV Med
9. Crawford KW, Spritzler J, Kalayjian RC, Parsons T, Landay A, Pollard R, et al. AIDS Clinical Trials Protocol 5015 Team. Age-related changes in plasma concentrations of the HIV protease inhibitor lopinavir
. AIDS Res Hum Retroviruses
10. Winston A, Jose S, Gibbons S, Back D, Stohr W, Post F, et al. UK Collaborative HIV Cohort Study. Effects of age on antiretroviral plasma drug concentration in HIV-infected subjects undergoing routine therapeutic drug monitoring
. J Antimicrob Chemother
11. Elliot ER, Wang X, Singh S, Simmons B, Vera JH, Miller RF, et al. Increased dolutegravir peak concentrations in people living with human immunodeficiency virus aged 60 and over, and analysis of sleep quality and cognition
. Clin Infect Dis
12. Cuzin L, Katlama C, Cotte L, Pugliese P, Cheret A, Bernaud C, et al. Dat’AIDS Study Group. Ageing with HIV: do comorbidities and polymedication drive treatment optimization?
. HIV Med
13. McNicholl IR, Gandhi M, Hare CB, Greene M, Pierluissi E. A pharmacist-led program to evaluate and reduce polypharmacy and potentially inappropriate prescribing in Older HIV-positive patients
14. World Health Organization. Definition of an older or elderly person. 2010. Available at: https://www.who.int/healthinfo/survey/ageingdefnolder/en/
. [Accessed 27 June 2018]
15. Singh S, Bajorek B. Defining ‘elderly’ in clinical practice guidelines for pharmacotherapy
. Pharm Pract (Granada)
16. Vigouroux C, Bastard JP, Capeau J. Emerging clinical issues related to management of multiorgan comorbidities and polypharmacy
. Curr Opin HIV AIDS
17. Lee HC, Tl Huang K, Shen WK. Use of antiarrhythmic drugs in elderly patients
. J Geriatr Cardiol
18. Marzolini C, Livio F. Prescribing issues in elderly individuals living with HIV
. Expert Rev Clin Pharmacol
19. Vass M, Hendriksen C. Medication for older people–aspects of rational therapy from the general practitioner's point of view
. Z Gerontol Geriatr
20. Aouri M, Calmy A, Hirschel B, Telenti A, Buclin T, Cavassini M, et al. A validated assay by liquid chromatography-tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV positive patients
. J Mass Spectrom
21. Courlet P, Spaggiari D, Cavassini M, Du Pasquier RA, Alves Saldanha S, Buclin T, et al. Determination of nucleosidic/tidic reverse transcriptase inhibitors in plasma and cerebrospinal fluid by ultra-high-pressure liquid chromatography coupled with tandem mass spectrometry
. Clin Mass Spec
22. Fayet A, Beguin A, Zanolari B, Cruchon S, Guignard N, Telenti A, et al. A LC-tandem MS assay for the simultaneous measurement of new antiretroviral agents: raltegravir, maraviroc, darunavir, and etravirine
. J Chromatogr B Analyt Technol Biomed Life Sci
23. Denney WS, Duvvuri S, Buckeridge C. Simple, automatic noncompartmental analysis: the PKNCA R Package
. J Pharmacokinet Pharmacodynamics
24. Cheng H, Rogers JD, Sweany AE, Dobrinska MR, Stein EA, Tate AC, et al. Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin
. Pharm Res
25. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics
26. Greenblatt DJ, Divoll M, Abernethy DR, Moschitto LJ, Smith RB, Shader RI. Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity
. Br J Clin Pharmacol
27. Arab-Alameddine M, Lubomirov R, Fayet-Mello A, Aouri M, Rotger M, Buclin T, et al. Swiss HIV Cohort Study. Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals
. J Antimicrob Chemother
28. Molto J, Xinarianos G, Miranda C, Pushpakom S, Cedeno S, Clotet B, et al. Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients
. Clin Pharmacokinet
29. European Medicine Agency. Prezista, summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/prezista-epar-product-information_en.pdf
. [Accessed 15 July 2019]
30. European Medicine Agency. Tivicay, summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/tivicay-epar-product-information_en.pdf
. [Accessed 15 July 2019]
31. Barcelo C, Aouri M, Courlet P, Guidi M, Braun DL, Gunthard HF, et al. Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting
. J Antimicrob Chemother
32. Zhang J, Hayes S, Sadler BM, Minto I, Brandt J, Piscitelli S, et al. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients
. Br J Clin Pharmacol
33. Francois P, Patrick M, Florence B, Marie-Claude G. Dolutegravir population pharmacokinetics in a real-life cohort of people living with HIV infection: a covariate analysis
. Ther Drug Monit
34. Bouazza N, Treluyer JM, Ghosn J, Hirt D, Benaboud S, Foissac F, et al. Evaluation of effect of impaired renal function on lamivudine pharmacokinetics
. Br J Clin Pharmacol
35. Moore KH, Yuen GJ, Hussey EK, Pakes GE, Eron JJ Jr, Bartlett JA. Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials
. Antimicrob Agents Chemother
36. European Medicine Agency. Epivir, summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/epivir-epar-product-information_en.pdf
. [Accessed 15 July 2019]
* Laurent Arthur Decosterd Catia Marzolini are equal contributors to the work.