Combined antiretroviral treatments (ARVs) have increased the life expectancy of people living with HIV (PLWH) close to the general population . Consequently, PLWH have an identical high prevalence for age-related comorbidities, such as cardiovascular conditions, leading to complex drug associations with a higher risk for drug--drug interactions (DDIs) . One current issue is the lack of knowledge concerning the magnitude and clinical management of DDIs in aging PLWH. However, despite the high DDI potential of ARVs, it is neither feasible nor ethically possible to conduct clinical studies for every single drug combination. Additionally, elderly PLWH are underrepresented in clinical studies. The decline in hepatic and renal blood flow and in the glomerular filtration rate drives age-related pharmacokinetic changes of non-HIV drugs and likely impacts ARV pharmacokinetics . The impact of aging on metabolizing enzymes and drug transporters activity is either controversially discussed or lacking in the literature , which in addition to pharmacokinetic alterations could both affect the magnitude of DDIs in the elderly.
The aim of this study was to quantify the DDI magnitudes between cardiovascular drugs (i.e. amlodipine, atorvastatin, rosuvastatin) and ARVs in aging PLWH to provide guidance on DDI management in this fragile population.
This was a prospective clinical study including PLWH aged at least 55 years in Lausanne and Basel that are enrolled in the Swiss HIV Cohort Study . Included PLWH received amlodipine, atorvastatin and/or rosuvastatin with a dolutegravir or a boosted darunavir-containing regimen. PLWH were excluded if they had severe comorbidities, such as advanced renal impairment (KDOQI 4-5); heart failure (NYHA 3-4); cirrhosis (Child-Pugh score C) or if they were receiving comedications with inhibitory or inducing properties. Consenting PLWH came to the HIV clinic in the morning for the collection of serial blood samples over 24 h. The Ethics Committee of Vaud and Northwest/Central Switzerland approved the study protocol (CER-VD 2018-00369), which is registered at ClinicalTrials.gov (NCT03515772). Written informed consent was collected for each participant.
Plasma samples were isolated by centrifugation and stored at -80 °C until batch analysis. Plasma levels determination was performed in the Laboratory of Clinical Pharmacology in Lausanne, using liquid chromatography coupled with tandem mass spectrometry .
All doses were normalized as amlodipine, atorvastatin, and rosuvastatin exhibit dose-proportional pharmacokinetics. Pharmacokinetic parameters were calculated noncompartmentally from the measured concentration--time profiles in Matlab 2017a. The mean and standard deviation (SD) of the area under the curve (AUC) were calculated for the comedication received with either dolutegravir or boosted darunavir. The DDI magnitudes were calculated as the AUC of the comedication in the presence of boosted darunavir [inhibitory effects on cytochrome P450 3A4 (CYP3A4) and/or hepatic/intestinal transporters] divided by the AUC of the comedication in the presence of dolutegravir (no inhibitory effects).
A structured literature search was performed using the MEDLINE database to screen for studies investigating the same DDI magnitudes in young adults to evaluate the impact of aging.
A total of 21 white PLWH (four women) aged 56–80 years were included in the study. Amlodipine was taken by eight PLWH (dolutegravir: n = 6; boosted darunavir: n = 2) aged 64.8 ± 7.0 years. The AUC of amlodipine (dose-normalized to 5 mg) was 1155 ± 414 and 2425 ± 739 ng h/ml in combination with dolutegravir and boosted darunavir, resulting in an AUC-ratio of 2.10 ± 0.99 (Table 1). In young adults aged 20–50 years, the increase in amlodipine exposure in the presence of boosted indinavir was 1.89  and in the presence of ritonavir was 2.11 .
Atorvastatin was investigated in nine aging PLWH (dolutegravir: n = 4; boosted darunavir: n = 5) aged 64.1 ± 8.0 years at a dose of 10 mg. The AUC of atorvastatin in the presence of dolutegravir was 31.4 ± 4.7 ng h/ml and increased to 193 ± 133 ng h/ml in PLWH receiving boosted darunavir. The resulting AUC ratio was 6.16 ± 4.35. No study could be identified in young individuals for atorvastatin in the presence of boosted darunavir, but for boosted saquinavir (AUC ratio: 3.93)  and boosted tipranavir (AUC ratio: 9.36) .
Rosuvastatin was administered to six PLWH (dolutegravir: n = 2 boosted darunavir: n = 4) aged 67.7 ± 5.3 years and concentrations were dose-normalized to 10 mg. The rosuvastatin AUC in the presence of dolutegravir and boosted darunavir was 104.2 ± 32.6 and 166.9 ± 75.5 ng h/ml. The resulting AUC ratio was 1.60 ± 0.88. One clinical study investigated rosuvastatin exposure in the presence of boosted darunavir in young adults aged 20–50 years and reported an AUC ratio of 1.57 ± 0.54 .
Clinical studies concerning the impact of aging on DDI magnitudes involving ARVs do not exist, leading to uncertainty concerning the clinical management of DDIs in aging PLWH. To our knowledge, our study is the first to investigate DDIs of commonly used comedications (amlodipine, atorvastatin, rosuvastatin) and boosted darunavir in PLWH aged at least 55 years. The obtained AUC ratios in aging PLWH were in the same range as DDI magnitudes reported in young individuals aged 20--50 years, thus, demonstrating that aging has a marginal impact on DDI magnitudes.
Two clinical studies with midazolam and clarithromycin (inhibition) or rifampicin (induction) elucidated no age-related changes of the DDI magnitudes, which support our study results [12–14].
Several limitations should be acknowledged. Firstly, the small number of patients led to an observational study design. Nevertheless, the obtained clinical data show the real-life scenario of amlodipine, atorvastatin, and rosuvastatin in aging PLWH receiving boosted darunavir. Secondly, concentration--time profiles for the comedications in the presence of dolutegravir and boosted darunavir came from two different groups of patients because of medical and ethical reasons. Thirdly, clinical data for our investigated DDIs in young individuals were not obtained in the same study but gathered from published clinical trials that did not administer the same protease inhibitors as in our study. In the case of amlodipine, ritonavir itself is enough to inhibit CYP3A4 completely and thus, the second protease inhibitor can be neglected . In the case of atorvastatin, the inhibition of OATP1B1 (organic anion transporting polypeptide) and P-gp (P-glycoprotein) adds to the CYP3A4 inhibition. Saquinavir and ritonavir show the least impact on OATP1B1 followed by darunavir and tipranavir with the latter one being a strong P-gp inhibitor [16,17]. Therefore, our results for atorvastatin and boosted darunavir are in line with published studies using either saquinavir or tipranavir.
In conclusion, our clinically observed data demonstrate that DDI magnitudes between ARVs and comedications appear to be similar in aging PLWH compared with young individuals and thus, the clinical management of DDIs can be similar. Further research is warranted in the future to investigate more DDI scenarios with a larger study population including more women to further support the clinical management of DDIs in aging PLWH.
This work was supported by two Swiss National Science Foundation grants (Grant No: 166204 for Basel and 165956 for Lausanne), the OPO Foundation, and the Isaac Dreyfus Foundation (Basel).
The authors would like to thank the patients for supporting the clinical studies. We also like to thank the study nurses (Ms Deolinda Alves and Valérie Sormani, and Ms Silke Purschke and Vanessa Grassedonio) from the Service of Infectious Diseases at the University Hospital of Lausanne, and the Clinical Trial Unit at the University Hospital Basel for conducting the full pharmacokinetic clinical investigations. The support of the Swiss HIV Cohort Study is highly acknowledged. Members of the Swiss HIV Cohort Study are:
Aebi-Popp K, 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.
Source of funding: Swiss National Science Foundation (Grant No: 166204, 165956), the OPO Foundation, and the Isaac Dreyfus Foundation.
Authors contributions: study design and documentation to support the clinical study: F.S., C.M., P.C.; recruitment of participants: M.S., M.C., M.B., C.M., P.C; laboratory work: L.A.D., S.A.S., P.C.; analysis and interpretation of data: F.S., C.M., P.C.; manuscript draft: F.S., P.C. Critical review and approval of manuscript: all authors.
Conflicts of interest
F.S., L.A.D., M.B., P.C. declare no conflict of interest. M.S.'s institution received honoraria for advisory boards from Gilead, Mepha, MSD, Sandoz and ViiV Healthcare. M.S. received travel grants from Gilead and MSD. 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.
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