Antiretroviral therapy in elderly individuals living with HIV Catia Marzolini University Hospital & University of Basel University of Liverpool Disclosures Research Grant: Gilead Speaker: MSD, Gilead Aging of HIV population Age distribution of PLWH in the SHCS Proportion of > 50 years old PLWH in a multi-site cohort in Brazil 100% % patients 80% >70 60% 61-70 51-60 40% 41-50 31-40 21-30 20% 18-20 0% 86 88

90 92 94 96 98 year 00 02 04 06 08 10 12 14 16 Mathematical models using data from US, Italian and Dutch HIV Cohort project that 30-40% of PLWH will be > 60-65 years with > 3 comorbidities by 2030-2035. Smit M et al. Lancet Infect Dis 2015; Smit M et al. PLoS One 2017 PLWH > 50 years old prevalence of > 2 comorbidities prevalence of > 3 comorbidities Most common comorbidities: hyperlipidemia and diabetes

Castilho JL et al. J Int AIDS Soc 2019 Polypharmacy in PLWH and uninfected individuals Prevalence of polypharmacy (> 5 non-HIV drugs) in PLWH and uninfected individuals who picked up prescription drugs in hospital and community pharmacies in the region of Madrid P values refer to comparisons of proportions of patients with polypharmacy ( 5 Co-meds) between groups Lopez-Centeno B et al. Glasgow HIV Conference 2018 Prevalence of polypharmacy in PLWH Reference Country N Age Polypharmacy Livio F et al. Int Work Clin Pharm HIV 2018 Switzerland 111 > 75 60 % Courlet P et al. CROI 2019 Switzerland 131 > 65

46 % Guaraldi G et al. BMC Geriatr 2018 Italy 1258 > 65 37 % Justice A et al. AIDS 2018 USA 1311 > 65 43 % Halloran MO et al. Antivir Ther 2019 UK/Ireland 698 > 50 30 % Lopez-Centeno B et al. HIV Drug Ther, Glasgow 2018 Spain 10073 > 50

47 % Nunez-Nunez M et al. Farm Hosp 2018 Spain 242 > 50 48 % Ruzicka DJ et al. BMJ Open 2018 Japan 526 > 50 35% Ssonko M et al. BMC Geriatr 2018 Uganda 411 > 50 15 % Krentz H et al. AIDS Pat Care STDS 2016 Canada 386

> 50 43 % Holtzman C et al. J Gen Intern Med 2013 USA 1312 > 50 54 % Consequences of polypharmacy Polypharmacy > 5 medications Nonadherence Drug-drug interactions Possible causes: Side effets High pill burden Complex dosing regimens Depression Neurocognitive impairment Size of tablets Limited health literacy

(misunderstanding of instructions) Health beliefs (being unconvinced about necessity of medication) Adverse drug reactions Most common drug classes associated with ADR in elderly: Cardiovascular drugs Diuretics Anticoagulants NSAIDs Antidiabetics Geriatric syndromes Falls Cognitive decline Orthostatic hypotension Older PLWH receive more medications and therefore are at > risk for DDIs between HIV/non-HIV drugs and between non-HIV/non-HIV drugs Shah B et al. Clin Geriatr Med 2012, Gellad WF et al. Am J Geriatr Pharmacother 2011, Halloran MO et al. Antivir Ther 2019 Aging & comorbidities pose additional therapeutic challenges Drug-disease interactions

Examples Disease Drug Potential adverse reaction Diabetes corticosteroids increase in blood glucose level Parkinson antipsychotics aggravation of movement disorder Renal failure NSAIDs decrease of glomerular filtration rate Age associated changes in pharmacokinetics PK parameter Altered physiology with aging Comments Absorption gastric pH modification of drug absorption Distribution

albumin body fat lean muscle and total body water free fraction of drugs Vd of lipophilic drugs plasma concentration of hydrophilic drugs Metabolism hepatic mass hepatic blood flow reduced hepatic clearance Elimination kidney mass glomerular filtration rate renal blood flow reduced renal clearance Wooten JM. South Med J 2012, Marzolini C et al. Expert Rev Clin Pharmacol 2019 PK of ritonavir (100 mg QD) in elderly & magnitude of DDIs in elderly Adults aged 20-50 years Adults aged 55-60 years Adults aged 65-80 years Impact of age on DDI magnitude AUC Rivaroxaban + DRV/r AUC Rivaroxaban alone DRV/r +/- rivaroxaban

Observed clinical data Mean of all predictions Mean of each virtual trial men women 95% CI of predictions DDIs have a similar magnitude in elderly compared to young adults Advanced age does not impact ritonavir exposure to a clinically significant extent Dumond J et al. HIV Medicine 2013; Stader F et al. International Workshop Clin Pharmacol Antivir Ther 2019; Stader F et al. CROI 2019 Aging & comorbidities pose additional therapeutic challenges Age associated changes in pharmacodynamics: - changes in affinity of some medications to receptor sites or in number of receptors affect efficacy or increase sensitivity to certain drugs - regulation of some physiologic processes (i.e renal hemodynamics) altered with aging Examples Drug class Potential PD issues Comments Antihypertensives orthostatic hypotension start with lower dose Benzodiazepines sensitivity (sedation, confusion)

use with caution and for short period of time, use lowest dose Opioids sensitivity use with caution, use lowest dose -blockers -receptors function may require -blocker dose Diuretics sensitivity drug effect monitor blood pressure and electrolytes Vitamin K antagonists sensitivity (inhibition synthesis of vitamin K dependent clotting factors) start with lower dose and adjust based on INR Anticholinergic agents sensitivity (delirium, dry mouth, avoid constipation, urinary retention, cognitive impairment, falls)

Wooten JM. South Med J 2012, Marzolini C et al. Expert Rev Clin Pharmacol 2019 Drugs with anticholinergic effects and cognitive performance worse cognitive performance Cognitive performance Total number of anti-cholinergic drugs Rubin L et al. JAIDS 2018 Selected anticholinergic drugs amitriptyline clozapine imipramine promethazine atropine darifenacin nortriptyline scopolamine chlorpheniramine desipramine olanzapine thioridazine chlorpromazine

diphenhydramine oxybutynin tolterodine clomipramine doxepin paroxetine trimipramine Boustani M et al. Aging Health 2008 www.hiv-druginteractions.org www.hiv-druginteractions.org Prevalence of prescribing issues in SHCS patients > 75 years Overall prescribing issues : 69% participants www.hiv-druginteractions.org Incorrect drug dosage: 25% No indication: 21% Prescription omission: 19% Inappropriate drug: 19%

Deleterious DDIs: 14% Treatment duration exceeding recommendations: 2% 40% of the prescribing issues could possibly lead to deleterious clinical consequences Prescribing issues more frequent with non-HIV comeds Education on geriatric medicine principles and periodic review of prescriptions could reduce polypharmacy and prescribing errors WEPEB314 Cabanilla G et al. Risk of polypharmacy and inappropriate prescribing in persons living with HIV > 65 years of age Livio F. International Workshop Clin Pharmacol Antivir Ther 2018 Interventions to limit/manage polypharmacy 1) Medication reconciliation Establish list of current prescription & over-the-counter drugs to be updated at each medical visit 2) Periodic medication review Check indication discontinuation of unecessary drugs Identify medications treating adverse effects of other medications discontinue drug that is causing side effect if possible Check dosing of medications simplification of dosing regimen when possible Check for drug-drug interactions ARV with low DDI potential when possible Check for inappropriate drugs in elderly Check for any missing medicine Beers and STOPP/START criteria 3) Medication prioritization Consider risk/benefit of each medication within the context of a given patients care goals, current level of functioning, life expectancy and preference Shah B et al. Clin Geriatr Med 2012, Edelman E et al. Drugs Aging 2013, OMahony D et al. Age and Ageing 2015, American Geriatrics Society. J Am Geriatr Soc 2015 Risk and cost associated with DDIs in elderly PLWH Frequency, risks and costs attributable to red flag DDIs (Liverpool database) using French nationwide health e-records for 2016:

9076 PLWH, mean age: 71 + 5 years, median non-HIV comeds (IQR): 14 (9-21) 16.8% > 1 DDI, unboosted INI associated with lower risk for DDI (OR: 0.02), boosted PIs increased risk for DDI (OR: 4.12) Presence of DDIs associated with additional 2693 USD/year Incidence DDI (100 person-years) Incidence of DDI per 100 person-years 10 most frequent encountered DDIs PI Risk 68.7 Cushing syndrome 58.7 57.8 ARV efficacy NNRTI hypotension & cardiac disorders severe hypotension QT prolongation QT prolongation INSTI 28.9 29.4 rhabdomyolysis 6.5

ATV ATV/r DRV/r LPV/r RPV ETV bleeding 3.4 NVP 1.3 EFV EVG/c 0.5 0.2 DTG RAL respiratory depression & hematologic abnorm. QT prolongation Desmessine L et al. Open Forum Infect Dis 2019 Mechanisms of drug-drug interactions with antiretroviral agents Inhibition/induction of hepatic cytochromes, glucuronidation, or drug transporters victim doravirine

rilpivirine bictegravir dolutegravir raltegravir maraviroc perpetrator PI/r PI/c elvitegravir/c efavirenz etravirine nevirapine Inhibition of renal drug transporters victim perpetrator tenofovir bictegravir dolutegravir cobicistat ritonavir Inhibition/induction intestinal cytochromes or drug transporters Metabolism victim perpetrator doravirine rilpivirine bictegravir

Tenofovir (TDF, TAF) maraviroc PI/r PI/c elvitegravir/c Change gastric pH liver Absorption victim atazanavir rilpivirine Chelation with mineral supplements Excretion victim kidney small intestine bictegravir dolutegravir elvitegravir/c raltegravir Marzolini C et al. Expert Rev Clin Pharmacol 2019 Drug-drug interactions profiles of antiretroviral drugs boosted ARV Efavirenz

no interaction interaction of clinical relevance n 700 comedications Raltegravir Dolutegravir Bictegravir Etravirine Doravirine Rilpivirine Interaction of weak clinical relevance deleterious interaction www.hiv-druginteractions.org Amber/red DDIs of ARV regimens with treatments of common comorbidities Gibbons S et al. 20th Workshop on Clin Pharmacol of HIV 2019, www.hiv-druginteractions.org Selected drug-drug interactions of interest in elderly PLWH Drug class ARV comment PPIs, antacids, H2 inhibitors ATV RPV Decreased solubility of ATV, RPV. Contraindicated with PPIs; antacids, H2 inhibitors: separate drug intake.

Calcium, mineral supplements, antacids INSTIs Chelation with divalent cations causing reduced absorption of INSTIs. Separate drug intake. Corticosteroids PI/r PI/c EVG/c Risk of Cushing syndrome (cave: eye drops, local injection, topical administration). Triamcinolone, budesonide, fluticasone, mometasone are contraindicated. Antidepressants PI/r PI/c EVG/c Avoid tricyclic antidepressants due to anticholinergic effects. Caution: escitalopram/citalopram + ATV, LPV or SQV (risk QT interval prolongation). Benzodiazepines PI/r PI/c EVG/c Avoid in elderly due to risk of cognitive impairment, falls and fractures. Midazolam, triazolam are contraindicated. Chemotherapy drugs

PI/r PI/c EVG/c Risk of chemotherapy related toxicities. Limited data to guide DDIs management. Favour ARVs with a low potential for metabolic DDIs when possible. Marzolini C et al. Expert Rev Clin Pharmacol 2019, www.hiv-druginteractions.org Selected drug-drug interactions of interest in elderly PLWH Drug class ARV comment NSAIDs Calcium channel blockers TDF PI/r PI/c EVG/c PI/r PI/c EVG/c PI/r PI/c EVG/c DTG, BIC PI/r PI/c EVG/c PI/r PI/c EVG/c Avoid long term use and closely monitor renal function.

Increased exposure. Start at lower dose and titrate based on response to therapy. Lecarnidipine is contraindicated. Statins Antidiabetics Anticoagulants vitamin K antagonists Direct acting anticoagulants Increased exposure of some statins, risk of rhabdomylosis. Simvastatin, lovastatin are contraindicated. DTG increases metformin exposure. Avoid high dose metformin. BIC: consider dose adjustment in patients with moderate renal impairment. Saxagliptin: limit to 2.5 mg daily with boosted ARVs. Adjust dosage by closely monitoring INR. Dosage adjustement might be needed when switching booster. Apixaban, rivaroxaban: avoid. Dabigatran: possible with PI/r but not recommended with PI/c. Edoxaban: consider a dose reduction from 60 to 30 mg. Marzolini C et al. Expert Rev Clin Pharmacol 2019, www.hiv-druginteractions.org Drug-drug interactions between boosted ARV and statins Differences in magnitude of drug-drug interactions with statins explained by different metabolic pathways and affinities to drug transporters. Atorvastatin + (CYP3A4 + transporters) Rosuvastatin + ATV/c

ATV/r DRV/c DRV/r LPV/r EVG/c 822% 290% 490% 213% 93% 48% 107% 38% 242% Atorvastatin + DRV/r Liver (transporters)

OATP1B1 inhibition: ATV > LPV > DRV > RTV, Cobi Recommendations Atorvastatin Rosuvastatin ATV/c DRV/c NR/lowest dose Max: 10 mg/d lowest dose Max: 40 mg/d (US label: 20 mg/d) lowest dose Max: 10 mg/d CYP3A4 Rosuvastatin + DRV/r Liver lowest dose Max: 20 mg/d www.hiv-druginteractions.org Anticoagulants + ritonavir or cobicistat boosting PK/PD study for dabigatran + RTV or Cobi Switch from ATV/r QD to DRV/c reduction of warfarin dose by 60% dabigatran alone dabigatran adm 2 h before RTV

dabigatran adm together with RTV dabigatran alone dabigatran adm 2 h before Cobi dabigatran adm together with Cobi RTV: mixed inhibitory/inducing effect on P-gp Cobi: only inhibitory effect on P-gp PK PD boosted regimens: use vitamin K antagonists and monitor INR or use heparin derivatives boosted regimens: avoid rivaroxaban, apixaban. Possible to coadminister PI/r with dabigatran (dosage adjustment might be needed in patients with mild or moderate renal impairment), consider dose adjustment with edoxaban Tseng A et al. AIDS 2017, Kumar P et al. AAC 2017, www.hiv-druginteractions.org Drug-drug interactions between boosted ARV and antiplatelets drugs PD effect (platelet receptor blockade measured with VerifyNow) PK effect Clopidogrel active metabolite Prasugrel active metabolite AUC -69% AUC -52% Clopidogrel 44% HIV patients did not achieve platelet inhibition Prasugrel platelet inhibition remains

adequate in all patients efficient platelet inhibition antiplatelet drug alone antiplatelet drug + RTV/Cobicistat boosted regimen Second independent clinical study: clopidogrel + RTV clopidogrel active met. AUC -49% healthy volunteers HIV patients Second independent clinical study: platelet aggregation inhibition: 51% (clopidogrel alone) vs 31% (clopidogrel + RTV) Cases reports of the deleterious DDI between clopidogrel and boosted regimens start to emerge use prasugrel unless patient has a clinical condition (e.g. history of stroke or transient ischaemic attack) which contraindicates its use in which case an alternative HIV regimen should be considered Marsousi N et al. Clin Pharmacokinet 2018; Itkonen MK et al. Clin Pharmacol Ther 2018, Bravo I et al. BJCP 2018, www.hiv-druginteractions.org Outcomes of drug-drug interactions in real-life www.clinicalcasesDDIs.com The page can be used for: - Reporting new clinical cases on drug combinations - Searching for information on specific combinations. - Share information on real-life experience about drug combinations that may be used in the clinic.

www.hiv-druginteractions.org + www.hep-druginteractions.org + www.cancer-druginteractions.org Summary DDIs are practically unavoidable in HIV care but mostly manageable. Potential for DDIs to be considered systematically when selecting an antiretroviral regimen or when adding new medications to an existing HIV treatment. Searchable online databases constitute valuable tools to recognise and manage DDIs. Think beyond DDIs in elderly PLWH dose carefully; adapt dosage; check for inappropriate drugs; prioritize medications Acknowledgements Liverpool website team & editorial board Manuel Battegay David Back Felix Stader Saye Khoo Marco Siccardi Franoise Livio Fiona Mara Glasgow Katie McAllister Katie Moss Liverpool Liverpool

Justin Chiong Jasmine Martin Liverpool Liverpool Marta Boffito Alison Boyle London Glasgow See you in Basel

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