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Elderly HIV+ Physiologic Changes, Polypharmacy, Prescribing Issues
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Prescribing issues in elderly individuals living with HIV REVIEW
Catia Marzolinia,b and Françoise Livioc
19 Jun 2019 EXPERT REVIEW OF CLINICAL PHARMACOLOGY
Considering the potential negative consequences of poly-pharmacy, efforts should be made to reduce unnecessary comedications.
In this context, the concept of deprescribing has gained increasing attention as a means to reduce unnecessary/inappropriate polypharmacy in elderly individuals.
Age-dependent physiological changes can also modify drug pharmacodynamics resulting in a more or less pronounced drug effect, particularly for medications belonging to the cardiovascular or central nervous systems (CNS). Differences in drug response can be explained by changes in the affinity to receptor sites or in the number of receptors as well as changes in homeostatic processes with aging.
One third of elderly HIV group takes complex regimens and risks drug interactions - Inappropriate medications were noted in 14% of elderly patients.The researchers stressed that the complex antiretroviral regimens taken by one third of people 65 or older have a high potential for causing DDIs. They called for "education on geriatric medicine principles and periodic medications review . . . to limit the risk of prescribing errors in this vulnerable, growing population." (03/08/19)
Model suggests physiologic changes with aging underlie ritonavir PK shifts - (05/20/19)
Physiologically based pharmacokinetic modelling to determine pharmacokinetic alterations driving ritonavir exposure changes in aging people living with HIV - (05/16/19)
Aging At CROI 2019 - (04/02/19)
I Keep Forgetting HIV, Aging, and Cognitive Disorders - (03/29/19)
THE CHALLENGES OF HIV TREATMENT IN AN ERA OF POLYPHARMACY (ABSTRACT 120)
David Back
University of Liverpool, Liverpool, United Kingdom
http://www.croiwebcasts.org/console/player/41280?mediaType=slideVideo&&crd_fl=0&ssmsrq=1563388575007&ctms=5000&csmsrq=5057
ABSTRACT
Introduction: Combined antiretroviral therapy has transformed HIV infection into a chronic disease thus people living with HIV (PLWH) live longer. As a result, the management of HIV infection is becoming more challenging as elderly experience age-related comorbidities leading to complex poly-pharmacy and a higher risk for drug-drug or drug-disease interactions. Furthermore, age-related physiological changes affect pharmacokinetics and pharmacodynamics thereby predisposing elderly PLWH to incorrect dosing or inappropriate prescribing and consequently to adverse drug reactions and the subsequent risk of starting a prescribing cascade.
Areas covered: This review discusses the demographics of the aging HIV population, physiological changes and their impact on drug response as well as comorbidities. Particular emphasis is placed on common prescribing issues in elderly PLWH including drug-drug interactions with antiretroviral drugs. A PubMed search was used to compile relevant publications until February 2019.
Expert opinion: Prescribing issues are highly prevalent in elderly PLWH thus highlighting the need for education on geriatric prescribing principles. Adverse health outcomes potentially associated with polypharmacy and inappropriate prescribing should promote interventions to prevent harm including medication reconciliation, medication review, and medication prioritization according to the risks/benefits for a given patient. A multidisciplinary team approach is recommended for the care of elderly PLWH.
Normal aging and HIV infection are characterized by inter-connected immune-inflammatory processes, which may potentiate each other [42]. Consistent with this assumption, age-related co-morbidities tend to occur at an earlier age in PLWH compared to age-matched uninfected individuals. Besides chronic immune activation by HIV infection, the earlier onset of comorbidities in PLWH may also relate to behavioral, lifestyle factors (e.g. smoking, alcohol consumption, drug use) and viral co-infections (e.g. hepatitis, sexually transmitted dis-eases), all of which place them at higher risk of acquiring comorbidities [43]. In addition, chronic exposure to antiretroviral drugs, especially the first generation of PIs, NNRTIs, and NRTIs is associated with various toxicities leading for instance to metabolic disorders (e.g. dyslipidemia is frequently observed with the PIs fosamprenavir, indinavir, lopinavir, the NNRTI efavirenz, the NRTI stavudine; hyperlactatemia can occur with the NRTIs zidovudine, stavudine, didanosine)[44,45]. The NtRTI tenofovir disoproxil fumarate can cause renal toxicity [46], efavirenz can lead to CNS side effects (i.e. sleep disturbance, headache, depression, suicidal ideation) whereas hypersensitivity reactions have been reported for the NNRTI nevirapine [45].
highlighting the need for more pharmacokinetic studies......in the French Dat'AIDS cohort, 18.4% of PLWH aged ≥75 years had ≥4 comorbidities versus 4.3% of those aged 50-74 years [30].......With the advent of potent antiretroviral treatments, the HIV population is aging and experience age-related conditions, such as cardiovascular diseases, chronic kidney disease, hypertension, diabetes mellitus, dyslipidemia, chronic obstructive pulmonary dis-ease, cancer, osteoarthritis, osteoporosis, and neurocognitive impairment. Number of age-associated comorbidities was also significantly higher in PLWH aged ≥65 years compared to those aged 50 to 64 years in the SHCS [31]. In a cross-sectional study nested in the latter cohort, PLWH aged ≥75 years had a median of 7 comorbidities: the 10 most frequent in decreasing order of frequency were hyperten-sion, chronic kidney disease, dyslipidemia, neurocognitive disorders, osteoporosis, polyneuropathy, cancer, coronary heart disease, arthrosis, and diabetes mellitus [26]........Age-dependent physiological changes can also modify drug pharmacodynamics resulting in a more or less pronounced drug effect, particularly for medications belonging to the cardiovascular or central nervous systems (CNS)......On a general note, the long-term use of benzodiazepines should be avoided in elderly PLWH due to the increased sensitivity and related risk of cognitive impairment, balance problems, falls and consequently fractures [20,21].....The use of non-benzodiazepine sedative-hypnotics is also problematic and has been associated with an increased risk of falls in older adults (≥71 years) [22]. The risk/benefit balance of sedative hypnotics proved indeed to be unfavorable in elderly. ......due to a reduction in cholinergic receptors in the brain, elderly PLWH are also more likely to experience central anticholinergic adverse reactions (i.e. cognitive impairment, delirium) therefore drugs with anticholinergic properties should be avoided [24]. Of interest, HIV-infected women receiving more than one medication with anticholinergic properties were shown to have lower learning and executive performance compared to women not treated with such medications. .......When considering all women exposed to anticholinergic drugs, the cognitive performance was shown to be worse in HIV-infected compared to uninfected women suggesting that viral proteins may cause an additive effect to anticholinergic drugs [25]. Drug classes with potential different pharmacodynamics response in elderly PLWH are presented in Table 2 [9,17,18]......knowledge of which drugs to adjust in case of renal function impairment is essential for safe prescribing. Although one limitation is that dosage recommendations in case of severe renal dysfunction (i.e. eGFR <30 mL/min/1.73 m2 [27]) are not always available, particularly for older drugs. Of note, caution should be exercised when estimating the renal function using plasma creatinine or equations incorporating creatinine (e.g. crea-tinine clearance Cockcroft-Gault, eGFR CKD-EPI, and MDRD) as older adults have a lower production of creatinine due to a reduced muscle mass [28]. For drugs undergoing hepatic metabolism, one key principle is to start low, go slow and titrate, at least for chronic treatments such as antihypertensives, statins antidepressants. As a rule of thumb, older individuals need about 50-75% of the optimal dose for younger individuals [29].
Future research should aim at specifically including PLWH aged ≥65 years to better document drug pharmacokinetics, pharmacodynamics, and DDIs and thereby prevent unwanted drug effects in this vulnerable, growing population. In addition, efforts should be made to understand how comorbidities cluster together. This would enable to develop targeted interventions and guidelines addressing more specifically the needs of PLWH with multiple comorbidities. Randomized clinical studies evaluating strategies to reduce unnecessary polypharmacy and their impact on the quality of life of aging PLWH are warranted.
Considering the potential negative consequences of poly-pharmacy, efforts should be made to reduce unnecessary comedications. Future studies are needed to evaluate the impact of polypharmacy reduction on the prevention of harmful health outcomes........Other adverse health outcomes associated with polypharmacy include functional physical decline, cognitive impairment, falls and related fractures, hospitalization and premature mortality [65-69]. However, causality assessment between polypharmacy and the aforementioned outcomes is challenging, as residual confounding factors linked to disease burden are difficult to eliminate in observational studies.
Of interest, these studies show that prescribing issues in older PLWH are more frequently observed for non-HIV drugs and go beyond the well-known issue of DDIs with antiretroviral drugs suggesting the need for education on geriatric medicine principles. Furthermore, prescribing issues in older PLWH is at least as prevalent as in older HIV-uninfected people.
In a prospective study, 54% and 63% of PLWH aged ≥50 (n = 248) had inappropriate prescriptions using the STOPP (2008) and Beers criteria (2012), respectively. The number of medications was significantly associated with having a Beers or STOPP criteria iden-tified. These prescription issues were corrected, but the impact of the intervention was not evaluated [56].
In a retrospective study of SHCS, 69% of PLWH aged ≥75 (n = 111) had at least one prescribing error. The analysis was performed using several tools: Beers and STOPP/START criteria, Anticholinergic Risk Scale [92], DDI checker (www.hiv-druginteractions.org), published DDIs studies and package inserts. Overall, 169 prescribing issues were detected and included: incorrect drug dosage (25%), absence of indication (21%), medication omission (19%), medication not appro-priate in elderly (19%), deleterious DDIs (14%) and treatment duration exceeding recommendations (2%). The proportion of patients with more than one prescribing issue was significantly higher in those with polypharmacy [26].
Elderly PLWH are particularly at risk population for prescribing cascades, since they are often both polymedicated and particularly vulnerable to adverse drug reactions due to pharmacokinetic, pharmacodynamic and homeostatic processes changes with aging as discussed in section 2.
In this context, the concept of deprescribing has gained increasing attention as a means to reduce unnecessary/inappropriate polypharmacy in elderly individuals [174,175]. Deprescribing is the act of tapering and/or stopping drugs whose potential harms outweigh benefits under the close supervision of health-care providers. The decision to discontinue a treatment should take into account the indication and the tolerance of the medication, the potential for DDIs and the treatment goals for a given patient. Despite proven benefits, clinicians are often reluctant to stop medications, especially if they did not initiate the treatment, and the patient seems to be tolerating the medication, maybe due to some subjective irrational fear for potential deleterious consequences. On the other hand, deprescribing can also be interpreted by the patient and the family as 'giving up care', especially if adequate explanation is not provided.
Medication prioritization: a balance is required between over- and under-prescribing. Several medications are often required to manage elderly individuals with multiple conditions. Decision to prescribe is often based on disease-specific clinical practice guidelines, which may result in care that is impractical or harmful particularly if the guidelines are not interpreted critically considering the clinical context of a specific patient [171,172]. For a hypothetical elderly patient with chronic obstructive pulmonary disease, diabetes mellitus, osteoporosis, hypertension and arthrosis, clinical practice guidelines would require prescribing 12 different medications [171]. Thus, the appropriateness of pharmacological treat-ments should be assessed critically and tailored to the needs of individuals (patient-centered care) [173]. The decision to prescribe should consider the risk/benefit of each medication, the care goals, the remaining life expectancy and current level of functioning as well as the patient preference, particularly in frail individuals.
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see pdf for full review.
1. The 'graying' of the HIV epidemic
Due to effective antiretroviral treatments, HIV infection has evolved from a deadly to a chronic disease. As a result, the persons living with HIV (PLWH) are aging and have a life expectancy close to the general population [1-3], although differences in estimates are observed depending on HIV trans-mission risk group, race, gender, lifestyle and CD4 cell counts at antiretroviral treatment initiation [4]. The growing proportion of elderly PLWH is diverse and includes patients diag-nosed several years ago and who are aging with HIV infection as well as patients infected at an older age [5]. A mathematical model using data from the Dutch HIV cohort ATHENA projected that the median age of patients on antiretroviral treatment will increase from 43.9 years in 2010 to 56.6 in 2030. PLWH aged ≥60 years will represent 40% of the HIV population with 28% having ≥3 comorbidities. Consequently, it is estimated that 54% of PLWH will be prescribed co-medications by 2030, compared with 13% in 2010, with 20%taking ≥3 co-medications [6]. Similar projections are observed when modeling Italian and American HIV population data [7]. The 'graying' of the HIV epidemic brings new challenges as elderly experience more age-related comorbidities leading to complex polypharmacy and a higher risk for drug-drug inter-actions (DDIs). In addition, age-related physiological changes affect pharmacokinetics and pharmacodynamics thereby predisposing elderly PLWH to incorrect dosing and inappropri-ate prescribing.
This review covers age-related physiological changes and their impact on drug response with particular emphasis on common prescribing issues in elderly PLWH. A PubMed search was used to compile all relevant publications until February 2019.
In the following sections, the term elderly refers as being ≥65 years in accordance with the World Health Organization definition of elderly or older individuals [8].
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