| |
The challenge of HIV treatment in an era of polypharmacy
|
| |
| |
Download the PDF here
"There is a need for more pharmacokinetic data in elderly PLWH, especially those with comorbidities or frailty.....Since elderly individuals are often excluded from clinical trials, there is a lack of data on the effect of ageing on the pharmacokinetics of antiretroviral drugs"
1. Altogether, the presence of comorbidities and age‐related physiological changes predispose elderly PLWH not only to the well‐known risk of DDI with antiretroviral drugs but also to other prescribing issues as discussed in the following sections. The high prevalence of prescribing issues in elderly PLWH highlights the need for ongoing education on prescribing principles and the optimal management of individual patients. The knowledge of adverse health outcomes associated with polypharmacy and inappropriate prescribing should ensure that there are interventions to prevent harm including medication reconciliation, medication review and medication prioritization according to the risks/benefits for each patient.
2. Polypharmacy is commonly defined as the concurrent administration of ≥5 medications, a cut‐off that has been associated with an increased risk of adverse health outcome 44. In HIV medicine, the term polypharmacy most often refers to non‐HIV medications given in addition to antiretroviral drugs. Polypharmacy has been shown to be common in PLWH aged ≥50 years, ranging from 15% up to 94% as reported by several HIV Cohort analyses.
3. As expected, the number of comorbidities in PLWH has been shown to increase with age: 18.4% of PLWH aged ≥75 years from the French Dat'AIDS cohort had ≥4 comorbidities versus 4.3% of those aged 50 to 74 years. A similar picture is observed in the Swiss HIV Cohort Study (SHCS) as the number of age‐associated comorbidities is significantly higher in PLWH aged 65 years compared to those aged 50 to 64 years 35. Importantly, the study of the SHCS has demonstrated that the higher number of comorbidities with ageing is correlated with a higher use of comedications and consequently a higher risk to have polypharmacy.
4. comorbidities patterns were shown to affect differently health outcomes with, for example cardiovascular disease being associated with poorer physical health, higher risk of functional impairment, hospitalization and a higher number of medical visits.
5. Polypharmacy brings several challenges. The related increase in pill burden can have a negative effect of treatment adherence.
6. Polypharmacy may increase the risk of adverse drug reactions due to the use of medications with overlapping side effects, which may convert asymptomatic side effects to a reason for hospitalization.
7. Polypharmacy has been associated with several adverse health outcomes including physical decline, cognitive impairment, falls, hospitalization and mortality.
8. polypharmacy has been associated with an increased risk of DDIs and other prescribing issues such as inappropriate drug use, prescribing cascade or drug‐disease interactions.
9. pharmacodynamics can also be impacted by age‐associated physiological changes leading in a more or less pronounced drug effect, particularly for cardiovascular or central nervous systems drugs. The modification of the pharmacodynamic effect is driven by changes in the affinity to receptor sites or in their number as well as the alteration of homeostatic processes with advanced age 17. One important example relates to the reduction in cholinergic receptors in the brain which means that elderly PLWH are more likely to experience central anticholinergic adverse reactions (i.e. cognitive impairment, delirium) therefore drugs with anticholinergic properties should be avoided.
10. Inappropriate drugs for use in elderly PLWH are generally defined as drugs for which the risk of an adverse event outweighs the clinical benefit.
The availability of potent antiretroviral therapy has transformed HIV infection into a chronic disease such that people living with HIV (PLWH) have a near normal life expectancy. [Actually, recent studies find PWH have reduced life expectancy. It may depend on personal characteristics. In recent study at CROI 2020 by Julia Marcus for Kaiser there was 9 years reduced life expectancy but PWH with worse health or social disparities performed worse. Overall, the studies are not conclusive & try to predict the future which is difficult & in fact everyone is different. Jules Levin]
However, there are continuing challenges in managing HIV infection, particularly in older patients, who often experience age‐related comorbidities resulting in complex polypharmacy and an increased risk for drug‐drug interactions. Furthermore, age‐related physiological changes may affect the pharmacokinetics and pharmacodynamics of both antiretrovirals and comedications thereby predisposing elderly to adverse drug reactions. This review provides an overview of the therapeutic challenges when treating elderly PLWH (i.e. >65 years). Particular emphasis is placed on drug‐drug interactions and other common prescribing issues (i.e. inappropriate drug use, prescribing cascade, drug‐disease interaction) encountered in elderly PLWH.
Discussion
Prescribing issues are common in elderly PLWH due to the presence of age‐related comorbidities, organ dysfunction and physiological changes leading to a higher risk for drug‐drug interactions, drugs dosage errors and inappropriate drug use.
Conclusions
The high prevalence of prescribing issues in elderly PLWH highlights the need for ongoing education on prescribing principles and the optimal management of individual patients. The knowledge of adverse health outcomes associated with polypharmacy and inappropriate prescribing should ensure that there are interventions to prevent harm including medication reconciliation, medication review and medication prioritization according to the risks/benefits for each patient.
Conclusions
DDIs in HIV really came to the forefront of attention more than 20 years ago with the PI era and the realization that boosting of the PI often also resulted in the boosting of other comedications. Although we have moved into the INI era and have unboosted regimens with a greatly reduced liability to DDIs, there still needs to be an awareness of relevant DDIs both with INI and the earlier generation antiretroviral drugs which are still important in certain settings. This is particularly relevant in the older population who often have multiple comorbidities and therefore polypharmacy. DDIs are still an issue we have to face and manage.
Strategies to prevent prescribing errors are important which must include education on key DDIs with each class of antiretroviral drugs and on prescribing principles for specific groups of patients. Medication reconciliation and regular medication review is essential with de‐prescribing if appropriate.
As we look to the future, there are clearly exciting developments in antiretroviral therapy particularly in relation to long‐acting injectables and implants. The question then is "will DDIs still be an issue"? Despite bypassing gastrointestinal absorption there are still hepatic DDIs to consider (and maybe interactions relating to the injection or implant site) and so we need to be clear on the process of generating key data (likely PBPK modelling) and the strategies to deal with clinically relevant DDIs.
Introduction
Effective antiretroviral treatments mean that persons living with HIV (PLWH) have a chronic disease with a life expectancy close to the general population 1, 2, 3, although there are differences in estimates when considering parameters such as HIV transmission risk group, lifestyle, race, gender or CD4 cell counts at treatment initiation 4. Older PLWH includes patients infected at an older age as well as patients diagnosed previously and who are ageing with HIV infection 5. Several modelling studies 6, 7 have projected the increase in median age of patients on antiretroviral treatment over the next decade. Forty percent of the HIV population will be constituted of PLWH aged ≥60 years of whom 28% are predicted to have ≥3 comorbidities 6.
However, age‐related comorbidities result in complex polypharmacy and an increased risk for drug‐drug interactions (DDIs). Furthermore, physiological changes related to ageing may affect pharmacokinetics and pharmacodynamics thereby putting elderly PLWH at risk of inappropriate prescribing. It should be noted that according to the World Health Organization 8, the term elderly refers to ≥65 years old.
Ageing leads to physiological, anatomical and biological modifications that can alter drug pharmacokinetics 9, 10. These changes include a reduced gastric acid secretion and a delayed gastric emptying time, although the clinical relevance remains unclear 10. Drug distribution may be impaired by the reduction in total body water and lean body mass with a relative increase in body fat and an increased distribution of lipophilic drugs. In addition, decreased serum albumin leads to an increase in unbound drug and uptake in peripheral tissue. The observed decrease in hepatic clearance (30% to 40%) in older age results from the decline in both liver mass and blood flow rather than changes in the activity of hepatic enzymes 11. Liver mass reduces by 10% to 15% and by 20% per age decade after the age of 65 years in women and men respectively 10. For many drugs, the most apparent effect of ageing is the progressive decrease in renal clearance explained by a lower glomerular filtration rate 10 resulting in a reduced clearance of renally eliminated drugs. Since elderly individuals are often excluded from clinical trials, there is a lack of data on the effect of ageing on the pharmacokinetics of antiretroviral drugs. Available data have shown that the exposure of the non‐nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz and the integrase inhibitor (INI) raltegravir was not significantly changed in PLWH >60 or 45 to 79 years, whereas plasma concentrations of protease inhibitors (PI) were increased 12, 13, 14. Ageing impacted differently nucleoside reverse transcriptase inhibitors (NRTI)/nucleotide reverse transcriptase inhibitors (NtRTI) as tenofovir exposure was reduced by 8% to 13%, whereas conversely emtricitabine was increased by 19% to 73% in PLWH ≥55 years 15. Dolutegravir maximal concentrations were shown to be increased by 25% in PLWH ≥60 years, however, this change did not modify sleep or daytime functioning 16. There is a need for more pharmacokinetic data in elderly PLWH, especially those with comorbidities or frailty.
The pharmacodynamics can also be impacted by age‐associated physiological changes leading in a more or less pronounced drug effect, particularly for cardiovascular or central nervous systems drugs. The modification of the pharmacodynamic effect is driven by changes in the affinity to receptor sites or in their number as well as the alteration of homeostatic processes with advanced age 17. One important example relates to the reduction in cholinergic receptors in the brain which means that elderly PLWH are more likely to experience central anticholinergic adverse reactions (i.e. cognitive impairment, delirium) therefore drugs with anticholinergic properties should be avoided 18.
Altogether, the presence of comorbidities and age‐related physiological changes predispose elderly PLWH not only to the well‐known risk of DDI with antiretroviral drugs but also to other prescribing issues as discussed in the following sections.
.
|
|
| |
| |
|
|
|
