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Review

Polypharmacy in the HIV-infected older adult population

, &
Pages 749-763 | Published online: 21 Jun 2013

Abstract

The prevalence of human immunodeficiency virus (HIV) infection among people older than 50 years is increasing. Older HIV-infected patients are particularly at risk for polypharmacy because they often have multiple comorbidities that require pharmacotherapy. Overall, there is not much known with respect to both the impact of aging on medication use in HIV-infected individuals, and the potential for interactions with highly active antiretroviral therapy (HAART) and coadministered medications and its clinical consequences. In this review, we aim to provide an overview of polypharmacy with a focus on its impact on the HIV-infected older adult population and to also provide some clinical considerations in this high-risk population.

Introduction: HIV, aging, and comorbidities

Acquired immunodeficiency syndrome (AIDS)-related mortality of human immunodeficiency virus (HIV)-infected people in the United States has been reduced over the years, and this trend is in large part a result of the introduction of highly active antiretroviral therapy (HAART).Citation1 As a result, HIV-infected individuals are living longer. By 2015, more than one-half of all HIV-infected individuals in the United States will be older than 50 years of age.Citation2 The prevalence of HIV in this age group is expected to be significant considering the increased life expectancy of the general population and the increased survival of HIV-infected individuals. In the general population, those who are 50 years and older are not referred to as “older adults.” However, in the HIV/AIDS population, this subset of the population does carry the label “older adults.” The Centers for Disease Control and Prevention applies this label and considers this subset of the population as a separate group, mainly because early in the HIV epidemic, this age group was much older than the mean age of HIV-infected patients.Citation2

Studies have shown that in the current environment, where the number of HIV-infected older adults has continued to increase year after year, there has been a similar increase in the number of comorbid conditions concomitantly present in these individuals and also an increased use of medications. In one study that investigated HIV-infected individuals aged 55 years and older in New York City, 89% had one or more comorbidities, or an average of 2.4 comorbid conditions per person, and 81% received medications unrelated to HIV.Citation3 In that study, the most common comorbidities were hypertension, chronic obstructive pulmonary disease, and diabetes mellitus.

Additionally, it is believed that HIV infection, and quite possibly its treatment, may be contributing to the acceleration of the aging process by several years when compared with those who are not infected with HIV. Dyslipidemia, dysregulation of glucose metabolism, reduced bone density and osteopenia, hypogonadism, renal and hepatic disorders, psychiatric illness, neurocognitive impairment, and coronary artery disease are all conditions likely to occur earlier in HIV-infected individuals compared with their unaffected peers.Citation4 Another study that compared HIV-infected veterans 50 years of age and older to non-HIV-infected veterans of similar age found that the older HIV-infected veterans had higher odds of multimorbidity.Citation5 This study also concluded that when compared to non-HIV infected individuals, the HIV-infected veterans experienced a more pronounced increase in disease burden (hypertension, diabetes mellitus, vascular, pulmonary, and renal disease) as well as an increase disease prevalence as they aged.

A signature collaboration group with cohorts spanning the world was formed to provide information about the prognosis of individuals starting HAART for the first time. The Antiretroviral Therapy (ART) Cohort Collaboration looked at specific causes of mortality of HIV-infected individuals who initiated HAART. They discovered that deaths classified as AIDS-related decreased with increasing duration of HAART therapy. Older age (≥50 years) was strongly associated with increased rates of non-AIDS-related malignancy and cardiovascular disease (CAD), and the cause of death least associated with age was AIDS. Furthermore, there was a marked increase in the rates of renal death in patients >60 years old. The abovementioned results further demonstrate the burden of chronic comorbid diseases in this population.

As a result of the increased average age of HIV-infected individuals since the introduction of HAART, patients are more often exposed to disease- and treatment-related morbidities, which in turn has led to an increased likelihood of polypharmacy.Citation6 Overall, there is not much known about the impact of aging on medication use in HIV-infected individuals; the potential for interactions with HAART and coadministered medications; and the impact of these factors on therapy tolerability and virological response.

Overview of polypharmacy

Polypharmacy can be simply defined as the concomitant use of multiple medications;Citation7 however, polypharmacy also has multiple definitions within the scientific literature such as the use of a large number of medications, the use of potentially inappropriate medications, medication underuse, and medication duplication.Citation8,Citation9 The two most commonly cited definitions are more specific and are: (1) the use of six or more medications; or (2) the use of a potentially inappropriate drug for which the medication does not match the diagnosis.Citation10

The use of multiple medications is certainly a relevant issue, especially in the older adult population. A national survey by Kaufman et alCitation11 found that 90% of people aged 65 and older use at least one medication per week, more than 40% of this population use five or more different medications per week, and 12% of this population use ten or more medications. Noteworthy, in the same population class, the authors found a 14% increase in fall risk with the addition of any additional medication after four drugs, regardless of drug class.Citation12 Studies have shown that the frequency of unnecessary or not recommended medication use is higher in patients who take many medications compared with those who take few medications.Citation13,Citation14

It is important to note some of the negative consequences as a result of polypharmacy. To start, patients taking multiple drugs for multiple chronic medical conditions have a potentially increased risk of falls,Citation12 drug–drug interactions (DDIs), and adverse drug events (ADEs).Citation15,Citation16 ADEs and DDIs in older adults not only increase morbidity and mortality,Citation15 but they also are a common cause of emergency hospitalizations and represent common occurrences in both the hospital and ambulatory settings.Citation17,Citation18 An example of an ADE with polypharmacy is the increased risk of serious hypoglycemia when prescribed sulfonylureas or insulin therapy with the use of five or more therapeutic classes.Citation19 Drug interactions can also be associated with an increased risk of toxicity. Some common interactions include combining digoxin with diuretics, resulting in digoxin toxicity including arrhythmias and hyperkalemia; the use of nonsteroidal antiinflammatory drugs and diuretics resulting in renal failure; and combinations or narcotics and antidepressants causing central nervous system depression and sedation.Citation20 That being said, the identification and the management of such interactions are absolutely important for delivering quality patient care.

It has been reported that ADEs are common and often preventable in older adults in the ambulatory setting. The rate of ADEs was 50.1 per 1000 person-years; 28% of ADEs were found to be preventable.Citation21 Field et alCitation22 conducted a large nested case control study in an ambulatory population and found that there was a dose–response association of ADEs with the Charlson Comorbidity Index score and number of scheduled medications. In the analysis of preventable ADEs, the dose–response relationship with comorbidity and number of medications persisted. Patients taking anticoagulants, antidepressants, antibiotics, cardiovascular drugs, diuretics, hormones, and corticosteroids were at increased risk for ADEs. Moreover, patients at greatest risk from polypharmacy were those who saw several doctors, had prescriptions filled at multiple pharmacies, and were older adults with multiple comorbidities.Citation23,Citation24

Polypharmacy can be linked to increased costs for both the patient and the health care system. Some of the medications older patients take, including over-the-counter medications, are often not covered by health insurance or Medicare. The result can be an increased financial burden for older patients whose income generally consists of using savings from a retirement account and a fixed income such as Social Security.Citation25 Not surprisingly, a study that compared two groups of Medicare patients found there was a statistically significant difference in statin use when comparing those with prescription drug coverage to those without prescription drug benefits (27.4% versus 4.1%).Citation26

Additionally, minor drug interactions can lead to increased clinic visits, a prescribing cascade where additional medications are given to treat new symptoms, or new lab or imaging studies. Serious adverse events from polypharmacy can lead to specialist visits, emergency department visits, and hospital admissions.Citation17,Citation27,Citation28 In a study from the 2000–2001 Medical Expenditure Panel Survey, it was found that the estimated total cost attributed to the use of potentially inappropriate medications in community-dwelling older adults was $7.2 billion.Citation29

There are two approaches to evaluate potentially inappropriate medication use in older adults: the Beers criteria and the Medication Appropriateness Index. The initial Beers criteria in 1991 consisted of lists of specific drugs or drug classes that were considered inappropriate based on preexisting conditions for nursing home residents; the list was expanded to include all settings of geriatric care in 1997, 2003, and 2012.Citation30Citation33 The Medication Appropriateness Index uses ten items to assess the degree of appropriateness of a particular medication along with a three-point Likert rating scale.Citation34 Inappropriate medication use in the ambulatory setting has been shown to be prevalent in 65% of older adults,Citation35 but concomitantly, these same patients are often not prescribed potentially beneficial medications.Citation9

Another problem with a large number of medications being prescribed is the increase in “pill burden,” which can potentially affect compliance because patients simply get tired of taking their medications and miss doses as a result. Most of the literature that examines dosing regimens and compliance has been conducted in the HIV-infected population in which nearly perfect adherence is required to achieve and sustain viral suppression, maintain immune health, and slow disease progression.Citation36 Not surprisingly, literature on the relationship of regimen factors and adherence in HIV disease indicates that higher dose frequency and greater regimen complexity result in poorer adherence.Citation36

Polypharmacy in HIV-infected patients

Polypharmacy is common in the HIV-infected older adult population. Marzolini et alCitation37 in a Swiss cohort study compared HIV-infected older adults who were aged ≥50 years with younger HIV-infected patients (aged <50) on HAART; they found that older patients were more likely to receive one or more comedications compared with younger patients (82% versus 61%, P < 0.001). This study also determined that older patients had more frequent potential for DDIs when compared with the younger patients (51% versus 35%, P < 0.001). Furthermore, HIV-infected older adults generally used a higher number of comedications and certain therapeutic drug classes more frequently when compared with the HIV-infected younger patients. Some of the drugs studied were cardiovascular drugs (53% in the older group versus 19% in the younger group), gastrointestinal medications (10% versus 6%), and hormonal agents (6% versus 3%). The potential for DDIs with HAART in the older adult group occurred mainly with cardiovascular drugs (27%), central nervous system agents (22%), and methadone (6%). It should be noted, however, that medications used in the older patient group and the younger patient group were not significantly different with respect to the effect on antiretroviral tolerability and response.Citation37 Another study reviewed the prevalence and risk factors for clinically significant drug interactions with HAART, and it was found that those subjects aged >42 years with more than three comorbidities and a treatment plan consisting of three or more antiretroviral agents or a protease inhibitor (PI) were at an independently increased risk of a clinically significant drug interaction.Citation38 It has been shown that HIV-infected patients aged 50 years or older have a better adherence rate to HAART treatment than their younger counterparts;Citation39Citation42 as a result, this can increase the likelihood of potential drug interactions.

There are currently six classes of antiretroviral medications approved for use in the United States and these include nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors (NNRTIs), PIs, integrase inhibitors, fusion inhibitors, and CCR5 antagonists.Citation43 Treatment with HAART has the potential for DDIs. As a class effect, PIs can inhibit cytochrome P450 3 A (CYP3 A) to varying degrees and to some extent other isoenzymes, with ritonavir (RTV) being the most potent.Citation44Citation46 RTV is used to “boost” the levels of other PIs by inhibiting their metabolism. Inhibition of CYP450 (CYP3 A) can cause an increased plasma concentration of CYP450 CYP3 A substrates, either antiretroviral or nonantiretroviral, which has the potential for toxicity. On the contrary, NNRTIs such as nevirapine, efavirenz, etravirine, and PIs, such as lopinavir and tipranavir, are inducers of CYP3 A, which can lower the concentration of some CYP3 A substrates.Citation47 Interactions involving efavirenz, nevirapine, etravirine, and other medications that are metabolized through CYP450 3 A4 can lead to decreased plasma concentrations of coadministered medications, potentially leading to their decreased efficacy. Nucleoside reverse transcriptase inhibitors, maraviroc, raltegravir, and enfuvirtide do not inhibit or induce CYP450 isoenzymes, and clinically significant DDIs with these medications are uncommon.Citation48

The combination of HAART and polypharmacy significantly increases the chance of adverse outcomes stemming from the potential DDIs. Some of these negative outcomes include drug toxicity, poorer HAART adherence, loss of efficacy of the coadministered medication, and virologic breakthrough.

Consequences of polypharmacy in older HIV-infected patients

The consequences of polypharmacy are significant in older adults infected with HIV. Of note, the combination of medications used to treat chronic diseases and HAART in older adults infected with HIV increases the chance for DDIs, which can lead to the loss of efficacy of medications and toxicity. Older adults are even more susceptible to drug interactions than their younger counterparts. First, older adults infected with HIV suffer from aging-related comorbid illness. Second, age-related physiologic changes affect the pharmacokinetic and pharmacodynamic properties of medications. These physiologic changes can be explained by a number of factors including patient genetics, lifestyle, and their specific environment. Simultaneously, these changes contribute to interpatient variability and may add complexity to the management of drug interactions in our older adult population. Pharmacokinetic alterations with aging alone can result in changes to both a person’s body composition and to the function of drug-eliminating organs. For example, lipophilic drugs in combination with the normal age-related changes to the patient’s body composition (eg, the increased proportion of fat mass with loss of lean mass and decreased total body water) tend to result in an increased volume of distribution and a prolonged half-life, whereas water-soluble drugs tend to have a decreased volume of distribution.Citation49

Hepatic metabolism and renal elimination are major routes of drug clearance, including the clearance of HAART. Some age-related changes include a decline in liver and renal function, which may result in impaired drug elimination and drug accumulation.Citation50 Liver volume and hepatic blood flow decrease with increasing age.Citation51,Citation52 This relationship needs to be taken into account when prescribing potentially hepatotoxic agents, such as the majority of PIs and NNRTIs.Citation53 Given the hepatotoxicity with multidrug HAART and potential interactions with other medications including lipid lower agents, over-the-counter medications, and antituberculosis therapy, it is important to monitor liver function in older adults with HIV.Citation54

Additionally, on average in adults, the glomerular filtration rate decreases about 1% per year with increasing age,Citation55 and the methods for estimating renal function may overestimate this function in older adults by not taking their lowered relative muscle mass into account.Citation56 In older adults with HIV, this problem is further complicated because this population characteristically has lower muscle mass than their counterparts and often, confounding factors that can further decrease renal function – diabetes mellitus, hypertension, low CD4 cell count, race, and use of the antiretrovirals tenofovir and indinavir.Citation57Citation60 Estimating renal function is therefore even more difficult in HIV-infected older adults and affects the dosing and prescription of renally excreted medications. For example, cobicistat reduces the apparent estimated glomerular filtration rate by 15% on the initiation of treatment with this drug as a result of reduced tubular excretion of creatinine.Citation61,Citation62

Significant DDIs between HAART and various important drug classes are summarized in . The actual prevalence of ADEs and DDIs in the HIV-infected older adults is not known. Indeed, most of the studies that have been conducted with respect to antiretroviral metabolism have excluded subjects of advanced age with comorbid disease. In short, there is little data on the toxicities of antiretrovirals, especially with respect to HIV-infected older adults. More targeted research is needed.

Table 1 Summary of drug-drug interaction with HAART and various drug classesCitation4,Citation6,Citation48,Citation68,Citation135

Drug–drug interactions by system

Cardiovascular medications

CAD is one of the most common comorbidities in the aging HIV-infected population, and cardiovascular drugs are the most frequently prescribed medications in this population.Citation37 CAD prevalence in this population is likely due to a combination of factors including increasing age and habits such as tobacco use, as well as toxicity from HAART.Citation63 Prolonged treatment with HAART has been shown to be associated with an increased prevalence of hypertension in HIV-infected individuals and also with elevated blood pressure,Citation64 which may be seen in association with the fat redistribution/lipodystrophy syndrome.Citation65,Citation66

Hypertension is an important modifiable cardiac risk factor in HIV-infected patients; treating those who are older and on HAART can be challenging. Dihydropyridine calcium channel blockers (CCBs) have been shown to interact with HAART. Boosted PIs may increase the concentration of CCB in the serum and can potentially prolong the heart’s PR interval, thus causing first-degree heart block and augment the hypotensive effect.Citation67 However, NNRTIs such as efavirenz and nevirapine can have the opposite effect on medication levels and have been shown to decrease CCB serum concentrations; this may require further dose adjustments to achieve a steady state.Citation68 Diltiazem area under the curve (AUC) is increased 125% by atazanavir; if coadministering these medications, the diltiazem dose should be reduced by 50% and electrocardiography monitoring is recommended. It is possible that other PIs increase the levels of diltiazem; therefore, they should be used with caution and the diltiazem dose adjusted to clinical response and toxicities.Citation68

The antiarrhythmic agents, amiodarone and dronedarone (class 3 antiarrhythmics), are contraindicated in patients receiving PIs. As potent CYP3 A4 inhibitors, PIs have the potential to significantly reduce the metabolism of these agents and can cause serious and life-threatening adverse events. The concurrent use of lidocaine and saquinavir is contraindicated because saquinavir may increase the serum concentration of lidocaine, and therefore, its arrhythmogenic effect.Citation68

Digoxin is prescribed for conditions that are common in older adults, including heart failure and atrial fibrillation with a rapid ventricular rate.Citation69 Between 60% and 80% of digoxin is eliminated by the kidneys.Citation70 Therefore, those older patients with HIV who have an increased risk of chronic kidney disease and also low body mass older patients are often subject to an increased risk of toxicity. For this reason, close monitoring of digoxin serum concentration in older HIV-infected individuals is crucial. Saquinavir/RTV increases the digoxin AUC about 49%, and this is most likely via P-glycoprotein inhibition. Given the relatively narrow therapeutic window of digoxin, caution should be exercised when these drugs are administered together.Citation68 It has been recommended that digoxin doses be reduced and that digoxin serum concentrations be monitored.Citation71

Warfarin is known to interact with many drugs through a variety of mechanisms. NNRTIs and PIs are the antiretrovirals most likely to interact with warfarin. Among the NNRTIs, induction of warfarin metabolism is likely with nevirapine. The inhibition of warfarin metabolism can occur with efavirenz, delavirdine, or etravirine coadministration. Interactions with PIs, such as RTV, are also common.Citation72 Liedtke and RathbunCitation43 have concluded that patients on warfarin and antiretrovirals need close international normalized ratio monitoring, and also that empiric warfarin dosage adjustments are difficult to recommend given the limited clinical evidence available and the absence of formal pharmacokinetic studies for most agents.

HAART treatment has not only been correlated with increased CAD, but also with increases in total cholesterol levels and triglyceride levels.Citation73 Significant DDIs have been reported between antiretrovirals and agents prescribed to treat hyperlipidemia. Simvastatin and lovastatin, which are metabolized via the cytochrome P-450 system, are contraindicated with any PI. Low-dose pravastatin, atorvastatin, or rosuvastatin are recommended. These agents can be titrated up as needed.Citation4 Atorvastatin should not exceed 20 mg daily when used with darunavir/RTV, fosamprenavir/RTV, saquinavir/RTV, or fosamprenavir. Atorvastatin is contraindicated with tipranavir.Citation74,Citation75

No dose adjustment is necessary for pitavastatin when used with PIs. The rosuvastatin AUC is increased 48% with darunavir/RTV and the peak concentrations to 139%; therefore, the dose of rosuvastatin must be titrated carefully and the lowest necessary dose used, along with careful monitoring for toxicities. The lipid-lowering benefits of rosuvastatin may be blunted when used in combination with darunavir/RTV.Citation76 Pravastatin AUC is also increased 81% by concurrent use of darunavir/RTV, requiring the use of the lowest possible dose of pravastatin and careful monitoring.Citation77 Additionally, efavirenz has been shown to be associated with reduced inhibition of 5-hydroxy-3-methylglutaryl-coenzyme A reductase activity during coadministration with simvastatin, atorvastatin, and pravastatin.Citation78

Genitourinary medications

Benign prostatic hypertrophy (BPH) is common as men age.Citation79 Biopsy-proven BPH prevalence increases from 40% to 50% in men aged 51–60 years, and this rate exceeds 80% in men older than 80 years.Citation80 BPH has been shown to have a substantial negative effect on quality of life, with symptoms that interfere with activities of daily living.Citation81 Medications used to treat BPH can interact with antiretrovirals in the aging HIV population. PIs may significantly increase concentrations of á-adrenergic antagonists such as alfuzosin. Coadministration is not recommended, given increased risk of orthostatic hypotension. Also, boosted PIs with RTV may increase the dose concentration of tamsulosin, and concurrent use is not recommended.Citation82 Fewer interactions are expected between PIs and other á-antagonists such as doxazosin and prazosin; however, close monitoring is recommended.

Erectile dysfunction has been reported to be a common problem in HIV-infected men. Studies have reported a prevalence rate between 53% and 71%.Citation83 Caution should be exerted with concomitant use of PI and erectile dysfunction drugs such as sildenafil, given the potential for PIs to increase the levels of sildenafil.Citation6,Citation84 Sildenafil should be started at 25 mg every 48 hours and monitored for adverse events. The starting dose of tadalafil, also prescribed for erectile dysfunction, should be 5 mg such that it does not exceed a single dose of 10 mg in a 72-hour period. Monitoring for adverse effects of tadalafil, such as hypotension, is recommended.Citation85

Gastrointestinal medications

Interactions between HAART and acid-reducing medications are common in older adults. In older HIV-infected patients treated with HAART, an increased frequency of reflux symptoms, gastroesophageal reflux disease, and H. pylori infection has been observed.Citation86 That being said, the treatment of reflux diseases can be problematic because some HAART medications require an acidic environment. The coadministration of H-2 receptor antagonists and atazanavir/RTV in HIV-infected patients has been shown to reduce the effect of atazanavir by approximately 20%. The dose of H-2 receptor antagonist should not exceed the equivalent of 40 mg of famotidine twice daily in those naïve to antiretroviral medications, or 20 mg twice daily in antiretroviral-experienced patients.Citation68 Atazanavir should be administered more than 10 hours after the H-2 receptor antagonist.Citation87 Proton pump inhibitors (PPIs) should not exceed a dose equivalent to omeprazole 20 mg daily in PI-naïve patients. PPIs should be administered 12 hours before atazanavir/RTV. PPIs are not recommended in patients receiving unboosted atazanavir.Citation88 PPIs increase the AUC of saquinavir by 82%. When using these medications concomitantly, it is necessary to monitor for saquinavir toxicity.Citation89 Rilpivirine needs an acidic environment for absorption, and H-2 receptor antagonists as well as PPIs can decrease its absorption.Citation68

Psychiatric medications

As many as 10% of adults 60 years of age or older who are seen in primary care settings have clinically significant depression.Citation90 Additionally, major depressive disorder has been shown to be twice as likely to occur in patients with HIV as in those who do not have HIV infection.Citation91 Understandably, depression is very common in older adults with HIV. Selective serotonin reuptake inhibitors are often the prescribed treatment for depression in HIV-infected individuals,Citation92 and these inhibitors are believed to be better tolerated than tricyclic antidepressants (TCAs).Citation93 It is expected that all boosted PIs increase the levels of TCAs: the use of the lowest possible dose of the TCA and monitoring of drug levels are recommended.Citation68 Escitalopram and citalopram are often the preferred selective serotonin reuptake inhibitors. The AUC of paroxetine is decreased by the concurrent use of boosted darunavir and fosamprenavir,Citation94 and titration of the paroxetine dose based on clinical response is recommended.

Trazodone levels increase with the use of unboosted atazanavir and all boosted PIs, thereby increasing the risk for central nervous system and cardiovascular adverse events.Citation95 Using the lowest dose of trazodone and monitoring for adverse events is recommended. The combination of lopinavir/RTV and bupropion results in a decrease in the bupropion AUC and requires titration of the bupropion dose based on clinical response.Citation96

Midazolam and triazolam are contraindicated with all PIs.Citation97Citation100 Several commonly used benzodiazepines are metabolized by CYP3 A4. These include alprazolam, clonazepam, diazepam, and funitrazepam: CYP3 A4 inhibitors cause their levels to rise, resulting in possible toxicities such as over-sedation and central nervous system depression. RTV has been shown to increase blood levels and effects of the benzodiazepine and CYP3 A4 substrate alprazolam.Citation100

Antimicrobials/antifungals

The coadministration of CYP3 A4 inhibitors results in an increased drug exposure to macrolides such as clarithromycin and erythromycin, and this can cause prolonged QTc.Citation101,Citation102 QTc prolongation may lead to torsades de pointes, and older adults are particularly at increased risk for this life-threatening arrhythmia. The clarithromycin AUC can increase 94% with the concurrent use of atazanavir/RTV, thus leading to prolonged QTc; the clarithromycin dose should be reduced by 50% or an alternative antibiotic considered. The same recommendation applies for the concurrent use of clarithromycin with all other boosted PIs because they also may cause an increase in clarithromycin. Another antimicrobial to be aware of is rifampin, which is a potent inducer of both cytochrome P-450 oxidative enzymes and the P-glycoprotein transport system. Rifampin is contraindicated with all PIs because it reduces the therapeutic response and can result in therapeutic failure or a toxic reaction.Citation103

The azole antifungals have long been described as potentially arrhythmogenic drugs.Citation104 The coadministration with other compounds that inhibit CYP3 A4 may have an additive effect, potentially leading to arrhythmias. When boosted PIs are to be used concomitantly with itraconazole, monitoring levels of the antifungal is advised to guide dosage adjustments; high doses (>200 mg/day) of itraconazole are not recommended. Voriconazole should not be administered with boosted PIs because they decrease the voriconazole AUC. Unboosted atazanavir and fosamprenavir could possibly cause increases on voriconazole; therefore, monitoring for toxicities is necessary. Posaconazole causes increases in the AUC of atazanavir (both boosted and unboosted); therefore, patients who are receiving this combination should be monitored for atazanavir adverse events. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to patients outweighs the risk.Citation105 The use of high doses of fluconazole with tipranavir is not recommended. No dose adjustment of fluconazole is necessary with boosted atazanavir or saquinavir.

Systemic and inhaled steroids

The use of systemic, intranasal, or inhaled budesonide in combination with PIs is not recommended unless the potential benefits outweigh the risks, because this combination may result in decreased levels of PIs and an increase in glucocorticoids that can result in Cushing’s syndrome.Citation106,Citation107 Similarly, inhaled or intranasal fluticasone or systemic prednisone in combination with any boosted PI should be avoided, because it can result in adrenal insufficiency and Cushing’s syndrome.Citation108 The use of dexamethasone can cause a decrease in the levels of PIs and should therefore be used with caution.

Narcotic pain medications

Opioids are often used to treat pain in older patients to improve quality of life and function. The concurrent use of lopinavir/RTV increases the oxycodone AUC 2.6-fold. A reduction in the dose of oxycodone may be needed in addition to close monitoring for adverse opioid effects that indicate it may be necessary to reduce the oxycodone dose.Citation109 Boosted atazanavir, darunavir, and fosamprenavir cause a 16%–18% decrease in the methadone AUC, whereas lopinavir/RTV decreases the methadone AUC 26%–53% and saquinavir/RTV decreases it 19%. As a result, the concomitant use of boosted PI and methadone may cause opioid withdrawal such that the dose of methadone may need to be increased, in particular with higher reductions in AUC.Citation110Citation113

Osteoporosis therapies

Osteoporosis is common in HIV-infected persons and has a threefold higher prevalence compared with HIV-negative individuals.Citation114 The etiology of osteoporosis in HIV-infected patients is likely multifactorial, involving traditional risk factors as well as the direct effects of chronic HIV infection and antiretroviral therapy.Citation115 Emerging evidence suggests that the increase in the prevalence of osteoporosis in HIV-infected persons translates into a higher risk for fracture.Citation116,Citation117 As a result, it likely leads to excess morbidity and mortality as the HIV-infected patient ages. Bisphosphonates are generally considered first-line therapy for persons with a history of fragility fracture and/or osteoporosis as diagnosed by dual-energy X-ray absorptiometry. Both alendronate and zoledronic acid have been shown in randomized controlled trials to significantly improve bone mineral density at the lumbar spine and total hip in HIV-infected patients treated for 96 weeks, with no known DDIs between the bisphosphonates and HAART.Citation118,Citation119

Clinical considerations for polypharmacy

A thorough review of medications is absolutely essential when managing HIV-infected older adults. It should be protocol for the health care provider to perform an annual medication reconciliation and a medication review at every visit, especially after hospital stays: hospital admission is a known risk factor for using an increased number of both appropriate and inappropriate medications.Citation120 Following such a protocol will help generate a complete and accurate list of active medications that is useful and readily available.

Indeed, when looking at the general population, discrepancies have been noted in the following domains: what medications patients should be taking; what medications they are actually taking; and what physicians have recorded in the patients’ records.Citation121 Additionally, in a survey of Medicare beneficiaries, more than 35% of patients reported that they had not spoken with their doctor in the past 12 months about their different medications.Citation122 This should be of concern to clinical providers and provides a reason to consider changing the routine protocol.

In the ambulatory setting, there is little direct evidence to support any one method of medication review as superior to another.Citation123 Even so, a method that has been advocated for is the “brown bag” review. In the “brown bag” review, patients are asked to bring all their medications to the office, including prescription medications, over-the-counter medications, vitamins, and herbal preparations. This method helps start a conversation and provides a clear picture of the patient’s most up-to-date medication use.Citation124

Once all of the patient’s medications have been reconciled, it is helpful to review an array of issues, including: adherence to medication; the indications for medication; the effectiveness of the medication; and the patient’s tolerance of the medication. Patients are often reluctant to admit to nonadherence,Citation125 and clues can be obtained from observing medication organization, pill counts, and refill history.Citation124 Barriers to nonadherence include patients’ forgetting to take their pills, not believing the drug is effective, and having difficulty taking or tolerating the pills. Additionally, the cost of medications might also be limiting adherence. It may be appropriate for the clinical provider to answer questions from the patient and to reassure them concerning the effectiveness of any given medication to increase compliance.Citation124

Health care providers are often hesitant to stop medications, especially if they did not initiate the treatment. The decision to discontinue a medication is multifactorial and should take into account the indication for the medication, the interaction of the medication with other prescribed medications, tolerance of the medication, and the patient’s goals of care as well. Treatment targets are very often derived from studies completed in younger and healthier patients, and there is often little evidence to guide prescription in older adults with multimorbidity.Citation126

To summarize, it is extremely important to have a complete and accurate medication history prior to starting additional medications (). When prescribing a new medication, health care providers should be careful to choose the drug with the highest therapeutic ratio provided efficacy is comparable, because sometimes ADEs are dose related. For example, higher doses of atypical antipsychotics were shown to cause more Parkinsonism in older adults than did lower-dosed treatment.Citation127 Doses should be titrated up carefully from a low starting dose in patients where pharmacodynamic or pharmacokinetic sensitivity are likely to be concerns. In certain cases, therapeutic monitoring of plasma drug concentrations may be an aid to treatment, such as for hypothyroidism.Citation128 However, clinical judgment is also essential in titrating drug dosages.

Table 2 General considerations for managing polypharmacy in older adults

The prescriber should pay particular attention to avoid combinations that demonstrate known additional or synergistic toxic effects (eg, two medications with anticholinergic activity). Additionally, when multiple medications are required, such as in HIV-infected individuals, a dosing schedule should be established to clarify times of medication administration. Current evidence suggests that more efforts are needed to ensure patients receive clear and consistent information supporting safe medication use.Citation129,Citation130

Sometimes simplicity is the best solution. It may be ideal to have as few physicians as needed to address a patient’s care. This move to better integrate care can help with managing polypharmacy as well as providing nonconflicting and good communications between health care providers and caregivers. A work group comprising leading researchers and clinicians across the country was formed as part of the HIV and Aging Consensus Project. The aim of this project was to recommend treatment strategies for clinicians who manage HIV-infected older adults. To address the above-mentioned concern, this work group recommended that individuals use either only one pharmacy or a pharmacy with an integrated computer network, and if possible, use a HIV-specialty pharmacy.Citation131 Having a clinical pharmacist assist with prescriptions can help to reduce inappropriate prescribing and thereby decrease the rate of drug-related problems.Citation132,Citation133 Another method that may be helpful in managing the complex challenge of polypharmacy in HIV-infected older adults is the development of a clinic for HIV-infected patients over 50 years of age comparable to that developed in London.Citation134

Conclusion

Over the last few decades, the number of HIV-infected older adults has increased significantly. Older patients with HIV-infection have several comorbidities requiring multiple pharmacotherapies that can increase their risk of polypharmacy and related adverse events. However, little is known about the impact of aging on medication use in HIV-infected older individuals, the potential for interactions with HAART and administered medications, and the impact of this on therapy tolerability and virological response with aging. Reducing pill burden, careful titration of medications, and increasing awareness of common DDIs can prevent coadministration of potentially harmful combinations and reduce unnecessary polypharmacy-related adverse events in this population. More studies need to be conducted to assess the long-term safety and efficacy of HAART in older adults with HIV infection.

Acknowledgments

The University of Rochester CTSA award KL2 RR024136 funded this work.

Disclosure

The authors report no conflict of interest in this work. The sponsor had no role in this work.

References

  • Antiretroviral Therapy Cohort CollaborationLife expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studiesLancet2008372963529329918657708
  • EffrosRBFletcherCVGeboKAging and infectious diseases: workshop on HIV infection and aging: what is known and future research directionsClin Infect Dis200847454255318627268
  • ShahSSMcGowanJPSmithCBlumSKleinRSComorbid conditions, treatment, and health maintenance in older persons with human immunodeficiency virus infection in New York CityClin Infect Dis200235101238124312410484
  • SimoneMJAppelbaumJHIV in older adultsGeriatrics2008631261219061274
  • GouletJLFultzSLRimlandDAging and infectious diseases: do patterns of comorbidity vary by HIV status, age, and HIV severity?Clin Infect Dis200745121593160118190322
  • GeboKAEpidemiology of HIV and response to antiretroviral therapy in the middle aged and elderlyAging Health20084661562719915688
  • BushardtRLJonesKWNine key questions to address polypharmacy in the elderlyJAAPA2005185323715918615
  • HajjarERCaferoACHanlonJTPolypharmacy in elderly patientsAm J Geriatr Pharmacother20075434535118179993
  • HanlonJTSchmaderKERubyCMWeinbergerMSuboptimal prescribing in older inpatients and outpatientsJ Am Geriatr Soc200149220020911207875
  • BushardtRLMasseyEBSimpsonTWAriailJCSimpsonKNPolypharmacy: misleading, but manageableClin Interv Aging20083238338918686760
  • KaufmanDWKellyJPRosenbergLAndersonTEMitchellAARecent patterns of medication use in the ambulatory adult population of the United States: the Slone surveyJAMA2002287333734411790213
  • FreelandKNThompsonANZhaoYLealJEMauldinPDMoranWPMedication use and associated risk of falling in a geriatric outpatient populationAnn Pharmacother20124691188119222872750
  • ZhanCSanglJBiermanASPotentially inappropriate medication use in the community-dwelling elderly: findings from the 1996 Medical Expenditure Panel SurveyJAMA2001286222823282911735757
  • FialováDTopinkováEGambassiGAdHOC Project Research GroupPotentially inappropriate medication use among elderly home care patients in EuropeJAMA2005293111348135815769968
  • BuajordetIEbbesenJErikssenJBrørsOHilbergTFatal adverse drug events: the paradox of drug treatmentJ Intern Med2001250432734111576320
  • NolanLO’MalleyKPrescribing for the elderly. Part I: sensitivity of the elderly to adverse drug reactionsJ Am Geriatr Soc19883621421493276767
  • BudnitzDSLovegroveMCShehabNRichardsCLEmergency hospitalizations for adverse drug events in older AmericansN Engl J Med2011365212002201222111719
  • LazarouJPomeranzBHCoreyPNIncidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studiesJAMA199827915120012059555760
  • ShorrRIRayWADaughertyJRGriffinMRIncidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureasArch Intern Med199715715168116869250229
  • BjörkmanIKFastbomJSchmidtIKBernstenCBPharmaceutical Care of the Elderly in Europe Research (PEER) GroupDrug–drug interactions in the elderlyAnn Pharmacother200236111675168112398558
  • GurwitzJHFieldTSHarroldLRIncidence and preventability of adverse drug events among older persons in the ambulatory settingJAMA200328991107111612622580
  • FieldTSGurwitzJHHarroldLRRisk factors for adverse drug events among older adults in the ambulatory settingJ Am Geriatr Soc20045281349135415271125
  • JörgensenTJohanssonSKennerfalkAWallanderMASvärdsuddKPrescription drug use, diagnoses, and healthcare utilization among the elderlyAnn Pharmacother20013591004100911573845
  • LeesJChanAPolypharmacy in elderly patients with cancer: clinical implications and managementLancet Oncol201112131249125721741307
  • MaddenJMGravesAJZhangFCost-related medication nonadherence and spending on basic needs following implementation of Medicare Part DJAMA2008299161922192818430911
  • FedermanADAdamsASRoss-DegnanDSoumeraiSBAyanianJZSupplemental insurance and use of effective cardiovascular drugs among elderly medicare beneficiaries with coronary heart diseaseJAMA2001286141732173911594898
  • MillerRRHospital admissions due to adverse drug reactions. A report from the Boston Collaborative Drug Surveillance ProgramArch Intern Med197413422192234843186
  • RochonPAGurwitzJHOptimising drug treatment for elderly people: the prescribing cascadeBMJ19973157115109610999366745
  • FuAZJiangJZReevesJHPotentially inappropriate medication use and healthcare expenditures in the US community-dwelling elderlyMed Care200745547247617446834
  • American Geriatrics Society 2012 Beers Criteria Update Expert PanelAmerican Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adultsJ Am Geriatr Soc201260461663122376048
  • FickDMCooperJWWadeWEWallerJLMacleanJRBeersMHUpdating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of expertsArch Intern Med2003163222716272414662625
  • BeersMHExplicit criteria for determining potentially inappropriate medication use by the elderly. An updateArch Intern Med199715714153115369236554
  • BeersMHOuslanderJGRollingherIReubenDBBrooksJBeckJCExplicit criteria for determining inappropriate medication use in nursing home residents. UCLA Division of Geriatric MedicineArch Intern Med19911519182518321888249
  • HanlonJTSchmaderKESamsaGPA method for assessing drug therapy appropriatenessJ Clin Epidemiol19924510104510511474400
  • SteinmanMALandefeldCSRosenthalGEBerthenthalDSenSKaboliPJPolypharmacy and prescribing quality in older peopleJ Am Geriatr Soc200654101516152317038068
  • IngersollKSCohenJThe impact of medication regimen factors on adherence to chronic treatment: a review of literatureJ Behav Med200831321322418202907
  • MarzoliniCBackDWeberRSwiss HIV Cohort Study MembersAgeing with HIV: medication use and risk for potential drug–drug interactionsJ Antimicrob Chemother20116692107211121680580
  • MillerCDEl-KholiRFaragonJJLodiseTPPrevalence and risk factors for clinically significant drug interactions with antiretroviral therapyPharmacotherapy200727101379138617896893
  • AmmassariAMurriRPezzottiPAdICONA Study GroupSelf-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infectionJ Acquir Immune Defic Syndr200128544544911744832
  • BarclayTRHinkinCHCastellonSAAge-associated predictors of medication adherence in HIV-positive adults: health beliefs, self- efficacy, and neurocognitive statusHealth Psychol2007261404917209696
  • HinkinCHHardyDJMasonKIMedication adherence in HIV-infected adults: effect of patient age, cognitive status, and substance abuseAIDS200418Suppl 1S19S2515075494
  • PatersonDLSwindellsSMohrJAdherence to protease inhibitor therapy and outcomes in patients with HIV infectionAnn Intern Med20001331213010877736
  • LiedtkeMDRathbunRCWarfarin-antiretroviral interactionsAnn Pharmacother200943232232819196837
  • de MaatMMEkhartGCHuitemaADKoksCHMulderJWBeijnenJHDrug interactions between antiretroviral drugs and comedicated agentsClin Pharmacokinet200342322328212603174
  • FellayJMarzoliniCDecosterdLVariations of CYP3 A activity induced by antiretroviral treatment in HIV-1 infected patientsEur J Clin Pharmacol2005601286587315657782
  • EaglingVABackDJBarryMGDifferential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavirBr J Clin Pharmacol19974421901949278209
  • RheeMSGreenblattDJPharmacologic consideration for the use of antiretroviral agents in the elderlyJ Clin Pharmacol200848101212122518812611
  • NachegaJBHsuAJUthmanOASpinewineAPhamPAAntiretroviral therapy adherence and drug–drug interactions in the aging HIV populationAIDS201226Suppl 1S39S5322781176
  • KlotzUPharmacokinetics and drug metabolism in the elderlyDrug Metab Rev2009412677619514965
  • SitarDSAging issues in drug disposition and efficacyProc West Pharmacol Soc200750162018605223
  • MarchesiniGBuaVBrunoriAGalactose elimination capacity and liver volume in aging manHepatology198885107910833417228
  • WynneHACopeLHMutchERawlinsMDWoodhouseKWJamesOFThe effect of age upon liver volume and apparent liver blood flow in healthy manHepatology1989922973012643548
  • ManfrediRHIV infection and advanced age emerging epidemiological, clinical, and management issuesAgeing Res Rev200431315415164725
  • SulkowskiMSDrug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitorsClin Infect Dis200438Suppl 2S90S9714986280
  • ClarkWFSontropJMMacnabJJUrine volume and change in estimated GFR in a community-based cohort studyClin J Am Soc Nephrol20116112634264121885793
  • GuptaSKEustaceJAWinstonJAGuidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of AmericaClin Inf Dis2005401115591585
  • ChoiAIRodriguezRABacchettiPBertenthalDVolberdingPAO’HareAMRacial differences in end-stage renal disease rates in HIV infection versus diabetesJ Am Soc Nephrol200718112968297417942954
  • MocroftAKirkOGatellJChronic renal failure among HIV-1-infected patientsAIDS20072191119112717502722
  • ScherzerREstrellaMLiYAssociation of tenofovir exposure with kidney disease risk in HIV infectionAIDS201226786787522313955
  • KalayjianRCFranceschiniNGuptaSKSuppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney diseaseAIDS200822448148718301060
  • CohenCElionRRuanePRandomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infectionAIDS2011256F7F1221412057
  • ElionRCohenCGatheJGS-US-216-0105 Study TeamPhase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infectionAIDS201125151881188621811136
  • WormSWSabinCWeberRRisk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) studyJ Infect Dis2010201331833020039804
  • SeabergECMuñozALuMMulticenter AIDS Cohort StudyAssociation between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003AIDS200519995396015905677
  • SattlerFRQianDLouieSElevated blood pressure in subjects with lipodystrophyAIDS200115152001201011600829
  • HadiganCMeigsJBCorcoranCMetabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophyClin Infect Dis200132113013911118392
  • GlesbyMJAbergJAKendallMAet al; for Adult AIDS Clinical Trials Group A5159 Protocol Team. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockersClin Pharmacol Ther200578214315316084849
  • AIDSinfoGuidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents [webpage on the Internet]Rockville, MDDepartment of Health and Human Services2013 Available from: http://aidsinfo.nih.gov/guidelinesAccessed 27 Feb, 2013
  • ChengJWRybakIUse of digoxin for heart failure and atrial fibrillation in elderly patientsAm J Geriatr Pharmacother20108541942721335295
  • KoupJRGreenblattDJJuskoWJSmithTWKoch-WeserJPharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion dosesJ Pharmacokinet Biopharm1975331811921159622
  • SchmittCKaeserBRiekMBechNKreuzerCEffect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probeInt J Clin Pharmacol Ther201048319219920197013
  • KnoellKRYoungTMCousinsESPotential interaction involving warfarin and ritonavirAnn Pharmacother19983212129913029876810
  • KaminDSGrinspoonSKCardiovascular disease in HIV-positive patientsAIDS200519764165215821390
  • DubéMPCaddenJJLipid metabolism in treated HIV InfectionBest Prac Res Clin Endocrinol Metab2011253429442
  • DubéMPSteinJHAbergJAAdult AIDS Clinical Trials Group Cardiovascular SubcommitteeHIV Medical Association of the Infectious Diseases Society of AmericaGuidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials GroupClin Infect Dis200337561362712942391
  • SamineniDDesaiPBSallansLFichtenbaumCJSteady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatinJ Clin Pharm2012526922931
  • AquilanteCLKiserJJAndersonPLInfluence of SLCO1B1 polymorphisms on the drug-drug interaction between darunavir/ritonavir and pravastatinJ Clin Pharm2012521117251738
  • GerberJGRosenkranzSLFichtenbaumCJet al; for AIDS Clinical Trials Group A5108 Team. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 StudyJ Acquir Immune Defic Syndr200539330731215980690
  • GarrawayWMCollinsGNLeeRJHigh prevalence of benign prostatic hypertrophy in the communityLancet199133887654694711714529
  • BerrySJCoffeyDSWalshPCEwingLLThe development of human benign prostatic hyperplasia with ageJ Urol198413234744796206240
  • KirbyRSThe natural history of benign prostatic hyperplasia: what have we learned in the last decade?Urology2000565 Suppl 13611074195
  • Franco-SalinasGde la RosetteJJMichelMCPharmacokinetics and pharmacodynamics of tamsulosin in its modified-release and oral controlled absorption system formulationsClinical Pharmacokinet2010493177188
  • LallemandFSalhiYLinardFGiamiARozenbaum W. Sexual dysfunction in 156 ambulatory HIV-infected men receiving highly active antiretroviral therapy combinations with and without protease inhibitorsJ Acquir Immune Defic Syndr200230218719012045681
  • CoronaGRazzoliEFortiGMaggiMThe use of phosphodiesterase 5 inhibitors with concomitant medicationsJ Endocrinol Invest200831979980818997493
  • GurSKadowitzPJGokceASikkaSCLokmanUHellstromWJUpdate on drug interactions with phosphodiesterase-5 inhibitors prescribed as first-line therapy for patients with erectile dysfunction or pulmonary hypertensionCurr Drug Metab201314226526923140258
  • NkuizeMDe WitSMulsVArvanitakisMBusetMUpper gastrointestinal endoscopic findings in the era of highly active antiretroviral therapyHIV Med201011641241720146733
  • WangXBoffitoMZhangJEffects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patientsAIDS Patient Care STDS201125950951521770762
  • LuberADBrowerRKimDSilvermanRPeloquinCAFrankISteady-state pharmacokinetics of once-daily fosamprenavir/ritonavir and atazanavir/ritonavir alone and in combination with 20 mg omeprazole in healthy volunteersHIV Med20078745746417760738
  • WinstonABackDFletcherCEffect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteersAIDS200620101401140616791014
  • LynessJMCaineEDKingDACoxCYoedionoZPsychiatric disorders in older primary care patientsJ Gen Intern Med199914424925410203638
  • CieslaJARobertsJEMeta-analysis of the relationship between HIV infection and risk for depressive disordersAm J Psychiatry2001158572573011329393
  • CaballeroJNahataMCUse of selective serotonin-reuptake inhibitors in the treatment of depression in adults with HIVAnn Pharmacother200539114114515562140
  • ElliottAJUldallKKBergamKRussoJClaypooleKRoy-ByrnePPRandomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatientsAm J Psychiatry199815533673729501747
  • van der LeeMJBlenkeAARongenGAInteraction study of the combined use of paroxetine and fosamprenavir-ritonavir in healthy subjectsAntimicrob Agents Chemother200751114098410417846135
  • GreenblattDJvon MoltkeLLHarmatzJSShort-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodoneJ Clin Pharmacol200343441442212723462
  • HogelandGWSwindellsSMcNabbJCKashubaADYeeGCLindleyCMLopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjectsClin Pharmacol Ther2007811697517186001
  • MerryCMulcahyFBarryMGibbonsSBackDSaquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV diseaseAIDS19971122682699030388
  • SchmittCHofmannCRiekMPatelAZwanzigerEEffect of saquinavir-ritonavir on cytochrome P450 3 A4 activity in healthy volunteers using midazolam as a probePharmacotherapy200929101175118119792991
  • BrackettCCSevere prolonged sedation associated with coadministration of protease inhibitors and intravenous midazolam during bronchoscopy: a commentaryPharmacotherapy2013335e85e8623065869
  • GreenblattDJvon MoltkeLLDailyJPHarmatzJSShaderRIExtensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: the clinical dilemma of concurrent inhibition and inductionJ Clin Psychopharmacol199919429329610440454
  • OwensRCJrQT prolongation with antimicrobial agents: understanding the significanceDrugs200464101091112415139788
  • OwensRCJrNolinTDAntimicrobial-associated QT interval prolongation: pointes of interestClin Infect Dis200643121603161117109296
  • BaciewiczAMChrismanCRFinchCKSelfTHUpdate on rifampin, rifabutin, and rifapentine drug interactionsCurr Med Res Opin201329111223136913
  • De PontiFPoluzziECavalliARecanatiniMMontanaroNSafety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overviewDrug Saf200225426328611994029
  • KrishnaGMotonAMaLMartinhoMSeiberlingMMcLeodJEffects of oral posaconazole on the pharmacokinetics of atazanavir alone and with ritonavir or with efavirenz in healthy adult volunteersJ Acquir Immune Defic Syndr200951443744419623694
  • YoganathanKDavidLWilliamsCJonesKCushing’s syndrome with adrenal suppression induced by inhaled budesonide due to a ritonavir drug interaction in a woman with HIV infectionIntl J STD AIDS2012237520521
  • FrankelJKPackerCDCushing’s syndrome due to antiretroviral-budesonide interactionAnn Pharmacother201145682382421558486
  • PenzakSRFormentiniEAlfaroRMLongMNatarajanVKovacsJPrednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteersJ Acquir Immune Defic Syndr200540557358016284534
  • NieminenTHHagelbergNMSaariTIOxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavirEur J Clin Pharmacol2010661097798520697700
  • ClarkeSMulcahyFBerginCAbsence of opioid withdrawal symptoms in patients receiving methadone and the protease inhibitor lopinavir-ritonavirClin Infect Dis20023481143114511915005
  • BartPARizzardiPGGallantSMethadone blood concentrations are decreased by the administration of abacavir plus amprenavirTher Drug Monit200123555355511591903
  • SekarVTomakaFLefebvreEPharmacokinetic interactions between darunavir/ritonavir and opioid maintenance therapy using methadone or buprenorphine/naloxoneJ Clin Pharmacol201151227127820421512
  • JamoisCSmithPMorrisonREffect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapyAddict Biol200914332132719523046
  • BrownTTQaqishRBAntiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic reviewAIDS200620172165217417086056
  • Walker HarrisVBrownTTBone loss in the HIV-infected patient: evidence, clinical implications, and treatment strategiesJ Infect Dis2012205Suppl 3S391S39822577213
  • TortiCMazziottiGSoldiniPAHigh prevalence of radiological vertebral fractures in HIV-infected malesEndocrine201241351251722198528
  • YoungBDaoCNBuchaczKBakerRBrooksJTHIV Outpatient Study (HOPS) InvestigatorsIncreased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000–2006Clin Infect Dis20115281061106821398272
  • BollandMJGreyABHorneAMAnnual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trialJ Clin Endocrinol Metab20079241283128817227801
  • Rozenberg S, Lanoy E, Bentata M, et al; for ANRS 120 Fosivir Study Group. Effect of alendronate on HIV-associated osteoporosis: a randomized, double-blind, placebo-controlled, 96-week trial (ANRS 120)AIDS Res Hum Retroviruses201228997298022353022
  • BeersMHDangJHasegawaJTamaiIYInfluence of hospitalization on drug therapy in the elderlyJ Am Geriatr Soc19893786796832754151
  • BedellSEJabbourSGoldbergRDiscrepancies in the use of medications: their extent and predictors in an outpatient practiceArch Intern Med2000160142129213410904455
  • WilsonIBSchoenCNeumanPPhysician-patient communication about prescription medication nonadherence: a 50-state study of America’s seniorsJ Gen Intern Med200722161217351835
  • BayoumiIHowardMHolbrookAMSchabortIInterventions to improve medication reconciliation in primary careAnn Pharmacother200943101667167519737997
  • SteinmanMAHanlonJTManaging medications in clinically complex elders: “There’s got to be a happy medium”JAMA2010304141592160120940385
  • OsterbergLBlaschkeTAdherence to medicationN Eng J Med20053535487497
  • BoydCMDarerJBoultCFriedLPBoultLWuAWClinical practice guidelines and quality of care for older patients with multiple comorbid disease: implications for pay for performanceJAMA2005294671672416091574
  • RochonPAStukelTASykoraKAtypical antipsychotics and parkinsonismArch Int Med2005165161882188816157833
  • ClarkeNKabadiUMOptimizing treatment of hypothyroidismTreat Endocrinol20043421722116026104
  • WolfMSShekellePChoudhryNKAgnew-BlaisJParkerRMShrankWHVariability in pharmacy interpretations of physician prescriptionsMed Care200947337037319194338
  • WolfMSCurtisLMWaiteKHelping patients simplify and safely use complex prescription regimensArch Intern Med2011171430030521357804
  • Work Group forHIVAging Consensus PanelSummary report from the Human Immunodeficiency Virus and Aging Consensus Project: treatment strategies for clinicians managing older individuals with the human immunodeficiency virusJ Am Geriatr Soc201260597497922568508
  • HanlonJTWeinbergerMSamsaGPA randomized, controlled trial of a clinical pharmacist intervention to improve inappropriate prescribing in elderly outpatients with polypharmacyAm J Med199610044284378610730
  • VinksTHEgbertsTCde LangeTMde KoningFHPharmacist-based medication review reduces potential drug-related problems in the elderly: the SMOG controlled trialDrugs Aging200926212313319220069
  • WatersLPattersonBScourfieldAA dedicated clinic for HIV-positive individuals over 50 years of age: a multidisciplinary experienceInt J STD AIDS201223854655222930290
  • Edmunds-OgbuokiriJClinically significant drug interactions in the HIV-infected elderlyHIV Clin20112321215