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Antiretroviral therapy adherence and drug–drug interactions in the aging HIV population

Nachega, Jean B.a,b,c; Hsu, Alice J.d; Uthman, Olalekan A.e; Spinewine, Annef; Pham, Paul A.g

doi: 10.1097/QAD.0b013e32835584ea
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It is estimated that by 2015 more than half of all HIV-infected individuals in the United States will be 50 years of age or older. As this population ages, the frequency of non-AIDS related comorbidities increases, which includes cardiovascular, metabolic, gastrointestinal, genitourinary and psychiatric disorders. As a result, medical management of the aging HIV population can be complicated by polypharmacy and higher pill burden, leading to poorer antiretroviral therapy (ART) adherence. Adherence to ART is generally better in older populations when compared to younger populations; however, cognitive impairment in elderly patients can impair adherence, leading to worse treatment outcomes. Practical monitoring tools can improve adherence and increase rates of viral load suppression. Several antiretroviral drugs exhibit inhibitory and/or inducing effects on cytochrome P450 isoenzymes, which are responsible for the metabolism of many medications used for the treatment of comorbidities in the aging HIV population. The combination of ART with polypharmacy significantly increases the chance of potentially serious drug–drug interactions (DDIs), which can lead to drug toxicity, poorer ART adherence, loss of efficacy of the coadministered medication, or virologic breakthrough. Increasing clinicians awareness of common DDIs and the use of DDI programs can prevent coadministration of potentially harmful combinations in elderly HIV-infected individuals. Well designed ART adherence interventions and DDI studies are needed in the elderly HIV population.

aDepartment of International Health

bDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

cDepartment of Medicine and Centre for Infectious Diseases, Stellenbosch University, Faculty of Health Sciences Cape Town, Cape Town, South Africa

dDepartment of Pharmacy, The Johns Hopkins Hospital, Baltimore, Maryland, USA

eDepartment of Primary Care Sciences, Faculty of Health Sciences, Keele University, Keele, Staffordshire, UK

fUniversité catholique de Louvain, Louvain Drug Research Institute, Brussels, and CHU Mont-Godinne, Yvoir, Belgium

gDivision of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Correspondence to Jean B. Nachega, MD, PhD, Global Disease Epidemiology and Control Program, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, 615N Wolfe Street, Suite W5031, Baltimore, MD 21205, USA. Tel: +1 410 955 2378; fax: +1 410 502 6733; e-mail:

Received 12 December, 2011

Accepted 23 April, 2012

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The introduction of effective antiretroviral therapy (ART) has resulted in the reduction of AIDS-related mortality [1,2] and increased the life expectancy of HIV-infected individuals [3]. By 2015, it is projected that more than 50% of all HIV-infected individuals living in the United States will be 50 years of age or older [4]. With increasing age, the pattern of morbidity and mortality shifts from AIDS-related opportunistic infections to age-related comorbidities, such as cardiovascular disease, metabolic disorders, non-HIV-related malignancies, osteoporosis and decline in organ function (renal as well as hepatic) [2,5]. When controlling for sex, baseline CD4 cell count and year of therapy initiation, older age (50 years of age and older) was significantly associated with higher mortality [adjusted hazard ratio 1.23, 95% confidence interval (CI) 1.08–1.42] [6]. In addition, Goulet et al.[7] reported that HIV-infected veterans had a lower risk of hypertension, diabetes, vascular disease and psychiatric disorders. However, they had a higher risk of liver disease, renal disease, substance use disorder and multimorbidity. HIV infected veterans 50 years of age and older had higher odds of multimorbidity than HIV uninfected veterans 50 years of age and older.

Due to the above comorbidities, medical management of older HIV-infected individuals becomes complicated by polypharmacy. In an analysis of the Swiss HIV Cohort study, the combination of ART with polypharmacy significantly increased the chance of potentially serious drug–drug interactions (DDIs) [8], which can lead to drug toxicity, loss of efficacy of the coadministered medication and virologic breakthrough. When HIV-infected individuals at least 50 years of age were compared to HIV-infected individuals less than 50 years of age, older patients were more likely to receive concomitant medications versus younger patients (82 vs. 61%, P < 0.001), therefore, also had more DDIs (51 vs. 35%, P < 0.001). Certain therapeutic classes were prescribed more often in elderly patients, including cardiovascular drugs, gastrointestinal medications and hormonal agents. Elderly patients are two to three times more likely to develop an adverse drug reaction compared to younger patients [9]. There is a paucity of clinical and pharmacokinetic DDI studies in the older HIV population. In a cohort study of 1000 HIV-negative elderly patients more than 70 years old who were admitted to the hospital for an acute illness, 894 were receiving at least two medications. Of these 894 patients, 60.2% were exposed to potential DDI, and as a result of these DDI, 24% developed clinically significant side effects [10].

Other important ART considerations in the aging HIV population include issues related to adherence, as well as clinical/immunological response to ART. Poor adherence to ART in the aging HIV population can be the consequence of multiple factors including neurocognitive decline [11–13], social isolation/lack of social support and depression [14–17] and chronic adverse drug effects (e.g. lipodystrophy) [18]. High drug cost in uninsured or underinsured elderly patients is also associated with decreased adherence and poor outcome [19,20]. As an example, in the North American AIDS Cohort Collaboration on Research and Design cohort, it was found that older age (per 10 years increment) was associated with a 68% increase in death when ART was deferred [21,22] and that CD4 cell count at presentation for HIV care among patients older than 50 years old were lower [23]. Although elderly patients may have a higher baseline HIV viral load and lower CD4 cell count, their virologic response to ART is similar to younger HIV-infected individuals [24] but CD4 cell recovery after starting ART is generally lower in this elderly HIV-infected population [21,24,25]. However, these findings were not confirmed by Tumbarello et al.[26]. Among other factors, biological factors that negatively influence the risk of developing immune responses and immune reconstitution (e.g. advanced diseases at start of ART, thymic output, reduced bone marrow capacity) may affect outcome in the older HIV-infected patients [27–29].

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HIV treatment adherence in the aging population

Overall, higher adherence to ART is associated with older age, and although current combination ART can be forgiving of occasional lapses in adherence, higher levels of adherence is associated with the maximal likelihood of virologic suppression and lower level of drug resistance in both younger adults and older patients [30–32]. However, among older patients with HIV, those with documented cognitive decline are likely to have poor ART adherence, disease progression and death [33]. In a volunteer sample of 431 HIV-infected adult patients on ART, recruited from community agencies and university-affiliated infectious disease clinics in the Los Angeles area, neurocognitive measurements were conducted. These included tests on attention, information processing speed, learning/memory, verbal fluency, motor functioning and executive functioning. Medication adherence was measured using microchip-embedded pill bottle caps (Medication Event Monitoring System caps) and was self-reported. Structural equation modeling (SEM) techniques were used to evaluate factor models of cognition and adherence. The study found that mean adherence rates were higher among older (≥50 years) than younger (<50 years) HIV-positive adults. Nevertheless, the SEM analysis revealed that older patients with neurocognitive impairment were associated with poorer medication adherence [23]. When cognitive functions were examined individually, executive function, motor function and processing speed were most strongly correlated with adherence in this elderly group. Similar to younger patients, older HIV-positive individuals with neurocognitive impairment or drug abuse problems are at increased risk of suboptimal adherence to medications. The above findings highlight the importance of optimizing medication adherence rates and evaluating neurocognition in the growing population of elderly HIV-infected patients.

In 2008, Branas et al.[34] also found that older age was associated with higher ART adherence, however, the authors did not investigate neurocognition disorders as independent factors. In addition, they found a lower CD4 cell count increase after ART initiation in the older group. Hinkin et al.[33] found that in addition to neurocognition disorders, current drug abuse or dependence, but not current alcohol abuse or dependence, was also associated with suboptimal medication adherence.

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Antiretroviral therapy adherence interventions in the aging HIV population

There are limited interventional studies aimed to improve ART adherence in the elderly HIV population to guide or support specific recommendations. Although one could extrapolate from other interventions conducted in elderly patients affected by chronic conditions such as diabetes or hypertension, it is important to evaluate such interventions in the aging HIV population and more specifically those with neurocognition disorders and/or drug abuse. ART adherence interventions that have proven effective in the adult HIV-infected population includes electronic reminder devices [35,36], screening for and treating depression [37], addressing substance abuse [38], organizing pillboxes [39], increasing social support [40] and simplifying ART regimens by reducing pill burden and frequency (e.g. once-daily and one tablet fixed-dose combinations) [41]. These interventions are likely to be of value in the elderly HIV population, but specific data in this aging population are urgently needed.

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Immunologic and clinical response to antiretroviral therapy in the aging HIV population

HIV-infected patients over the age of 50 are more likely to present with lower CD4 cell counts and more advanced disease [23]. As a result, among patients who are older than 60 years of age, a higher proportion of these patients progressed to AIDS within 1 year of HIV diagnosis compared to younger patients (52 vs. 15%) [42].

Although older HIV-infected individuals are less likely to experience treatment failure with ART compared to younger patients due to better adherence, some studies suggest that older individuals have less CD4 cell recovery [43,44]. In a Spanish study, Nogueras et al.[24] showed that although HIV-infected older patients were more likely to have higher viral load and lower CD4 cell counts at baseline when presenting to the first clinic visit, they were not likely to achieve the same CD4 cell counts compared with younger individuals. Based on these observations, the Department of Health and Human Services guidelines recommended ART in all patients older than 50 years of age, regardless of CD4 cell count [45]. However, as shown by Tumbarello et al. [26], despite having lower baseline CD4 cell count and higher frequency of comorbid conditions, in multivariate analysis, there was no statistically significant difference between older and younger HIV-infected patients regarding viroimmunological response to ART.

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Antiretroviral drug–drug interactions in the aging HIV population

The combination of ART with polypharmacy for the management of comorbidities significantly increases the chance of potentially serious DDI, which can lead to drug toxicity and loss of efficacy. The effect of aging on drug metabolism and clearance adds another layer of complexity. Liver volume [46] and hepatic blood flow [47] decrease with increasing age. Comparisons of drug metabolism in vivo have been conducted in younger versus older HIV-negative patients. CYP1A2 activity seems to be preserved in older patients, particularly those who are nonsmokers [48]. Age does not seem to affect CYP2D6 metabolism, whereas CYP2D6 polymorphisms were found to significantly impact elimination rates[49]. The following age-related differences in CYP2C19 metabolism have been noted; older individuals who are either extensive metabolizers or intermediate metabolizers have approximately two-fold higher exposures to omeprazole compared to younger individuals. However, age had less effect on poor metabolizers [50]. Age does not appear to affect CYP2C9 metabolism of diclofenac and celecoxib [51]; however, warfarin is primarily metabolized through CYP2C9, and it has been shown that the average dose requirement for warfarin decreases as age increases [52]. Lastly, age has not been shown to significantly influence CYP3A metabolism [53] even in patients up to 100 years old [54]. This is important because CYP3A enzymes are involved in the metabolism of a majority of medications, and are the basis of many clinically important DDIs between ART and medications commonly prescribed in the aging population. These studies suggest that the overall hepatic elimination through CYP450 enzymes is relatively stable with increasing age. Similarly, phase II metabolism (glucuronidation, acetylation, and sulfatation) is also well preserved in older patients [55]. Enzyme induction also appears to be conserved in older patients, as rifampin was capable of inducing phase I and phase II pathways of metabolism to the same extent as in younger individuals [56].

On average, glomerular filtration declines by 1% per year [57]. HIV-infected patients are at increased risk for developing chronic kidney disease (CKD) with a prevalence of an estimated glomerular filtration rate less than 60 ml/min per 1.73 m2 reported in approximately 7% of HIV-infected patients [58]. In addition to older age, many other factors such as diabetes, hypertension, intravenous drug use, high viral load, low CD4 cell count, race, concurrent use of certain antiretrovirals [e.g. tenofovir, indinavir, atazanavir (ATV)] and hepatitis C coinfection have been associated with CKD in HIV-infected individuals [58–61]. In a large cohort study from the Veteran Health Administration involving over 10 000 HIV-infected patients, tenofovir use was associated with a 34% increased risk of proteinuria (95% CI 25–45%, P < 0.0001), 11% increased risk of rapid decline in kidney function (95% CI 3–18%, P = 0.0033), and 33% increased risk of CKD (95% CI 18–51%; P < 0.0001). Risk of tenofovir-associated nephrotoxicity did not further increase in a subgroup of patients older than 46 years [62]. However, in an expanded-access tenofovir study, older age was a baseline risk factor for increased serum creatinine [63]. It is important for clinicians to recognize that older HIV-infected patients may have decreased glomerular filtration rate, and as a result may be at higher risk of nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-induced toxicity if renal dosing guidelines are not followed [45].

Clinically significant DDI involving ART and medications used to treat cardiovascular diseases, metabolic, gastrointestinal, psychiatric disorders and other medications commonly used in the elderly population are reviewed here with recommendations provided for the selection of alternative agents to minimize potentially harmful DDI. As a class effect, protease inhibitors are inhibitors of CYP450 3A4 enzymes and to some extent of other isoenzymes, with the most potent being ritonavir (RTV), which is used to ‘boost’ the effect of other protease inhibitors by inhibiting their metabolism. Interactions between protease inhibitors and other medications metabolized through CYP450 may lead to increased plasma concentrations of the coadministered medication, potentially leading to serious/life-threatening adverse drug reactions. With the exception of delavirdine (DLV) and rilpivirine, nonnucleoside reverse transcriptase inhibitors (NNRTIs) including efavirenz (EFV), etravirine (ETR) and nevirapine (NVP) are moderate inducers in vivo of CYP450 3A4 enzymes, although EFV has been found in vitro to inhibit certain CYP450 enzymes as well [64]. Interactions involving EFV, NVP and ETR and other medications metabolized through CYP450 3A4 can lead to decreased plasma concentrations of the coadministered medication, potentially leading to decreased efficacy. NRTIs, maraviroc, raltegravir, rilpivirine and enfuvirtide do not inhibit or induce CYP450 isoenzymes; therefore, clinically significant DDI are uncommon.

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Drug–drug interactions with cardiovascular medications

Cardiovascular disease is one of the most common comorbidities in the aging HIV-infected population [8]. Coronary artery disease (CAD) is emerging as a complication in HIV-infected patients, which may be due to a combination of increasing age, toxicity from long-term ART [65] and potentially due to HIV immune activation. Prolonged treatment with ART is associated with a higher prevalence of hypertension in HIV-infected individuals [66]. Routine blood pressure monitoring and initiation of antihypertensive medications when indicated is essential to decrease the risk of developing hypertension-related morbidities [67]. DDI studies involving cardiovascular agents and antiretroviral drugs were conducted in young healthy volunteers. All dihydropyridine calcium channel blockers (CCBs) are metabolized via CYP3A4; as a result, all boosted protease inhibitors may increase CCB serum concentrations and can potentially prolong the PR interval and augment hypotensive effect. In a drug interaction study conducted with unboosted ATV, diltiazem area under the plasma concentration time curve (AUC) was increased by 225% and the PR interval was prolonged although the majority of patients were asymptomatic with first degree atrioventricular block [68]. Therefore, it is recommended to decrease the diltiazem dose by 50% and titrate slowly with close monitoring [69]. Similarly, use of other CCB that are more likely to prolong the PR interval (e.g. verapamil) with boosted protease inhibitors should be closely monitored. On the contrary, EFV, ETR and NVP have the potential to decrease CCB serum concentrations and dose adjustment of CCB at steady state may be needed. Digoxin serum concentrations were increased by 86% with RTV coadministration due to inhibition of P-glycoprotein (P-gp). [70]. In a cohort study involving 2030 HIV-negative elderly patients who were taking digoxin, if they had been hospitalized during the previous 2 months, they were at more than four times increased risk for additional hospitalizations due to digoxin toxicity [71]. With the increased risk of CKD and potential for DDI with boosted protease inhibitors, HIV-infected elderly patients may be at even higher risk for digoxin toxicity. Close monitoring of digoxin serum concentrations is critical in older HIV-infected patients.

Many antiarrhythmic medications are CYP450 3A4 substrates. The use of amiodarone, bepridil, flecainide, propafenone and quinidine are contraindicated with RTV boosted protease inhibitors (PI/r) due to the potential risk of exacerbating cardiac arrhythmias [72]. The use of disopyramide, dofetilide, lidocaine, mexiletine and procainamide with PI/r should be approached with caution due to the potential risk of significantly increasing antiarrhythmic serum concentrations.

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Drug–drug interactions with anticoagulation

Older age is associated with increased risk of major hemorrhage when taking warfarin [73]. Significant DDIs between warfarin, protease inhibitors and NNRTIs may further increase the risk of significant hemorrhage. Clinically relevant DDIs between anticoagulants and antiretrovirals are listed in Table 1[69,74,75]. Warfarin exists as two isomers that differ in potency and route of metabolism. S-warfarin is two to five times more potent than R-warfarin. The more potent S-isomer is a CYP2C9 substrate, whereas the R-isomer is metabolized via CYP1A2 and CYP3A4 [76,77]. Induction properties of NVP and lopinavir/RTV at steady state resulting in increased warfarin requirements have been reported [78]. RTV is a mixed CYP3A4 inhibitor and inducer and a mild CYP2C9 inhibitor. When RTV is added to a stable warfarin regimen, a supratherapeutic international normalized ratio (INR) may result initially. However, at steady state, subtherapeutic warfarin concentrations as a result of CYP3A4 induction may occur [79–81]. Although these early reports used higher than currently recommended doses of RTV, a 29% decrease in mean S-warfarin AUC was also observed with darunavir/RTV (DRV/r; 600/100 mg twice daily) [82]. In older patients, close INR monitoring should be performed when boosted protease inhibitors or NNRTIs are added to a stable warfarin regimen.

Dabigatran is a P-gp substrate, but not a substrate, inhibitor or inducer of CYP450 isoenzymes. Certain P-gp inhibitors (e.g. ketoconazole, dronedarone) increase dabigatran concentrations by approximately two-fold [75]. PI/r may inhibit P-gp and may increase dabigatran concentrations. Although clinical data are lacking, in patients with moderate renal impairment (creatinine clearance 15–30 ml/min), a lower dose of dabigatran should be considered in patients treated with boosted protease inhibitors.

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Drug–drug interactions with medications used in metabolic disorders

Significant DDI between antiretrovirals and antihyperlipidemic agents have been reported (Table 2) [64,72,83–92]. PI/r can significantly increase simvastatin and lovastatin concentrations. Coadministration of these 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors are not recommended due to the potential for rhabdomyolysis [87,88,92]. Moderate DDIs have been reported with protease inhibitors and atorvastatin [83–86], pravastatin [64,82,89] and rosuvastatin [90], but with close monitoring and dose adjustment, these ‘statins’ can be safely coadministered with protease inhibitors.

The incidence of T2DM is increased in older HIV-infected individuals, which may be linked to long-term use of ART [93,94]. Non-HIV infected elderly patients 65 years or older with diabetes were found to have a 36% increased risk of developing hypoglycemia while receiving sulfonylureas when compared with younger patients [95]. This risk of hypoglycemia may be even higher in HIV-infected elderly patients due to the presence of DDI between oral hypoglycemics and antiretrovirals. There are limited DDI studies conducted with antiretroviral drugs and oral hypoglycemic medications; however, based on the route of metabolism, there are some potentially significant DDIs [69]. PI/r may increase serum concentrations of sulfonylureas [96,97], pioglitazone [98], repaglinide [99,100] and nateglinide [101]; on the contrary, EFV, ETR and NVP may decrease concentrations of these agents. Rosiglitazone can be considered as an alternative agent with less potential for DDI with antiretrovirals [102,103]. Although DDI are unlikely to occur with metformin through CYP450 enzymes [104], declines in renal function due to increasing age, antiretrovirals (e.g. tenofovir [105]) or HIV-associated nephropathy (HIVAN) [106] can alter the serum concentration of metformin, predisposing to serious side effects including lactic acidosis [107]. Interactions with α-glucosidase inhibitors (acarbose, miglitol) and antiretrovirals are unlikely [108,109]. Among the dipeptidyl peptidase IV inhibitors, the saxagliptin dose should be limited to 2.5 mg once daily when coadministered with PI/r due to inhibition of CYP3A4-mediated metabolism of saxagliptin [110], and linagliptin coadministration with PI/r, EFV, ETR and NVP should be avoided [111]. Providers can consider using sitagliptin as an alternative agent [112]; however, close monitoring of blood glucose is recommended.

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Drug–drug interactions with medications used for genitourinary disorders

The prevalence of benign prostatic hyperplasia (BPH) is higher in elderly patients. Biopsy confirmed BPH increases from about 40 to 50% in men aged 51–60, to over 80% in men older than 80 years [113]. DDI with BPH medications and antiretroviral drugs are shown in Table 3[46,69,114–118]. PI/r may significantly increase concentrations of α-adrenergic antagonist such as alfuzosin and coadministration is not recommended [114]. Tamsulosin is a CYP3A4 and CYP2D6 substrate and its concentrations were increased 2.8-fold when coadministered with a strong CYP3A4 inhibitor (e.g ketoconazole) [115]. Similarly, other PI/r may increase tamsulosin concentration and increase the risk of orthostatic hypotension (especially with the first dose). However, minimal interactions are expected between protease inhibitors and other α antagonists (e.g. doxazosin, prazosin).

Erectile dysfunction has been reported in up to 74% of HIV-infected men [119]. The increased risks are multifactorial and include low testosterone, older age, diabetes, neuropathy, drug use and depression [120]. There are significant DDI between PI/r and drugs used for erectile dysfunction (Table 3). Concentrations of sildenafil [116], tadalafil [117] and vardenafil [118] can all be increased by 2.2–11-fold with PI/r. With PI/r coadministration, dose adjustment of erectile dysfunction agents is recommended to prevent unsafe drop in blood pressure.

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Drug–drug interactions with medications used for gastrointestinal disorders

Interactions with acid reducing agents and antiretroviral drugs are common in clinical practice. There have been significant increases seen over time in the frequencies of reflux symptoms, gastroesophageal reflux disease and Helicobacter pylori infections in HIV-infected individuals [121]. Additionally, HIV-infected individuals have been found to have elevated gastric pH values, which can lead to alteration in drug absorption [122]. Providers should be aware of clinically significant DDIs with acid-reducing agents and several antiretrovirals including ATV [68,123,124], unboosted fosamprenavir [83], nelfinavir [125], tipranavir [84] and rilpivirine [126]. These antiretroviral drugs require an acidic environment for absorption; therefore, any acid suppressant therapy (antacids, H2 receptor antagonists, proton pump inhibitors) has the potential to significantly reduce these antiretroviral serum concentrations, which can potentially lead to treatment failure of HIV. For example, the coadministration of ATV/RTV (ATV/r) with omeprazole resulted in a 76% decrease in ATV AUC [68]. Although the manufacturer suggests that ATV/r can be safely coadministered with low-dose (20 mg) omeprazole, most experts recommend switching to an alternative protease inhibitor such as DRV/r. Recommendations for the safe coadministration of these antiretroviral drugs with acid suppressants are summarized in Table 4[68,69,83,84,124–126].

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Drug–drug interactions with medications used for central nervous system disorders

Depression and other psychiatric conditions are prevalent in HIV-infected patients [12,127–131]. Non-HIV infected elderly patients taking psychotropics, antidepressants and benzodiazepines are at 78, 59 and 39% increased risk for fall, respectively [132]. However, treatment of depression is critical in the elderly HIV population because untreated depression negatively impacts progression to AIDS and death in patients with HIV [133]. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression in HIV-infected individuals [134], as they are better tolerated than tricyclic antidepressants (TCA). With protease inhibitor coadministration, orthostatic hypotension and anticholinergic side effects from TCAs can result in severe morbidity [72]. There are also several clinically significant DDI with other antidepressants that warrant a dosage reduction of the antidepressant listed in Table 5[64,69,72,82,126,135–153,156–163]. In general, the SSRIs including escitalopram and citalopram are preferred in HIV-infected patients requiring antidepressant therapy due to less potential for DDI with antiretrovirals [69].

The prevalence of HIV among psychiatric patients has been reported to range from 8 to 19% [164,165], and a significant proportion of patients with schizophrenia engage in high-risk sexual behaviors that increase the risk of acquiring HIV [166]. Atypical antipsychotics are preferred over conventional (typical) antipsychotics in the elderly population [167], but studies specific to the HIV population are lacking. The atypical antipsychotics are associated with undesired metabolic effects (hyperglycemia, hypercholesterolemia) [168], and coadminsitration with antiretroviral drugs that also increase risk of metabolic effects (e.g. protease inhibitors and hyperlipidemia) [169] can potentially increase the risk of cardiovascular diseases in HIV-infected individuals. Several antipsychotics have significant DDI with antiretrovirals and dosage reduction of the antipsychotic may be required (Table 5).

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Drug–drug interactions with osteoporosis medications

The prevalence of osteoporosis in HIV-infected individuals has been found to be three-fold higher compared with HIV-negative individuals [170], and the overall prevalence of patients with fracture was found to be 2.87 vs. 1.77 per 100 persons in HIV-infected vs. HIV-uninfected individuals (P < 0.0001) [171]. Tenofovir-containing antiretroviral regimens have been associated with larger decrease in spine and hip bone mineral density when compared with abacavir-containing regimens [172]. ATV/r and EFV have also been found to be associated with a decrease in spine and hip bone mineral density [173]. First-line therapy for osteoporosis consists of bisphosphonates, which have been demonstrated to be efficacious in patients with HIV-associated osteoporosis [174], and there are no known DDI between bisphosphonates and antiretrovirals. Calcium and vitamin D supplementation is often recommended for bone health, and significant DDI with calcium-containing products and several antiretrovirals are outlined in Table 4.

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Management of ART in the aging HIV population is a therapeutic challenge from many different perspectives. With increasing age, patterns of comorbidities are shifting to cardiovascular disorders, metabolic disorders, gastrointestinal/genitourinary disorders and psychiatric disorders. Treatment of these comorbidities introduces polypharmacy, increasing the risk of clinically significant DDIs, which can lead to adverse effects or treatment failure of HIV. Although adherence tends to be higher in older individuals compared to younger individuals, cognitive impairment can impair adherence, leading to worse treatment outcomes. Also, polypharmacy can contribute to medication fatigue. Healthcare providers caring for the elderly HIV population should communicate to their patients the critical need for adherence to ART, its short-term and long-term benefits and provide them with practical monitoring tools to achieve high adherence levels for maximum viral suppression, halt of disease progression and increase in quality of life. There is a need for targeted interventions to improve ART adherence in the aging HIV population. Screening and management for other age-related comorbidities (e.g. diabetes, high blood pressure), depression, cognitive decline and substance abuse should be a top priority. Several antiretroviral drugs exhibit inhibitory (protease inhibitors, DLV) and inducing (EFV, ETR, NVP) effects on CYP450 isoenzymes, which are responsible for the metabolism of many medications used for the treatment of comorbidities in the aging HIV population. Awareness of common DDI among elderly HIV-infected individuals are important to help prevent them and assure long-term success of ART. Healthcare providers should routinely screen patients’ medication lists to look for significant DDIs and perform drug interaction checks using available online resources (e.g., and prior to the initiation of new medications in HIV-infected individuals on ART. Although there are many drug interaction studies documenting significant DDIs between antiretroviral drugs and medications that are commonly prescribed in the elderly population, the majority of these pharmacokinetic studies were conducted in young, healthy volunteers who are not HIV-infected. As a result, these studies may not be generalizable to elderly HIV-infected patients. There is a need for investigations specifically in HIV-infected individuals, including those who are elderly.

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Dr Jean Nachega acknowledge support from the US NIH-FIC/HRSA PEPFAR Grant Award, T84HA21652-01-00 for Medical Education Partnership Initiative (MEPI); The European Developing Countries Clinical Trial Partnership (EDCTP) Senior Fellowship Award: TA-08-40200- 021; and The Wellcome Trust Southern Africa Consortium for Research Excellence (SACORE): WT087537MA.

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Conflicts of interest

There are no conflicts of interest.

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adherence; aging; antiretroviral therapy; drug–drug interactions

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