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Antiretroviral therapy adherence and drug–drug It is estimated that by 2015 more than half of all HIV-infected individuals in the UnitedStates 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 manage-ment of the aging HIV population can be complicated by polypharmacy and higher pillburden, leading to poorer antiretroviral therapy (ART) adherence. Adherence to ART isgenerally better in older populations when compared to younger populations; however,cognitive impairment in elderly patients can impair adherence, leading to worsetreatment outcomes. Practical monitoring tools can improve adherence and increaserates of viral load suppression. Several antiretroviral drugs exhibit inhibitory and/orinducing effects on cytochrome P450 isoenzymes, which are responsible for themetabolism of many medications used for the treatment of comorbidities in the agingHIV population. The combination of ART with polypharmacy significantly increases thechance of potentially serious drug–drug interactions (DDIs), which can lead to drugtoxicity, poorer ART adherence, loss of efficacy of the coadministered medication, orvirologic breakthrough. Increasing clinicians awareness of common DDIs and the use ofDDI programs can prevent coadministration of potentially harmful combinations inelderly HIV-infected individuals. Well designed ART adherence interventions and DDIstudies are needed in the elderly HIV population.
ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins Keywords: adherence, aging, antiretroviral therapy, drug–drug interactions shifts from AIDS-related opportunistic infections to age-related comorbidities, such as cardiovascular disease, The introduction of effective antiretroviral therapy (ART) has resulted in the reduction of AIDS-related osteoporosis and decline in organ function (renal as well mortality and increased the life expectancy of HIV- as hepatic) When controlling for sex, baseline CD4 infected individuals By 2015, it is projected that more cell count and year of therapy initiation, older age (50 than 50% of all HIV-infected individuals living in the years of age and older) was significantly associated with United States will be 50 years of age or older With higher mortality [adjusted hazard ratio 1.23, 95% increasing age, the pattern of morbidity and mortality confidence interval (CI) 1.08–1.42] In addition, 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 ofHealth 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, fUniversite´ catholique de Louvain, Louvain Drug Research Institute, Brussels, and CHU Mont-Godinne, Yvoir, Belgium, and 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 InternationalHealth, 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.
ISSN 0269-9370 Q 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Goulet et al. reported that HIV-infected veterans had a were not confirmed by Tumbarello et al. Among lower risk of hypertension, diabetes, vascular disease and other factors, biological factors that negatively influence psychiatric disorders. However, they had a higher risk of the risk of developing immune responses and immune liver disease, renal disease, substance use disorder and reconstitution (e.g. advanced diseases at start of ART, multimorbidity. HIV infected veterans 50 years of age and thymic output, reduced bone marrow capacity) may older had higher odds of multimorbidity than HIV affect outcome in the older HIV-infected patients uninfected veterans 50 years of age and older.
Due to the above comorbidities, medical management ofolder HIV-infected individuals becomes complicated bypolypharmacy. In an analysis of the Swiss HIV Cohortstudy, the combination of ART with polypharmacy significantly increased the chance of potentially serious drug–drug interactions (DDIs) which can lead todrug toxicity, loss of efficacy of the coadministered Overall, higher adherence to ART is associated with older medication and virologic breakthrough. When HIV- age, and although current combination ART can be infected individuals at least 50 years of age were compared forgiving of occasional lapses in adherence, higher levels to HIV-infected individuals less than 50 years of age, older of adherence is associated with the maximal likelihood of patients were more likely to receive concomitant virologic suppression and lower level of drug resistance medications versus younger patients (82 vs. 61%, in both younger adults and older patients P < 0.001), therefore, also had more DDIs (51 vs. 35%, However, among older patients with HIV, those with P < 0.001). Certain therapeutic classes were prescribed documented cognitive decline are likely to have poor more often in elderly patients, including cardiovascular ART adherence, disease progression and death In a drugs, gastrointestinal medications and hormonal agents.
volunteer sample of 431 HIV-infected adult patients on Elderly patients are two to three times more likely to ART, recruited from community agencies and university- develop an adverse drug reaction compared to younger affiliated infectious disease clinics in the Los Angeles area, patients There is a paucity of clinical and neurocognitive measurements were conducted. These pharmacokinetic DDI studies in the older HIV popu- included tests on attention, information processing speed, lation. In a cohort study of 1000 HIV-negative elderly learning/memory, verbal fluency, motor functioning and patients more than 70 years old who were admitted to the hospital for an acute illness, 894 were receiving at measured using microchip-embedded pill bottle caps least two medications. Of these 894 patients, 60.2% (Medication Event Monitoring System caps) and was self- were exposed to potential DDI, and as a result of these reported. Structural equation modeling (SEM) tech- DDI, 24% developed clinically significant side effects niques were used to evaluate factor models of cognition and adherence. The study found that mean adherencerates were higher among older (50 years) than younger Other important ART considerations in the aging HIV (<50 years) HIV-positive adults. Nevertheless, the SEM population include issues related to adherence, as well as analysis revealed that older patients with neurocognitive clinical/immunological response to ART. Poor adher- impairment were associated with poorer medication ence to ART in the aging HIV population can be the consequence of multiple factors including neurocognitive examined individually, executive function, motor func- decline social isolation/lack of social support tion and processing speed were most strongly correlated and depression and chronic adverse drug effects with adherence in this elderly group. Similar to younger (e.g. lipodystrophy) High drug cost in uninsured or patients, older HIV-positive individuals with neuro- underinsured elderly patients is also associated with cognitive impairment or drug abuse problems are at decreased adherence and poor outcome As an increased risk of suboptimal adherence to medica- example, in the North American AIDS Cohort tions.The above findings highlight the importance of Collaboration on Research and Design cohort, it was optimizing medication adherence rates and evaluating found that older age (per 10 years increment) was neurocognition in the growing population of elderly associated with a 68% increase in death when ART was deferred and that CD4 cell count at presentationfor HIV care among patients older than 50 years old were In 2008, Branas et al. also found that older age was lower Although elderly patients may have a higher associated with higher ART adherence, however, the baseline HIV viral load and lower CD4 cell count, their authors did not investigate neurocognition disorders as virologic response to ART is similar to younger HIV- independent factors. In addition, they found a lower infected individuals but CD4 cell recovery after CD4 cell count increase after ART initiation in the starting ART is generally lower in this elderly HIV- older group. Hinkin et al. found that in addition infected population However, these findings to neurocognition disorders, current drug abuse or Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Antiretrovirals in the aging HIV population Nachega et al.
dependence, but not current alcohol abuse or depen- between older and younger HIV-infected patients dence, was also associated with suboptimal medication regarding viroimmunological response to ART.
Antiretroviral drug–drug interactions in interventions in the aging HIV population The combination of ART with polypharmacy for the There are limited interventional studies aimed to improve management of comorbidities significantly increases the ARTadherence in the elderly HIV population to guide or chance of potentially serious DDI, which can lead to drug support specific recommendations. Although one could toxicity and loss of efficacy. The effect of aging on drug extrapolate from other interventions conducted in elderly metabolism and clearance adds another layer of complex- patients affected by chronic conditions such as diabetes or ity. Liver volume and hepatic blood flow decrease with increasing age. Comparisons of drug hypertension, it is important to evaluate such interven- metabolism in vivo have been conducted in younger tions in the aging HIV population and more specifically versus older HIV-negative patients. CYP1A2 activity those with neurocognition disorders and/or drug abuse.
seems to be preserved in older patients, particularly those ART adherence interventions that have proven effective who are nonsmokers Age does not seem to affect in the adult HIV-infected population includes electronicreminder devices screening for and treating CYP2D6 metabolism, whereas CYP2D6 polymorphisms depression addressing substance abuse organiz- were found to significantly impact elimination ing pillboxes increasing social support and The following age-related differences in CYP2C19 simplifying ART regimens by reducing pill burden and metabolism have been noted; older individuals who are frequency (e.g. once-daily and one tablet fixed-dose either extensive metabolizers or intermediate metaboli- combinations) These interventions are likely to be of zers have approximately two-fold higher exposures toomeprazole compared to younger individuals. However, value in the elderly HIV population, but specific data in age had less effect on poor metabolizers Age does this aging population are urgently needed.
not appear to affect CYP2C9 metabolism of diclofenacand celecoxib however, warfarin is primarilymetabolized through CYP2C9, and it has been shown that the average dose requirement for warfarin decreases as age increases Lastly, age has not been shown to significantly influence CYP3A metabolism even inpatients up to 100 years old This is important HIV-infected patients over the age of 50 are more likely because CYP3A enzymes are involved in the metabolism to present with lower CD4 cell counts and more of a majority of medications, and are the basis of many advanced disease As a result, among patients who are clinically important DDIs between ART and medications older than 60 years of age, a higher proportion of these commonly prescribed in the aging population. These patients progressed to AIDS within 1 year of HIV studies suggest that the overall hepatic elimination through diagnosis compared to younger patients (52 vs. 15%) CYP450 enzymes is relatively stable with increasing age.
Similarly, phase II metabolism (glucuronidation, acety- Although older HIV-infected individuals are less likely to lation, and sulfatation) is also well preserved in older experience treatment failure with ART compared to patients . Enzyme induction also appears to be younger patients due to better adherence, some studies conserved in older patients, as rifampin was capable of suggest that older individuals have less CD4 cell recovery inducing phase I and phase II pathways of metabolism to In a Spanish study, Nogueras et al. showed the same extent as in younger individuals that although HIV-infected older patients were morelikely to have higher viral load and lower CD4 cell counts On average, glomerular filtration declines by 1% per at baseline when presenting to the first clinic visit, they year . HIV-infected patients are at increased risk for were not likely to achieve the same CD4 cell counts developing chronic kidney disease (CKD) with a compared with younger individuals. Based on these prevalence of an estimated glomerular filtration rate less observations, the Department of Health and Human than 60 ml/min per 1.73 m2 reported in approximately 7% Services guidelines recommended ART in all patients of HIV-infected patients . In addition to older age, older than 50 years of age, regardless of CD4 cell count many other factors such as diabetes, hypertension, However, as shown by Tumbarello et al. despite intravenous drug use, high viral load, low CD4 cell count, having lower baseline CD4 cell count and higher race, concurrent use of certain antiretrovirals [e.g. teno- frequency of comorbid conditions, in multivariate fovir, indinavir, atazanavir (ATV)] and hepatitis C coinfec- analysis, there was no statistically significant difference tion have been associated with CKD in HIV-infected Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
individuals In a large cohort study from the long-term ART and potentially due to HIV immune Veteran Health Administration involving over 10 000 activation. Prolonged treatment with ART is associated HIV-infected patients, tenofovir use was associated with a with a higher prevalence of hypertension in HIV-infected 34% increased risk of proteinuria (95% CI 25–45%, individuals Routine blood pressure monitoring and P < 0.0001), 11% increased risk of rapid decline in kidney initiation of antihypertensive medications when indicated function (95% CI 3–18%, P ¼ 0.0033), and 33% increased is essential to decrease the risk of developing hyperten- risk of CKD (95% CI 18–51%; P < 0.0001). Risk of sion-related morbidities DDI studies involving tenofovir-associated nephrotoxicity did not further cardiovascular agents and antiretroviral drugs were increase in a subgroup of patients older than 46 years conducted in young healthy volunteers. All dihydropyr- However, in an expanded-access tenofovir study, idine calcium channel blockers (CCBs) are metabolized older age was a baseline risk factor for increased serum via CYP3A4; as a result, all boosted protease inhibitors creatinine . It is important for clinicians to recognize may increase CCB serum concentrations and can that older HIV-infected patients may have decreased potentially prolong the PR interval and augment glomerular filtration rate, and as a result may be at higher hypotensive effect. In a drug interaction study conducted risk of nucleoside/nucleotide reverse transcriptase inhibi- with unboosted ATV, diltiazem area under the plasma tor (NRTI)-induced toxicity if renal dosing guidelines are concentration time curve (AUC) was increased by 225% and the PR interval was prolonged although the majorityof patients were asymptomatic with first degree Clinically significant DDI involving ART and medi- atrioventricular block Therefore, it is recommended cations used to treat cardiovascular diseases, metabolic, to decrease the diltiazem dose by 50% and titrate slowly gastrointestinal, psychiatric disorders and other medi- with close monitoring Similarly, use of other CCB cations commonly used in the elderly population are that are more likely to prolong the PR interval (e.g.
reviewed here with recommendations provided for the verapamil) with boosted protease inhibitors should be selection of alternative agents to minimize potentially closely monitored. On the contrary, EFV, ETR and NVP harmful DDI. As a class effect, protease inhibitors are have the potential to decrease CCB serum concentrations inhibitors of CYP450 3A4 enzymes and to some extent of and dose adjustment of CCB at steady state may be other isoenzymes, with the most potent being ritonavir needed. Digoxin serum concentrations were increased by (RTV), which is used to ‘boost’ the effect of other 86% with RTV coadministration due to inhibition of P- protease inhibitors by inhibiting their metabolism. Inter- glycoprotein (P-gp). In a cohort study involving actions between protease inhibitors and other medications 2030 HIV-negative elderly patients who were taking metabolized through CYP450 may lead to increased digoxin, if they had been hospitalized during the previous plasma concentrations of the coadministered medication, 2 months, they were at more than four times increased potentially leading to serious/life-threatening adverse risk for additional hospitalizations due to digoxin toxicity drug reactions. With the exception of delavirdine (DLV) With the increased risk of CKD and potential for and rilpivirine, nonnucleoside reverse transcriptase DDI with boosted protease inhibitors, HIV-infected inhibitors (NNRTIs) including efavirenz (EFV), etra- elderly patients may be at even higher risk for digoxin virine (ETR) and nevirapine (NVP) are moderate toxicity. Close monitoring of digoxin serum concen- inducers in vivo of CYP450 3A4 enzymes, although trations is critical in older HIV-infected patients.
EFV has been found in vitro to inhibit certain CYP450enzymes as well . Interactions involving EFV, NVP Many antiarrhythmic medications are CYP450 3A4 and ETR and other medications metabolized through substrates. The use of amiodarone, bepridil, flecainide, CYP450 3A4 can lead to decreased plasma con- propafenone and quinidine are contraindicated with centrations of the coadministered medication, poten- RTV boosted protease inhibitors (PI/r) due to the tially leading to decreased efficacy. NRTIs, maraviroc, potential risk of exacerbating cardiac arrhythmias raltegravir, rilpivirine and enfuvirtide do not inhibit or The use of disopyramide, dofetilide, lidocaine, mexiletine induce CYP450 isoenzymes; therefore, clinically sig- and procainamide with PI/r should be approached with caution due to the potential risk of significantly increasingantiarrhythmic serum concentrations.
Drug–drug interactions withcardiovascular medications Drug–drug interactions withanticoagulation Cardiovascular disease is one of the most commoncomorbidities in the aging HIV-infected population Older age is associated with increased risk of major Coronary artery disease (CAD) is emerging as a hemorrhage when taking warfarin Significant DDIs complication in HIV-infected patients, which may be between warfarin, protease inhibitors and NNRTIs may due to a combination of increasing age, toxicity from further increase the risk of significant hemorrhage.
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Antiretrovirals in the aging HIV population Nachega et al.
Clinically relevant DDIs between anticoagulants and PI/r can significantly increase simvastatin and lovastatin concentrations. Coadministration of these exists as two isomers that differ in potency and route of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors metabolism. S-warfarin is two to five times more potent are not recommended due to the potential for rhabdo- than R-warfarin. The more potent S-isomer is a CYP2C9 myolysis Moderate DDIs have been reported substrate, whereas the R-isomer is metabolized via with protease inhibitors and atorvastatin pravas- CYP1A2 and CYP3A4 Induction properties of NVP and lopinavir/RTV at steady state resulting in monitoring and dose adjustment, these ‘statins’ can be increased warfarin requirements have been reported .
safely coadministered with protease inhibitors.
RTV is a mixed CYP3A4 inhibitor and inducer and a mildCYP2C9 inhibitor. When RTV is added to a stable The incidence of T2DM is increased in older HIV- warfarin regimen, a supratherapeutic international nor- infected individuals, which may be linked to long-term malized ratio (INR) may result initially. However, at steady use of ART Non-HIV infected elderly patients state, subtherapeutic warfarin concentrations as a result of 65 years or older with diabetes were found to have a 36% CYP3A4 induction may occur Although these increased risk of developing hypoglycemia while receiv- early reports used higher than currently recommended ing sulfonylureas when compared with younger patients doses of RTV, a 29% decrease in mean S-warfarin AUC was This risk of hypoglycemia may be even higher in also observed with darunavir/RTV (DRV/r; 600/100 mg HIV-infected elderly patients due to the presence of DDI twice daily) . In older patients, close INR monitoring between oral hypoglycemics and antiretrovirals. There are should be performed when boosted protease inhibitors or limited DDI studies conducted with antiretroviral drugs NNRTIs are added to a stable warfarin regimen.
and oral hypoglycemic medications; however, based onthe route of metabolism, there are some potentially Dabigatran is a P-gp substrate, but not a substrate, inhibitor significant DDIs PI/r may increase serum concen- or inducer of CYP450 isoenzymes. Certain P-gp inhibitors (e.g. ketoconazole, dronedarone) increase dabigatran concentrations by approximately two-fold contrary, EFV, ETR and NVP may decrease concen- . PI/r may inhibit P-gp and may increase dabigatran trations of these agents. Rosiglitazone can be considered concentrations. Although clinical data are lacking, in as an alternative agent with less potential for DDI with patients with moderate renal impairment (creatinine antiretrovirals Although DDI are unlikely to clearance 15–30 ml/min), a lower dose of dabigatran occur with metformin through CYP450 enzymes should be considered in patients treated with boosted declines in renal function due to increasing age, antiretrovirals (e.g. tenofovir or HIV-associatednephropathy (HIVAN) can alter the serumconcentration of metformin, predisposing to serious sideeffects including lactic acidosis Interactions with a-glucosidase inhibitors (acarbose, miglitol) and antiretro- Drug–drug interactions with medications peptidase IV inhibitors, the saxagliptin dose should belimited to 2.5 mg once daily when coadministered with Significant DDI between antiretrovirals and anti- PI/r due to inhibition of CYP3A4-mediated metabolism hyperlipidemic agents have been reported of saxagliptin and linagliptin coadministration with Table 1. Drug–drug interactions with antiplatelet and anticoagulant agents.
clopidogrel metabolite. Interaction unlikely with: PI/r, NVP, EFV, RPV, RAL, MVC, NRTIs PI/r may increase dabigatran concentrations in patients with moderate to severe renal dysfunction; dose reduction with CrCL 30–50 ml/min.
Interaction unlikely with: NNRTIs, RAL, MVC, NRTIs DRV/r, LPV/r, NVP, EFV may decrease S-warfarin ARV, antiretroviral; CrCL, creatinine clearance; DRV/r, darunavir/ritonavir; EFV, efavirenz; ETR, etravirine; INR, international normalized ratio;LPV/r, lopinavir/ritonavir; MVC, maraviroc; NRTI, Nucleoside Reverse Transcriptase Inhibitors; NNRTIs, Non-Nucleoside Reverse TranscriptaseInhibitors; NVP, nevirapine; PI/r, boosted PI; RAL, raltegravir; RPV, rilpivirine.
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Table 2. Drug–drug interactions with antihyperlipidemic agents.
Atorvastatin AUC " 2.5, 5.8, and 9.4-fold Avoid TPV/r with atorvastatin coadministration.
Other PI/r: start with atorvastatin 10 mg once daily, and then titrate to effect. Do not AUC # 43% with EFV co-administration.
exceed atorvastatin 20 mg with DRV/r, FPV/r,SQV/r. EFV, NVP, ETR: higher atorvastatindose may be needed.
Strong CYP3A4 inhibitor (e.g. itraconazole) significantly increases lovastatinconcentrations 20-fold. PI/r mayalso significantly increase lovastatinconcentrations.
AUC 26 and 20%, respectively.
ATV increases pitavastatin AUC 31%.
Higher pravastatin dose may be needed with TPV/r, LPV/r, ATV/r increase rosuvastatin PI/r: start with rosuvastatin 5 mg once daily, AUC 37, 110, and 213%, respectively.
then titrate to effect. Maximumrecommended rosuvastatin dose 10 mg/daywith LPV/r and ATV/r co-administration.
SQV/r increases simvastatin AUC 31-fold.
higher simvastatin dose may be needed.
ATV, atazanavir; ATV/r, atazanavir/ritonavir; AUC, area under the plasma concentration time curve; DRV/r, darunavir/ ritonavir; EFV, efavirenz;ETR, etravirine; FPV/r, fosamprenavir/ritonavir; LPV/r, lopinavir/ritonavir; NVP, nevirapine; PI/r, protease inhibitor /ritonavir; TPV/r, tipranavir/ritonavir; SQV/r, saquinavir/ritonavir.
PI/r, EFV, ETR and NVP should be avoided multifactorial and include low testosterone, older age, Providers can consider using sitagliptin as an alternative diabetes, neuropathy, drug use and depression agent however, close monitoring of blood glucose There are significant DDI between PI/r and drugs used for erectile dysfunction Concentrations ofsildenafil tadalafil and vardenafil can allbe increased by 2.2–11-fold with PI/r. With PI/rcoadministration, dose adjustment of erectile dysfunctionagents is recommended to prevent unsafe drop in blood Drug–drug interactions with medications The prevalence of benign prostatic hyperplasia (BPH) ishigher in elderly patients. Biopsy confirmed BPH increasesfrom about 40 to 50% in men aged 51–60, to over 80% in Drug–drug interactions with medications men older than 80 years DDI with BPH medications and antiretroviral drugs are shown in PI/r may significantly increase concentrations Interactions with acid reducing agents and antiretroviral of a-adrenergic antagonist such as alfuzosin and coadmi- drugs are common in clinical practice. There have been nistration is not recommended Tamsulosin is a significant increases seen over time in the frequencies of CYP3A4 and CYP2D6 substrate and its concentrations reflux symptoms, gastroesophageal reflux disease and were increased 2.8-fold when coadministered with a strong Helicobacter pylori infections in HIV-infected individuals CYP3A4 inhibitor (e.g ketoconazole) Similarly, Additionally, HIV-infected individuals have been other PI/r may increase tamsulosin concentration and found to have elevated gastric pH values, which can lead increase the risk of orthostatic hypotension (especially to alteration in drug absorption Providers should with the first dose). However, minimal interactions be aware of clinically significant DDIs with acid-reducing are expected between protease inhibitors and other a antagonists (e.g. doxazosin, prazosin).
unboosted fosamprenavir nelfinavirtipranavir and rilpivirine These Erectile dysfunction has been reported in up to 74% antiretroviral drugs require an acidic environment for of HIV-infected men The increased risks are absorption; therefore, any acid suppressant therapy Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Antiretrovirals in the aging HIV population Nachega et al.
Table 3. Drug-drug interactions with genitourinary medications.
consider tamsulosin dosereduction with the first dose AUC, area under the plasma concentration time curve; PI/r, protease inhibitor/ritonavir; RTV, ritonavir; IDV, indinavir.
(antacids, H2 receptor antagonists, proton pump inhibi- The prevalence of HIV among psychiatric patients has tors) has the potential to significantly reduce these been reported to range from 8 to 19% and a antiretroviral serum concentrations, which can poten- significant proportion of patients with schizophrenia tially lead to treatment failure of HIV. For example, the engage in high-risk sexual behaviors that increase the risk coadministration of ATV/RTV (ATV/r) with omepra- of acquiring HIV Atypical antipsychotics are zole resulted in a 76% decrease in ATV AUC preferred over conventional (typical) antipsychotics in the Although the manufacturer suggests that ATV/r can be elderly population but studies specific to the HIV safely coadministered with low-dose (20 mg) omeprazole, population are lacking. The atypical antipsychotics are most experts recommend switching to an alternative associated with undesired metabolic effects (hyperglyce- protease inhibitor such as DRV/r. Recommendations for mia, hypercholesterolemia) and coadminsitration the safe coadministration of these antiretroviral drugs with with antiretroviral drugs that also increase risk of metabolic effects (e.g. protease inhibitors and hyperlipi- demia) can potentially increase the risk ofcardiovascular diseases in HIV-infected individuals.
Several antipsychotics have significant DDI with anti-retrovirals and dosage reduction of the antipsychotic maybe required Drug–drug interactions with medicationsused for central nervous system disorders Depression and other psychiatric conditions are prevalentin Drug–drug interactions with osteoporosis infected elderly patients taking psychotropics, antidepress- ants and benzodiazepines are at 78, 59 and 39% increasedrisk for fall, respectively However, treatment of The prevalence of osteoporosis in HIV-infected individ- depression is critical in the elderly HIV population because uals has been found to be three-fold higher compared untreated depression negatively impacts progression to with HIV-negative individuals and the overall AIDS and death in patients with HIV Selective prevalence of patients with fracture was found to be serotonin reuptake inhibitors (SSRIs) are commonly 2.87 vs. 1.77 per 100 persons in HIV-infected vs. HIV- prescribed for depression in HIV-infected individuals uninfected individuals (P < 0.0001) Tenofovir- as they are better tolerated than tricyclic anti- containing antiretroviral regimens have been associated depressants (TCA). With protease inhibitor coadministra- with larger decrease in spine and hip bone mineral density tion, orthostatic hypotension and anticholinergic side when compared with abacavir-containing regimens effects from TCAs can result in severe morbidity .
There are also several clinically significant DDI with other associated with a decrease in spine and hip bone mineral antidepressants that warrant a dosage reduction of the density First-line therapy for osteoporosis consists of bisphosphonates, which have been demonstrated to be efficacious in patients with HIV-associated osteoporosis escitalopram and citalopram are preferred in HIV-infected and there are no known DDI between bispho- patients requiring antidepressant therapy due to less sphonates and antiretrovirals. Calcium and vitamin D supplementation is often recommended for bone health, Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Antiretrovirals in the aging HIV population Nachega et al.
Table 5. Drug–drug interactions with antidepressants / antipsychotics.
DRV/r decreased paroxetine AUC 39%, Titrate SSRI to effect. Escitalopram and NVP can decrease fluoxetineconcentrations. EFV and DRV/rdecrease sertraline AUC by 39 and49%, respectively.
concentrations at steady state.
Boosted PIs may increasevenlafaxine concentrations, whereasEFV, ETR, and NVP may decreasevenlafaxine concentrations.
Ketoconazole (CYP3A4 inhibitor)increased desvenlafaxineAUC 43%. Boosted PIs mayincrease desvenlafaxineconcentrations.
increased appetite and weightgain which is beneficial inHIV-associated wastingsyndrome.
trazodone dose with slow titration).
Monitor for nausea, dizziness,hypotension, and syncope. SQV/rcontraindicated with trazodone dueto risk of additive QT-prolongation.
Consider alternative antidepressant(e.g. SSRIs) dose. Consider alternativeantidepressant (e.g. SSRIs).
Decrease maraviroc dose to150 mg b.i.d. with nefazodonecoadministration.
Tricyclic Antidepressant (TCA): Desipramine AUC increased 145% closely for TCA toxicity. Avoid rilpivirinecoadministration with TCA due to riskof additive QT-prolongation.
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risperidone coadministration. RTVdecreased olanzapine AUC by 53%.
If coadministered with PIs, use with close adverse drug reaction. Consider alternative antipsychotic such as olanzapine. Pimozide is contraindicated with PIs due to risk ofQT-prolongation. Avoid rilpivirinecoadministration with typical antipsychoticsdue to risk of additive QT-prolongation.
AUC, area under the plasma concentration time curve; PI, protease inhibitor; DRV/r, darunavir/ritonavir; FPV/r, fosamprenavir/ritonavir; LPV/r,lopinavir/ritonavir; TPV/r, tipranavir/ritonavir; SQV/r, saquinavir/ritonavir; RTV, ritonavir; NFV, nelfinavir; EFV, efavirenz; ETR, etravirine; NVP,nevirapine.
and significant DDI with calcium-containing products population. Screening and management for other age- and several antiretrovirals are outlined in related comorbidities (e.g. diabetes, high blood pressure),depression, cognitive decline and substance abuse shouldbe a top priority. Several antiretroviral drugs exhibitinhibitory (protease inhibitors, DLV) and inducing (EFV, ETR, NVP) effects on CYP450 isoenzymes, which areresponsible for the metabolism of many medications used Management of ART in the aging HIV population is a for the treatment of comorbidities in the aging HIV therapeutic challenge from many different perspectives.
population. Awareness of common DDI among elderly With increasing age, patterns of comorbidities are shifting HIV-infected individuals are important to help prevent to cardiovascular disorders, metabolic disorders, gastroin- them and assure long-term success of ART. Healthcare testinal/genitourinary disorders and psychiatric disorders.
providers should routinely screen patients’ medication lists Treatment of these comorbidities introduces polyphar- to look for significant DDIs and perform drug interaction macy, increasing the risk of clinically significant DDIs, checks using available online resources (e.g. 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 the initiation of new medications in HIV-infected impairment can impair adherence, leading to worse individuals on ART. Although there are many drug treatment outcomes. Also, polypharmacy can contribute interaction studies documenting significant DDIs between to medication fatigue. Healthcare providers caring for the antiretroviral drugs and medications that are commonly elderly HIV population should communicate to their prescribed in the elderly population, the majority of these patients the critical need for adherence to ART, its short- pharmacokinetic studies were conducted in young, term and long-term benefits and provide them with healthy volunteers who are not HIV-infected. As a result, practical monitoring tools to achieve high adherence levels these studies may not be generalizable to elderly HIV- for maximum viral suppression, halt of disease progression infected patients. There is a need for investigations and increase in quality of life. There is a need for targeted specifically in HIV-infected individuals, including those interventions to improve ARTadherence in the aging HIV Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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