Glenn W. Wortmann, MD

A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.

What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?

Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.¹ Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.

In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.

NERVOUS SYSTEM

The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.

Encephalopathy and seizure

Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.^2,3

Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.^2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.^2–4

Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.²

Nonconvulsive status epilepticus

Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.^2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.

Class-specific neurologic effects

Certain antibiotics have class-specific effects:

Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.²

Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.⁶

Macrolides: dysequilibrium and potentially irreversible hearing loss.²

Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.⁷

Linezolid: optic and peripheral neuropathy²; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.⁸

Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.⁹

Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.¹⁰

HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS

Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.¹¹

Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.¹²

In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.¹³

Drug-induced thrombocytopenia has been described with penicillins, cephalo­sporins, sulfonamides, and vancomycin¹⁴ and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.¹⁵

The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.¹⁶ Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.¹⁶

Kermani et al¹⁷ described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.

Quinolones have also been reported to cause fatal hypersensitivity vasculitis.^18,19

CARDIOVASCULAR SYSTEM

Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a  macrolide is co-administered with a CYP3A4 inhibitor.

Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.

While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.²⁰ In addition, Owens and Nolin²⁰ reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.²¹

Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.²²

DIGESTIVE SYSTEM

Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.²³

Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.²⁴ It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.²⁵

Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.^24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.

Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.²⁴ Mixed liver injury, the most common, is defined as a ratio from 2 to 5.

Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.²⁶ Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.²⁴

ENDOCRINE SYSTEM

Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.²⁷ The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.²⁷

RESPIRATORY SYSTEM

Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.²⁸ The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.²⁹

Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.³⁰

RENAL SYSTEM

Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.^31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.

Advanced age is an important risk factor for renal dysfunction from quinolones,¹⁸ and penicillin G has been reported to cause glomerulonephritis.³¹

MUSCULOSKELETAL SYSTEM

Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.¹⁸ The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.³⁴

Daptomycin is known to cause elevations of creatine kinase.³⁴ Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.³⁵

REPRODUCTIVE SYSTEM

Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.³⁶

BACK TO OUR PATIENT

Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.

A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.

What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?

Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.¹ Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.

In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.

NERVOUS SYSTEM

The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.

Encephalopathy and seizure

Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.^2,3

Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.^2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.^2–4

Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.²

Nonconvulsive status epilepticus

Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.^2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.

Class-specific neurologic effects

Certain antibiotics have class-specific effects:

Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.²

Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.⁶

Macrolides: dysequilibrium and potentially irreversible hearing loss.²

Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.⁷

Linezolid: optic and peripheral neuropathy²; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.⁸

Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.⁹

Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.¹⁰

HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS

Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.¹¹

Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.¹²

In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.¹³

Drug-induced thrombocytopenia has been described with penicillins, cephalo­sporins, sulfonamides, and vancomycin¹⁴ and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.¹⁵

The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.¹⁶ Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.¹⁶

Kermani et al¹⁷ described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.

Quinolones have also been reported to cause fatal hypersensitivity vasculitis.^18,19

CARDIOVASCULAR SYSTEM

Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a  macrolide is co-administered with a CYP3A4 inhibitor.

Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.

While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.²⁰ In addition, Owens and Nolin²⁰ reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.²¹

Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.²²

DIGESTIVE SYSTEM

Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.²³

Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.²⁴ It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.²⁵

Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.^24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.

Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.²⁴ Mixed liver injury, the most common, is defined as a ratio from 2 to 5.

Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.²⁶ Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.²⁴

ENDOCRINE SYSTEM

Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.²⁷ The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.²⁷

RESPIRATORY SYSTEM

Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.²⁸ The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.²⁹

Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.³⁰

RENAL SYSTEM

Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.^31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.

Advanced age is an important risk factor for renal dysfunction from quinolones,¹⁸ and penicillin G has been reported to cause glomerulonephritis.³¹

MUSCULOSKELETAL SYSTEM

Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.¹⁸ The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.³⁴

Daptomycin is known to cause elevations of creatine kinase.³⁴ Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.³⁵

REPRODUCTIVE SYSTEM

Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.³⁶

BACK TO OUR PATIENT

Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.

A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.

What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?

Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.¹ Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.

In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.

NERVOUS SYSTEM

The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.

Encephalopathy and seizure

Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.^2,3

Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.^2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.^2–4

Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.²

Nonconvulsive status epilepticus

Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.^2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.

Class-specific neurologic effects

Certain antibiotics have class-specific effects:

Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.²

Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.⁶

Macrolides: dysequilibrium and potentially irreversible hearing loss.²

Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.⁷

Linezolid: optic and peripheral neuropathy²; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.⁸

Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.⁹

Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.¹⁰

HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS

Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.¹¹

Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.¹²

In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.¹³

Drug-induced thrombocytopenia has been described with penicillins, cephalo­sporins, sulfonamides, and vancomycin¹⁴ and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.¹⁵

The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.¹⁶ Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.¹⁶

Kermani et al¹⁷ described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.

Quinolones have also been reported to cause fatal hypersensitivity vasculitis.^18,19

CARDIOVASCULAR SYSTEM

Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a  macrolide is co-administered with a CYP3A4 inhibitor.

Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.

While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.²⁰ In addition, Owens and Nolin²⁰ reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.²¹

Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.²²

DIGESTIVE SYSTEM

Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.²³

Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.²⁴ It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.²⁵

Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.^24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.

Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.²⁴ Mixed liver injury, the most common, is defined as a ratio from 2 to 5.

Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.²⁶ Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.²⁴

ENDOCRINE SYSTEM

Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.²⁷ The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.²⁷

RESPIRATORY SYSTEM

Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.²⁸ The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.²⁹

Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.³⁰

RENAL SYSTEM

Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.^31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.

Advanced age is an important risk factor for renal dysfunction from quinolones,¹⁸ and penicillin G has been reported to cause glomerulonephritis.³¹

MUSCULOSKELETAL SYSTEM

Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.¹⁸ The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.³⁴

Daptomycin is known to cause elevations of creatine kinase.³⁴ Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.³⁵

REPRODUCTIVE SYSTEM

Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.³⁶

BACK TO OUR PATIENT

Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.

In the 1980s, human immunodeficiency virus (HIV) infection was considered untreatable and predictably lethal. Today, with highly effective antiretroviral therapy, it has become a chronic condition in which patients have a life expectancy comparable to that in the general population.

This change has led to new challenges for primary care physicians, many of whom now find themselves either the sole medical provider for or the comanager of aging HIV-infected patients. Given that about one-fifth of new HIV diagnoses are now in people over the age of 50, it is crucial that primary care providers be able to recognize and diagnose the disease in this population. In addition, they need to effectively manage the polypharmacy and subsequent drug interactions prevalent in older HIV-infected patients. Finally, the clinician must address comorbid diseases common in the elderly, specifically neurologic, cardiovascular, metabolic, and endocrine disorders, as well as performing routine cancer screening.

Take-home point

• As the number of people age 50 and older with HIV infection increases, primary care providers must be able to both recognize and manage the condition.

RISING PREVALENCE OF HIV IN THE ELDERLY

Globally, about 2.5 million people received a new diagnosis of HIV infection in 2011, and about 35 million people worldwide are currently living with it.¹ An estimated 1.1 million Americans are living with HIV, and of these, about 16% do not know they are infected.²

HIV patients who adhere to treatment and achieve a CD4 count above 350 and a low viral load have a normal life expectancy

Antiretroviral therapy has greatly improved the life expectancy of HIV-infected patients, and the number of HIV-infected people over age 50 continues to rise. A successfully treated HIV-positive person with a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.³ In 2011, nearly 20% of newly diagnosed HIV-infected people in the United States were over age 50, as were nearly 25% of those with a new diagnosis of acquired immune deficiency syndrome (AIDS).⁴ This year (2015), we expect that more than half of all HIV-infected people in the United States will be over age 50.⁵

The rising prevalence of HIV infection in this age group has prompted reevaluation of screening guidelines. The US Preventive Services Task Force recommends screening for HIV in all people ages 15 to 65, and also after age 65 in people at ongoing risk of infection.⁶ The American College of Physicians has suggested that the range for routine HIV screening be expanded to age 75.⁷ The cost-effectiveness of expanded and more frequent HIV testing appears to justify it.⁸

Take-home points

• An HIV-infected patient who is compliant with an appropriate antiretroviral regimen and has a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.
• Today, nearly 20% of newly diagnosed HIV-infected people and more than 50% of all HIV-infected people in the United States are over the age of 50.
• The age range for routine screening for HIV infection should be expanded.

HIGH-RISK GROUPS AMONG THE ELDERLY

Early in the HIV epidemic, older patients acquired HIV from blood transfusions received because of hemophilia and other disorders. However, this rapidly ceased after blood banks began screening blood products. Today, people over age 50 who acquire HIV have many of the same risk factors as younger people.

Men who have sex with men are the largest subgroup of HIV-infected people in the United States, even among those over age 50. In particular, white men who have sex with men now constitute the largest demographic group among the HIV-infected elderly.⁴

Intravenous drug users make up about 15% of older people with HIV.

Women who have sex with infected men or with men at risk of HIV infection make up the largest group of older women with HIV.⁴

Sex and the older person

Many older HIV-infected people remain sexually active and continue to engage in unprotected sexual intercourse far into advanced age. According to one survey, 53% of Americans ages 65 to 74 are engaging in sexual activity regularly; however, they are not using protective measures with up to 91% of casual partners and 70% of new partners.^9,10 Many widowed and divorced people are dating again, and they may be unfamiliar with condom use or may be reluctant to use condoms because condoms can often make it difficult to maintain an erection.

Drugs for erectile dysfunction are making it easier for the elderly to engage in both vaginal and anal intercourse, but often without a condom.⁹ Older women who no longer worry about getting pregnant may be less likely to insist their partners use a condom and to practice safe sex. In addition, age-related thinning and dryness can cause vaginal tears, increasing the risk of HIV transmission.¹¹

Take-home points

• People older than 50 have risk factors for HIV similar to those in younger people.
• Men who have sex with men compose the largest group of HIV-infected individuals in the elderly population.
• Unprotected sexual intercourse is common in the elderly for several reasons: unfamiliarity with condom use, difficulty maintaining an erection, lack of concern about possible pregnancy, and vaginal thinning and dryness in women.

UNDERDIAGNOSIS AND LATE DIAGNOSIS IN THE ELDERLY

The cumulative number of AIDS cases in adults age 50 and older increased nearly ninefold from 1990 to the end of 2009. Even more worrisome, one-half of HIV-positive adults over age 50 are diagnosed with AIDS simultaneously or within 1 year of their HIV diagnosis.⁴ This late diagnosis—and therefore late initiation of treatment—is associated with poorer health outcomes and more rapid disease progression.¹²

HIV infection in older adults often goes undiagnosed, for several reasons.

Providers may underestimate the risk in this population and therefore may not discuss HIV transmission or perform testing. Despite a US Centers for Disease Control and Prevention recommendation that people ages 13 to 64 be tested at least once, and more often if sexually active, only 35% of adults ages 45 to 64 have ever been tested for HIV infection.¹³

Age greater than 50 has been strongly associated with higher rates of non–AIDS-related cancers and cardiovascular disease

Older patients may not perceive themselves to be at risk of HIV infection because of lack of insight and information about its prevention and transmission. They are also less likely than younger adults to discuss their sexual habits or drug use with providers.¹⁴ In addition, compared with the young sexually active population, very little HIV prevention education is targeted to older people.¹⁵ Social stigmatization is also a concern for many HIV-infected elderly, as a perceived negative reputation within their community may prevent them from seeking care and disclosing their HIV status.

Take-home points

Reasons that HIV infection is underdiagnosed in the elderly include lack of:

• Provider recognition
• Insight and information about HIV prevention and transmission
• HIV-prevention education targeting the elderly
• Disclosure because of the social stigma of HIV infection.

HIV ACCELERATES AGING, AGING REDUCES IMMUNITY

Many HIV-positive people can expect to live as long as people in the general population, but those who are diagnosed late and thus are started on antiretroviral therapy later in the course of their infection have a reduced life expectancy. Longevity depends on both restoring the CD4 count to near-normal and suppressing the viral load to undetectable levels.^3,16 This is especially important for older adults, as HIV may accelerate aging, and aging itself may speed the progression of HIV disease, so that therapy may result in delayed or only partial restoration of immunity.

Older age at the time of HIV infection is a strong predictor of accelerated HIV disease progression in the absence of therapy.¹⁷ Left untreated, older patients with HIV lose CD4 cells and progress to AIDS and death faster than younger patients. The deleterious effects of chronic immune activation in the course of HIV infection, combined with the immune senescence of aging, are thought to promote this accelerated course.¹⁸

Recent data indicate that starting antiretroviral therapy early can help prevent the CD4-cell impairment that occurs with aging.¹⁹ However, in adults over age 50, the capacity to restore the CD4 count with antiretroviral therapy apears to be reduced, despite demonstrated viral load suppression and better adherence.²⁰ Although mean adherence rates appear higher in older HIV-infected patients, they are worse in those with neurocognitive impairment, highlighting the importance of evaluating neurocognition in this population.²¹

Decreased immune recovery and the subsequent increased risk of serious AIDS events are factors that now favor starting antiretroviral therapy in all HIV patients over age 50, regardless of CD4 count.

Take-home points

• Without treatment, HIV infection in older patients progresses more rapidly to AIDS and death than in younger patients.
• HIV-positive people over age 50 who have never received antiretroviral therapy should be strongly considered for it, regardless of the CD4 count.

SO MANY DRUGS, SO MANY INTERACTIONS

Since HIV patients are now living longer thanks to antiretroviral therapy, they are now experiencing more disease- and treatment-related problems. This has led to an increased likelihood of polypharmacy, defined here as the use of six or more medications.

In general, polypharmacy in the elderly is associated with adverse drug events, drug interactions, inappropriate medication use, delirium, falls, fractures, and poor medication adherence.^22,23 But it becomes even more of a problem in HIV-infected elderly patients, as various drug interactions can alter the effectiveness of the antiretroviral regimen and can result in drug toxicity.

The most common classes of medications used in the elderly are antihypertensives, lipid-lowering agents, antiplatelet medications, antidepressants, anxiolytics, sedatives, and analgesics, and many of these have notable interactions with current antiretroviral regimens.^24,25 Most medications, including antiretrovirals, are cleared by the liver or kidneys, and the function of these organs often decreases with age, resulting in impaired elimination and in drug accumulation.

Information on drug interactions is readily available from the US Department of Health and Human Services,²⁶ drug interaction databases,^27,28 and drug interaction software. The combination of antiretroviral therapy and preexisting polypharmacy significantly increases the risk of serious interactions, which can lead to drug toxicity, poorer adherence with antiretroviral therapy, loss of efficacy of the coadministered medication, or resurgence of HIV infection due to drug-drug interactions affecting the metabolism and ultimate efficacy of the antiretroviral therapy. An increased awareness of common drug-drug interactions can prevent coadministration of potentially harmful medications in elderly HIV patients.

Important interactions between antiretroviral drugs and other drug classes are summarized in Table 1.^25–28 Most notably:

• Simvastatin and lovastatin are contraindicated with any protease inhibitor.
• Proton pump inhibitors are not recommended for patients taking ritonavir-boosted atazanavir. If a proton pump inhibitor is necessary, the daily dose should not exceed 20 mg of omeprazole or its equivalent in patients who have never taken a protease inhibitor, and it should be taken 12 hours before boosted atazanavir.²⁶
• Corticosteroids, whether systemic, inhaled, or intranasal (eg, fluticasone, budesonide), should be avoided in combination with any protease inhibitor, as they can cause iatrogenic Cushing syndrome and also pose the risk of adrenal crisis during acute illness.²⁷

Take-home points

• In cases of preexisting polypharmacy, antiretroviral therapy can lead to significant drug toxicity, poor adherence to medications, and resurgence of HIV infection.
• Increased provider awareness of common drug-drug interactions can prevent the prescribing of potentially harmful drug combinations to HIV-infected elderly patients.

COMORBIDITIES

In recent years, more than half of the deaths in HIV patients on antiretroviral therapy have been from noninfectious comorbidities such as cardiovascular disease, bone disease, and renal failure, which often coexist and are associated with advanced age.²⁹ In fact, both older age and each additional year of antiretroviral therapy are independent predictors of polypathology (simultaneous occurrence of two or more defined diseases).³⁰ The Antiretroviral Therapy Cohort Collaboration found that age greater than 50 was strongly associated with increasing rates of non–AIDS-related malignancy and cardiovascular disease.³¹

CARDIOVASCULAR DISEASE

With the increasing life expectancy of HIV-infected adults on antiretroviral therapy, cardiovascular disease has become an important concern. HIV-infected adults appear to have a significantly greater risk of myocardial infarction and coronary artery disease than age-matched HIV-negative individuals.³² Strikingly, being older than 50 itself increases the risk of hospitalization for cardiovascular disease fivefold (incidence rate ratio 5.01, 95% confidence interval 3.41–7.38).³³ In addition, HIV infection is associated with a risk of acute myocardial infarction 50% higher than that explained by recognized risk factors.³⁴

This high prevalence of coronary artery disease is likely from a combination of factors, including increasing age and the chronic inflammation and immune activation associated with HIV infection.³⁵ An association between untreated HIV disease and markers of risk for cardiovascular disease has been identified.^36,37

HIV is associated with a 50% higher risk of acute myocardial infarction beyond traditional risk factors

In addition, antiretroviral therapy is associated with dyslipidemia, which is most pronounced with protease inhibitor regimens. Whether specific lipid changes associated with individual antiretroviral drugs affect cardiovascular risk remains uncertain. In the Data Collection on Adverse Events of Anti-HIV Drugs studies,³⁸ only cumulative exposure to indinavir, lopinavir-ritonavir, and didanosine was associated with an increased risk of myocardial infarction.³⁸

Traditional risk factors such as obesity, tobacco use, and genetic predisposition also apply to HIV-infected people.³⁹ In fact, the prevalence of traditional risk factors such as smoking and dyslipidemia is generally higher in HIV-infected people than in the general population, although this situation may be improving.⁴⁰

Science needs to elucidate the relationship between traditional and nontraditional risk factors for cardiovascular disease in older HIV-infected adults. In the meantime, older patients with HIV require aggressive management of modifiable risk factors.

Tools for assessing cardiovascular risk include the Framingham risk score⁴¹ and the Data Collection on Adverse Events of Anti-HIV Drugs 5-year risk calculator.⁴² The European AIDS Clinical Society guidelines recommend considering changing the antiretroviral regimen if the patient’s 10-year risk of cardiovascular disease is more than 20%.⁴³ Recommended strategies for reducing cardiovascular risk in elderly patients with HIV infection include counseling about smoking cessation and weight loss at every clinic visit and optimally controlling dyslipidemia and hypertension using nationally accepted standardized guidelines.⁴⁴

Take-home points

• HIV infection is associated with a 50% higher risk of acute myocardial infarction beyond that explained by traditional risk factors.
• Chronic inflammation, immune activation, and dyslipidemia associated with antiretroviral therapy all contribute to cardiovascular disease in HIV-infected patients.
• HIV-infected elderly patients require aggressive management of modifiable risk factors for cardiovascular disease.

ENDOCRINE DISEASE

Diabetes mellitus

The estimated prevalence of diabetes mellitus is 3% in HIV-infected people who have never received antiretroviral therapy, but glucose intolerance increases to the range of 10% to 25% in those who have started it.⁴⁵ Glucose disorders are associated with traditional risk factors as well as with HIV-associated factors such as lipodystrophy and antiretroviral therapy, specifically long-term use of protease inhibitors.⁴⁶ Although increasing age and obesity clearly play a role in the development of diabetes mellitus in this population, HIV-specific factors may also allow diabetes to develop at a lower level of adiposity than in people without HIV infection.⁴⁷

Strategies for preventing type 2 diabetes mellitus in HIV-infected patients focus on avoiding excessive weight gain, especially after starting antiretroviral therapy; regularly screening for diabetes using hemoglobin A_1c, both before and after starting antiretroviral therapy; and continuing to check hemoglobin A_1c every 6 months. The target hemoglobin A_1c should be less than 7.0%. This threshold should be increased to 8% in frail elderly adults if their anticipated life expectancy is less than 5 years, given their higher risk of hypoglycemia, polypharmacy, and drug interactions.⁴⁸ In addition, as in HIV-negative patients, diabetes screening should be performed if systolic blood pressure exceeds 135/80 mm Hg.

Insulin sensitizers such as metformin and thiazolidinediones should be considered for treating diabetes in HIV-infected patients if no contraindications exist. Consideration may also be given to switching the antiretroviral regimen from a protease inhibitor-based regimen to a nonnucleoside reverse transcriptase inhibitor-based regimen.⁴⁸

Take-home points

• Glucose intolerance has been associated with HIV-specific factors, including lipodystrophy and antiretroviral therapy.
• Avoiding excessive weight gain, use of insulin-sensitizing medications, and alteration in antiretroviral regimens should be considered for the treatment of diabetes mellitus in HIV infection.

Osteoporosis

Osteoporotic bone disease disproportionately affects patients with advanced HIV infection compared with patients of similar age.⁴⁹ Bone mineral density is lower and the fracture rate is higher in HIV-infected individuals.

The pathogenesis of bone disease appears to be multifactorial. Traditional risk factors include hypogonadism, smoking, alcohol use, and low body weight, while HIV-related risk factors include chronic immune activation and antiretroviral therapy.⁵⁰

Several antiretroviral regimens have been linked to clinically significant bone loss, including both tenofovir-based and protease inhibitor-based regimens.⁵¹ Most studies have shown that bone mineral density decreases by 2% to 6% in the first 2 years after starting these regimens⁵²; however, long-term effects on bone loss are unknown.

Questions remain. For example, what are the exact mechanisms that lead to the acute decrease in bone mineral density after starting antiretroviral therapy? And why is vitamin D deficiency is so prevalent in HIV infection, with low vitamin D levels seen in up to 60% to 75% of elderly HIV-infected patients?⁵³

Osteoporosis and vitamin D deficiency appear to be more prevalent with HIV infection

Both the Work Group for the HIV and Aging Consensus Project⁵⁴ and the European AIDS Clinical Society⁴³ recommend screening for and treating causes of secondary low bone mineral density in HIV-infected men over age 50 and postmenopausal HIV-infected women. These causes include vitamin D deficiency. As of 2013, the National Osteoporosis Foundation guidelines include HIV infection and antiretroviral therapy as osteoporosis risk factors that should trigger screening for low bone mineral density with dual-energy x-ray absorptiometry (DXA).⁵⁵

As in the general population, the preferred treatment for low bone mineral density in people with HIV is a bisphosphonate, in addition to ensuring adequate calcium and vitamin D intake. It is important to repeat DXA imaging every 2 years and to reassess the need for continued bisphosphonate therapy after 3 to 5 years because of a possible increased risk of fracture with prolonged use.

Take-home points

• Osteoporosis and vitamin D deficiency both appear to be more prevalent with HIV infection.
• HIV infection and antiretroviral therapy are risk factors that should prompt DXA screening to evaluate for osteoporosis.

NEUROCOGNITIVE DISORDERS

HIV-associated neurocognitive disorders are common, with an estimated 50% of HIV-infected patients experiencing some degree of cognitive loss and some progressing to dementia.⁵⁶ Unfortunately, studies suggest that cognitive disorders can occur despite good HIV control with antiretroviral therapy, with one report demonstrating that 84% of patients with cognitive complaints and 64% without complaints were affected by an HIV-associated neurocognitive disorder.⁵⁷

HIV-associated dementia is often subcortical, with fluctuating symptoms such as psychomotor retardation, difficulty multitasking, and apathy. In contrast to dementia syndromes such as Alzheimer disease, relentless progression is less common in HIV-infected patients who receive antiretroviral therapy.

The Mini-Mental State Examination should not be used to screen for HIV-associated neurocognitive disorders, as it does not assess the domains that are typically impaired. The Montreal Cognitive Assessment has been suggested as the best screening instrument in elderly HIV-infected patients; it is available at no cost at www.mocatest.org.⁵⁸

As HIV-associated neurocognitive disorder is a diagnosis of exclusion, an evaluation for alternative diagnoses such as syphilis, hypothyroidism, and depression is recommended. If an HIV-associated neurocognitive disorder is diagnosed, referral to specialty care should be considered, as interventions such as lumbar puncture to assess cerebrospinal fluid viral escape and changing the antiretroviral regimen to improve central nervous system penetration are possible options under study.

Patients with poorly controlled HIV and a depressed CD4 count are at risk of a number of central nervous system complications in addition to HIV-associated neurocognitive disorders, eg, central nervous system toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and primary central nervous system lymphoma. Adherence to an effective antiretroviral regimen is the primary prevention strategy.

Take-home points

• HIV-associated neurocognitive disorders and dementia can occur despite appropriate HIV control and adherence to antiretroviral therapy.
• Adherence to antiretroviral therapy is the primary prevention against most central nervous system complications in HIV infection.

GERIATRIC SYNDROMES

The aging HIV-infected adult may also be at increased risk of geriatric syndromes.

HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail

In particular, a frailty-related phenotype of weight loss, exhaustion, slowness, and low physical activity was more common in HIV-infected elderly than in noninfected elderly.⁵⁹ HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail, and the likelihood of frailty increases with age, duration of HIV infection, having a CD4 count lower than 350 × 10⁶/L, and having uncontrolled HIV replication.^60,61

Other geriatric syndromes such as falls, urinary incontinence, and functional impairment have been identified in 25% to 56% of older HIV-infected patients.⁶² Indeed, the combination of HIV and older age may adversely affect performance of instrumental activities of daily living.⁶³ Also, as previously mentioned, nondisclosure, fear of HIV-related social stigmatization, and a desire to be self-reliant are all factors that perpetuate the social isolation that is common among the HIV-infected elderly.

For these reasons, a comprehensive approach involving a geriatrician, an infectious disease specialist, and community social workers is needed to manage the care of this aging population.

Take-home point

• Geriatric syndromes have an important impact on health in aging HIV patients.

CANCER SCREENING IN HIV PATIENTS

People with HIV have an elevated risk of cancer. Specifically, compared with the general population, their risk is:

• 3,640 times higher for Kaposi sarcoma
• 77 times higher for non-Hodgkin lymphomas
• 6 times higher for cervical cancer.^64,65

These cancers are considered “AIDS-defining,” and fortunately, the development of effective antiretroviral therapy in the 1990s has led to a marked reduction in their incidence. However, the aging HIV population is now experiencing a rise in the incidence of non–AIDS-defining cancers, such as cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin lymphoma.⁶⁶ Table 2 shows the standardized incidence ratio of selected non–AIDS-defining cancers in HIV-infected patients as reported in several large international studies.^65,67,68 The etiology for the increased risk of non–AIDS-defining cancers in the HIV-infected population is not clear, but possible explanations include the virus itself, antiretroviral therapy, and co-infection with other viruses such as hepatitis B, hepatitis C, and Epstein-Barr virus.

Guidelines for cancer screening vary by organization, and the American Cancer Society, the National Cancer Institute, and the US Preventive Services Task Force do not have formal screening guidelines for the most common non–AIDS-defining cancers. The European AIDS Clinical Society, however, has proposed some screening recommendations for selected malignancies.⁴³

In general, screening recommendations are similar to those for HIV-negative patients. A specific difference for HIV-infected patients is in cervical cancer screening. HIV-infected women should undergo a Papanicolaou smear at 6-month intervals during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. There is no consensus as to whether human papillomavirus testing should be performed routinely on HIV-infected women.

At the time of this writing, there are no recommendations for routine screening for anal cancer, although some specialists recommend anal cytologic screening for HIV-positive men and women, and an annual digital anal examination may be useful to detect masses that could be anal cancer.⁶⁹

Take-home points

• The incidence of non–AIDS-defining cancers is rising in the aging HIV population.
• There are currently no formal recommendations for routine screening for anal cancer.

FINAL WORD

Because patients with HIV are living longer as a result of newer effective combination antiretroviral therapies, physicians face a new challenge of managing conditions in these patients that are traditionally associated with aging. Providers will need to improve their understanding of drug-drug interactions and polypharmacy issues and be able to address the complex medical and psychosocial issues in this growing population. As patients with HIV on effective antiretroviral therapy grow older, the burden of comorbid medical disease will continue to increase.

In the 1980s, human immunodeficiency virus (HIV) infection was considered untreatable and predictably lethal. Today, with highly effective antiretroviral therapy, it has become a chronic condition in which patients have a life expectancy comparable to that in the general population.

This change has led to new challenges for primary care physicians, many of whom now find themselves either the sole medical provider for or the comanager of aging HIV-infected patients. Given that about one-fifth of new HIV diagnoses are now in people over the age of 50, it is crucial that primary care providers be able to recognize and diagnose the disease in this population. In addition, they need to effectively manage the polypharmacy and subsequent drug interactions prevalent in older HIV-infected patients. Finally, the clinician must address comorbid diseases common in the elderly, specifically neurologic, cardiovascular, metabolic, and endocrine disorders, as well as performing routine cancer screening.

Take-home point

• As the number of people age 50 and older with HIV infection increases, primary care providers must be able to both recognize and manage the condition.

RISING PREVALENCE OF HIV IN THE ELDERLY

Globally, about 2.5 million people received a new diagnosis of HIV infection in 2011, and about 35 million people worldwide are currently living with it.¹ An estimated 1.1 million Americans are living with HIV, and of these, about 16% do not know they are infected.²

HIV patients who adhere to treatment and achieve a CD4 count above 350 and a low viral load have a normal life expectancy

Antiretroviral therapy has greatly improved the life expectancy of HIV-infected patients, and the number of HIV-infected people over age 50 continues to rise. A successfully treated HIV-positive person with a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.³ In 2011, nearly 20% of newly diagnosed HIV-infected people in the United States were over age 50, as were nearly 25% of those with a new diagnosis of acquired immune deficiency syndrome (AIDS).⁴ This year (2015), we expect that more than half of all HIV-infected people in the United States will be over age 50.⁵

The rising prevalence of HIV infection in this age group has prompted reevaluation of screening guidelines. The US Preventive Services Task Force recommends screening for HIV in all people ages 15 to 65, and also after age 65 in people at ongoing risk of infection.⁶ The American College of Physicians has suggested that the range for routine HIV screening be expanded to age 75.⁷ The cost-effectiveness of expanded and more frequent HIV testing appears to justify it.⁸

Take-home points

• An HIV-infected patient who is compliant with an appropriate antiretroviral regimen and has a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.
• Today, nearly 20% of newly diagnosed HIV-infected people and more than 50% of all HIV-infected people in the United States are over the age of 50.
• The age range for routine screening for HIV infection should be expanded.

HIGH-RISK GROUPS AMONG THE ELDERLY

Early in the HIV epidemic, older patients acquired HIV from blood transfusions received because of hemophilia and other disorders. However, this rapidly ceased after blood banks began screening blood products. Today, people over age 50 who acquire HIV have many of the same risk factors as younger people.

Men who have sex with men are the largest subgroup of HIV-infected people in the United States, even among those over age 50. In particular, white men who have sex with men now constitute the largest demographic group among the HIV-infected elderly.⁴

Intravenous drug users make up about 15% of older people with HIV.

Women who have sex with infected men or with men at risk of HIV infection make up the largest group of older women with HIV.⁴

Sex and the older person

Many older HIV-infected people remain sexually active and continue to engage in unprotected sexual intercourse far into advanced age. According to one survey, 53% of Americans ages 65 to 74 are engaging in sexual activity regularly; however, they are not using protective measures with up to 91% of casual partners and 70% of new partners.^9,10 Many widowed and divorced people are dating again, and they may be unfamiliar with condom use or may be reluctant to use condoms because condoms can often make it difficult to maintain an erection.

Drugs for erectile dysfunction are making it easier for the elderly to engage in both vaginal and anal intercourse, but often without a condom.⁹ Older women who no longer worry about getting pregnant may be less likely to insist their partners use a condom and to practice safe sex. In addition, age-related thinning and dryness can cause vaginal tears, increasing the risk of HIV transmission.¹¹

Take-home points

• People older than 50 have risk factors for HIV similar to those in younger people.
• Men who have sex with men compose the largest group of HIV-infected individuals in the elderly population.
• Unprotected sexual intercourse is common in the elderly for several reasons: unfamiliarity with condom use, difficulty maintaining an erection, lack of concern about possible pregnancy, and vaginal thinning and dryness in women.

UNDERDIAGNOSIS AND LATE DIAGNOSIS IN THE ELDERLY

The cumulative number of AIDS cases in adults age 50 and older increased nearly ninefold from 1990 to the end of 2009. Even more worrisome, one-half of HIV-positive adults over age 50 are diagnosed with AIDS simultaneously or within 1 year of their HIV diagnosis.⁴ This late diagnosis—and therefore late initiation of treatment—is associated with poorer health outcomes and more rapid disease progression.¹²

HIV infection in older adults often goes undiagnosed, for several reasons.

Providers may underestimate the risk in this population and therefore may not discuss HIV transmission or perform testing. Despite a US Centers for Disease Control and Prevention recommendation that people ages 13 to 64 be tested at least once, and more often if sexually active, only 35% of adults ages 45 to 64 have ever been tested for HIV infection.¹³

Age greater than 50 has been strongly associated with higher rates of non–AIDS-related cancers and cardiovascular disease

Older patients may not perceive themselves to be at risk of HIV infection because of lack of insight and information about its prevention and transmission. They are also less likely than younger adults to discuss their sexual habits or drug use with providers.¹⁴ In addition, compared with the young sexually active population, very little HIV prevention education is targeted to older people.¹⁵ Social stigmatization is also a concern for many HIV-infected elderly, as a perceived negative reputation within their community may prevent them from seeking care and disclosing their HIV status.

Take-home points

Reasons that HIV infection is underdiagnosed in the elderly include lack of:

• Provider recognition
• Insight and information about HIV prevention and transmission
• HIV-prevention education targeting the elderly
• Disclosure because of the social stigma of HIV infection.

HIV ACCELERATES AGING, AGING REDUCES IMMUNITY

Many HIV-positive people can expect to live as long as people in the general population, but those who are diagnosed late and thus are started on antiretroviral therapy later in the course of their infection have a reduced life expectancy. Longevity depends on both restoring the CD4 count to near-normal and suppressing the viral load to undetectable levels.^3,16 This is especially important for older adults, as HIV may accelerate aging, and aging itself may speed the progression of HIV disease, so that therapy may result in delayed or only partial restoration of immunity.

Older age at the time of HIV infection is a strong predictor of accelerated HIV disease progression in the absence of therapy.¹⁷ Left untreated, older patients with HIV lose CD4 cells and progress to AIDS and death faster than younger patients. The deleterious effects of chronic immune activation in the course of HIV infection, combined with the immune senescence of aging, are thought to promote this accelerated course.¹⁸

Recent data indicate that starting antiretroviral therapy early can help prevent the CD4-cell impairment that occurs with aging.¹⁹ However, in adults over age 50, the capacity to restore the CD4 count with antiretroviral therapy apears to be reduced, despite demonstrated viral load suppression and better adherence.²⁰ Although mean adherence rates appear higher in older HIV-infected patients, they are worse in those with neurocognitive impairment, highlighting the importance of evaluating neurocognition in this population.²¹

Decreased immune recovery and the subsequent increased risk of serious AIDS events are factors that now favor starting antiretroviral therapy in all HIV patients over age 50, regardless of CD4 count.

Take-home points

• Without treatment, HIV infection in older patients progresses more rapidly to AIDS and death than in younger patients.
• HIV-positive people over age 50 who have never received antiretroviral therapy should be strongly considered for it, regardless of the CD4 count.

SO MANY DRUGS, SO MANY INTERACTIONS

Since HIV patients are now living longer thanks to antiretroviral therapy, they are now experiencing more disease- and treatment-related problems. This has led to an increased likelihood of polypharmacy, defined here as the use of six or more medications.

In general, polypharmacy in the elderly is associated with adverse drug events, drug interactions, inappropriate medication use, delirium, falls, fractures, and poor medication adherence.^22,23 But it becomes even more of a problem in HIV-infected elderly patients, as various drug interactions can alter the effectiveness of the antiretroviral regimen and can result in drug toxicity.

The most common classes of medications used in the elderly are antihypertensives, lipid-lowering agents, antiplatelet medications, antidepressants, anxiolytics, sedatives, and analgesics, and many of these have notable interactions with current antiretroviral regimens.^24,25 Most medications, including antiretrovirals, are cleared by the liver or kidneys, and the function of these organs often decreases with age, resulting in impaired elimination and in drug accumulation.

Information on drug interactions is readily available from the US Department of Health and Human Services,²⁶ drug interaction databases,^27,28 and drug interaction software. The combination of antiretroviral therapy and preexisting polypharmacy significantly increases the risk of serious interactions, which can lead to drug toxicity, poorer adherence with antiretroviral therapy, loss of efficacy of the coadministered medication, or resurgence of HIV infection due to drug-drug interactions affecting the metabolism and ultimate efficacy of the antiretroviral therapy. An increased awareness of common drug-drug interactions can prevent coadministration of potentially harmful medications in elderly HIV patients.

Important interactions between antiretroviral drugs and other drug classes are summarized in Table 1.^25–28 Most notably:

• Simvastatin and lovastatin are contraindicated with any protease inhibitor.
• Proton pump inhibitors are not recommended for patients taking ritonavir-boosted atazanavir. If a proton pump inhibitor is necessary, the daily dose should not exceed 20 mg of omeprazole or its equivalent in patients who have never taken a protease inhibitor, and it should be taken 12 hours before boosted atazanavir.²⁶
• Corticosteroids, whether systemic, inhaled, or intranasal (eg, fluticasone, budesonide), should be avoided in combination with any protease inhibitor, as they can cause iatrogenic Cushing syndrome and also pose the risk of adrenal crisis during acute illness.²⁷

Take-home points

• In cases of preexisting polypharmacy, antiretroviral therapy can lead to significant drug toxicity, poor adherence to medications, and resurgence of HIV infection.
• Increased provider awareness of common drug-drug interactions can prevent the prescribing of potentially harmful drug combinations to HIV-infected elderly patients.

COMORBIDITIES

In recent years, more than half of the deaths in HIV patients on antiretroviral therapy have been from noninfectious comorbidities such as cardiovascular disease, bone disease, and renal failure, which often coexist and are associated with advanced age.²⁹ In fact, both older age and each additional year of antiretroviral therapy are independent predictors of polypathology (simultaneous occurrence of two or more defined diseases).³⁰ The Antiretroviral Therapy Cohort Collaboration found that age greater than 50 was strongly associated with increasing rates of non–AIDS-related malignancy and cardiovascular disease.³¹

CARDIOVASCULAR DISEASE

With the increasing life expectancy of HIV-infected adults on antiretroviral therapy, cardiovascular disease has become an important concern. HIV-infected adults appear to have a significantly greater risk of myocardial infarction and coronary artery disease than age-matched HIV-negative individuals.³² Strikingly, being older than 50 itself increases the risk of hospitalization for cardiovascular disease fivefold (incidence rate ratio 5.01, 95% confidence interval 3.41–7.38).³³ In addition, HIV infection is associated with a risk of acute myocardial infarction 50% higher than that explained by recognized risk factors.³⁴

This high prevalence of coronary artery disease is likely from a combination of factors, including increasing age and the chronic inflammation and immune activation associated with HIV infection.³⁵ An association between untreated HIV disease and markers of risk for cardiovascular disease has been identified.^36,37

HIV is associated with a 50% higher risk of acute myocardial infarction beyond traditional risk factors

In addition, antiretroviral therapy is associated with dyslipidemia, which is most pronounced with protease inhibitor regimens. Whether specific lipid changes associated with individual antiretroviral drugs affect cardiovascular risk remains uncertain. In the Data Collection on Adverse Events of Anti-HIV Drugs studies,³⁸ only cumulative exposure to indinavir, lopinavir-ritonavir, and didanosine was associated with an increased risk of myocardial infarction.³⁸

Traditional risk factors such as obesity, tobacco use, and genetic predisposition also apply to HIV-infected people.³⁹ In fact, the prevalence of traditional risk factors such as smoking and dyslipidemia is generally higher in HIV-infected people than in the general population, although this situation may be improving.⁴⁰

Science needs to elucidate the relationship between traditional and nontraditional risk factors for cardiovascular disease in older HIV-infected adults. In the meantime, older patients with HIV require aggressive management of modifiable risk factors.

Tools for assessing cardiovascular risk include the Framingham risk score⁴¹ and the Data Collection on Adverse Events of Anti-HIV Drugs 5-year risk calculator.⁴² The European AIDS Clinical Society guidelines recommend considering changing the antiretroviral regimen if the patient’s 10-year risk of cardiovascular disease is more than 20%.⁴³ Recommended strategies for reducing cardiovascular risk in elderly patients with HIV infection include counseling about smoking cessation and weight loss at every clinic visit and optimally controlling dyslipidemia and hypertension using nationally accepted standardized guidelines.⁴⁴

Take-home points

• HIV infection is associated with a 50% higher risk of acute myocardial infarction beyond that explained by traditional risk factors.
• Chronic inflammation, immune activation, and dyslipidemia associated with antiretroviral therapy all contribute to cardiovascular disease in HIV-infected patients.
• HIV-infected elderly patients require aggressive management of modifiable risk factors for cardiovascular disease.

ENDOCRINE DISEASE

Diabetes mellitus

The estimated prevalence of diabetes mellitus is 3% in HIV-infected people who have never received antiretroviral therapy, but glucose intolerance increases to the range of 10% to 25% in those who have started it.⁴⁵ Glucose disorders are associated with traditional risk factors as well as with HIV-associated factors such as lipodystrophy and antiretroviral therapy, specifically long-term use of protease inhibitors.⁴⁶ Although increasing age and obesity clearly play a role in the development of diabetes mellitus in this population, HIV-specific factors may also allow diabetes to develop at a lower level of adiposity than in people without HIV infection.⁴⁷

Strategies for preventing type 2 diabetes mellitus in HIV-infected patients focus on avoiding excessive weight gain, especially after starting antiretroviral therapy; regularly screening for diabetes using hemoglobin A_1c, both before and after starting antiretroviral therapy; and continuing to check hemoglobin A_1c every 6 months. The target hemoglobin A_1c should be less than 7.0%. This threshold should be increased to 8% in frail elderly adults if their anticipated life expectancy is less than 5 years, given their higher risk of hypoglycemia, polypharmacy, and drug interactions.⁴⁸ In addition, as in HIV-negative patients, diabetes screening should be performed if systolic blood pressure exceeds 135/80 mm Hg.

Insulin sensitizers such as metformin and thiazolidinediones should be considered for treating diabetes in HIV-infected patients if no contraindications exist. Consideration may also be given to switching the antiretroviral regimen from a protease inhibitor-based regimen to a nonnucleoside reverse transcriptase inhibitor-based regimen.⁴⁸

Take-home points

• Glucose intolerance has been associated with HIV-specific factors, including lipodystrophy and antiretroviral therapy.
• Avoiding excessive weight gain, use of insulin-sensitizing medications, and alteration in antiretroviral regimens should be considered for the treatment of diabetes mellitus in HIV infection.

Osteoporosis

Osteoporotic bone disease disproportionately affects patients with advanced HIV infection compared with patients of similar age.⁴⁹ Bone mineral density is lower and the fracture rate is higher in HIV-infected individuals.

The pathogenesis of bone disease appears to be multifactorial. Traditional risk factors include hypogonadism, smoking, alcohol use, and low body weight, while HIV-related risk factors include chronic immune activation and antiretroviral therapy.⁵⁰

Several antiretroviral regimens have been linked to clinically significant bone loss, including both tenofovir-based and protease inhibitor-based regimens.⁵¹ Most studies have shown that bone mineral density decreases by 2% to 6% in the first 2 years after starting these regimens⁵²; however, long-term effects on bone loss are unknown.

Questions remain. For example, what are the exact mechanisms that lead to the acute decrease in bone mineral density after starting antiretroviral therapy? And why is vitamin D deficiency is so prevalent in HIV infection, with low vitamin D levels seen in up to 60% to 75% of elderly HIV-infected patients?⁵³

Osteoporosis and vitamin D deficiency appear to be more prevalent with HIV infection

Both the Work Group for the HIV and Aging Consensus Project⁵⁴ and the European AIDS Clinical Society⁴³ recommend screening for and treating causes of secondary low bone mineral density in HIV-infected men over age 50 and postmenopausal HIV-infected women. These causes include vitamin D deficiency. As of 2013, the National Osteoporosis Foundation guidelines include HIV infection and antiretroviral therapy as osteoporosis risk factors that should trigger screening for low bone mineral density with dual-energy x-ray absorptiometry (DXA).⁵⁵

As in the general population, the preferred treatment for low bone mineral density in people with HIV is a bisphosphonate, in addition to ensuring adequate calcium and vitamin D intake. It is important to repeat DXA imaging every 2 years and to reassess the need for continued bisphosphonate therapy after 3 to 5 years because of a possible increased risk of fracture with prolonged use.

Take-home points

• Osteoporosis and vitamin D deficiency both appear to be more prevalent with HIV infection.
• HIV infection and antiretroviral therapy are risk factors that should prompt DXA screening to evaluate for osteoporosis.

NEUROCOGNITIVE DISORDERS

HIV-associated neurocognitive disorders are common, with an estimated 50% of HIV-infected patients experiencing some degree of cognitive loss and some progressing to dementia.⁵⁶ Unfortunately, studies suggest that cognitive disorders can occur despite good HIV control with antiretroviral therapy, with one report demonstrating that 84% of patients with cognitive complaints and 64% without complaints were affected by an HIV-associated neurocognitive disorder.⁵⁷

HIV-associated dementia is often subcortical, with fluctuating symptoms such as psychomotor retardation, difficulty multitasking, and apathy. In contrast to dementia syndromes such as Alzheimer disease, relentless progression is less common in HIV-infected patients who receive antiretroviral therapy.

The Mini-Mental State Examination should not be used to screen for HIV-associated neurocognitive disorders, as it does not assess the domains that are typically impaired. The Montreal Cognitive Assessment has been suggested as the best screening instrument in elderly HIV-infected patients; it is available at no cost at www.mocatest.org.⁵⁸

As HIV-associated neurocognitive disorder is a diagnosis of exclusion, an evaluation for alternative diagnoses such as syphilis, hypothyroidism, and depression is recommended. If an HIV-associated neurocognitive disorder is diagnosed, referral to specialty care should be considered, as interventions such as lumbar puncture to assess cerebrospinal fluid viral escape and changing the antiretroviral regimen to improve central nervous system penetration are possible options under study.

Patients with poorly controlled HIV and a depressed CD4 count are at risk of a number of central nervous system complications in addition to HIV-associated neurocognitive disorders, eg, central nervous system toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and primary central nervous system lymphoma. Adherence to an effective antiretroviral regimen is the primary prevention strategy.

Take-home points

• HIV-associated neurocognitive disorders and dementia can occur despite appropriate HIV control and adherence to antiretroviral therapy.
• Adherence to antiretroviral therapy is the primary prevention against most central nervous system complications in HIV infection.

GERIATRIC SYNDROMES

The aging HIV-infected adult may also be at increased risk of geriatric syndromes.

HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail

In particular, a frailty-related phenotype of weight loss, exhaustion, slowness, and low physical activity was more common in HIV-infected elderly than in noninfected elderly.⁵⁹ HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail, and the likelihood of frailty increases with age, duration of HIV infection, having a CD4 count lower than 350 × 10⁶/L, and having uncontrolled HIV replication.^60,61

Other geriatric syndromes such as falls, urinary incontinence, and functional impairment have been identified in 25% to 56% of older HIV-infected patients.⁶² Indeed, the combination of HIV and older age may adversely affect performance of instrumental activities of daily living.⁶³ Also, as previously mentioned, nondisclosure, fear of HIV-related social stigmatization, and a desire to be self-reliant are all factors that perpetuate the social isolation that is common among the HIV-infected elderly.

For these reasons, a comprehensive approach involving a geriatrician, an infectious disease specialist, and community social workers is needed to manage the care of this aging population.

Take-home point

• Geriatric syndromes have an important impact on health in aging HIV patients.

CANCER SCREENING IN HIV PATIENTS

People with HIV have an elevated risk of cancer. Specifically, compared with the general population, their risk is:

• 3,640 times higher for Kaposi sarcoma
• 77 times higher for non-Hodgkin lymphomas
• 6 times higher for cervical cancer.^64,65

These cancers are considered “AIDS-defining,” and fortunately, the development of effective antiretroviral therapy in the 1990s has led to a marked reduction in their incidence. However, the aging HIV population is now experiencing a rise in the incidence of non–AIDS-defining cancers, such as cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin lymphoma.⁶⁶ Table 2 shows the standardized incidence ratio of selected non–AIDS-defining cancers in HIV-infected patients as reported in several large international studies.^65,67,68 The etiology for the increased risk of non–AIDS-defining cancers in the HIV-infected population is not clear, but possible explanations include the virus itself, antiretroviral therapy, and co-infection with other viruses such as hepatitis B, hepatitis C, and Epstein-Barr virus.

Guidelines for cancer screening vary by organization, and the American Cancer Society, the National Cancer Institute, and the US Preventive Services Task Force do not have formal screening guidelines for the most common non–AIDS-defining cancers. The European AIDS Clinical Society, however, has proposed some screening recommendations for selected malignancies.⁴³

In general, screening recommendations are similar to those for HIV-negative patients. A specific difference for HIV-infected patients is in cervical cancer screening. HIV-infected women should undergo a Papanicolaou smear at 6-month intervals during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. There is no consensus as to whether human papillomavirus testing should be performed routinely on HIV-infected women.

At the time of this writing, there are no recommendations for routine screening for anal cancer, although some specialists recommend anal cytologic screening for HIV-positive men and women, and an annual digital anal examination may be useful to detect masses that could be anal cancer.⁶⁹

Take-home points

• The incidence of non–AIDS-defining cancers is rising in the aging HIV population.
• There are currently no formal recommendations for routine screening for anal cancer.

FINAL WORD

Because patients with HIV are living longer as a result of newer effective combination antiretroviral therapies, physicians face a new challenge of managing conditions in these patients that are traditionally associated with aging. Providers will need to improve their understanding of drug-drug interactions and polypharmacy issues and be able to address the complex medical and psychosocial issues in this growing population. As patients with HIV on effective antiretroviral therapy grow older, the burden of comorbid medical disease will continue to increase.

In the 1980s, human immunodeficiency virus (HIV) infection was considered untreatable and predictably lethal. Today, with highly effective antiretroviral therapy, it has become a chronic condition in which patients have a life expectancy comparable to that in the general population.

This change has led to new challenges for primary care physicians, many of whom now find themselves either the sole medical provider for or the comanager of aging HIV-infected patients. Given that about one-fifth of new HIV diagnoses are now in people over the age of 50, it is crucial that primary care providers be able to recognize and diagnose the disease in this population. In addition, they need to effectively manage the polypharmacy and subsequent drug interactions prevalent in older HIV-infected patients. Finally, the clinician must address comorbid diseases common in the elderly, specifically neurologic, cardiovascular, metabolic, and endocrine disorders, as well as performing routine cancer screening.

Take-home point

• As the number of people age 50 and older with HIV infection increases, primary care providers must be able to both recognize and manage the condition.

RISING PREVALENCE OF HIV IN THE ELDERLY

Globally, about 2.5 million people received a new diagnosis of HIV infection in 2011, and about 35 million people worldwide are currently living with it.¹ An estimated 1.1 million Americans are living with HIV, and of these, about 16% do not know they are infected.²

HIV patients who adhere to treatment and achieve a CD4 count above 350 and a low viral load have a normal life expectancy

Antiretroviral therapy has greatly improved the life expectancy of HIV-infected patients, and the number of HIV-infected people over age 50 continues to rise. A successfully treated HIV-positive person with a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.³ In 2011, nearly 20% of newly diagnosed HIV-infected people in the United States were over age 50, as were nearly 25% of those with a new diagnosis of acquired immune deficiency syndrome (AIDS).⁴ This year (2015), we expect that more than half of all HIV-infected people in the United States will be over age 50.⁵

The rising prevalence of HIV infection in this age group has prompted reevaluation of screening guidelines. The US Preventive Services Task Force recommends screening for HIV in all people ages 15 to 65, and also after age 65 in people at ongoing risk of infection.⁶ The American College of Physicians has suggested that the range for routine HIV screening be expanded to age 75.⁷ The cost-effectiveness of expanded and more frequent HIV testing appears to justify it.⁸

Take-home points

• An HIV-infected patient who is compliant with an appropriate antiretroviral regimen and has a CD4 count higher than 350 × 10⁶/L and a suppressed viral load now has a normal life expectancy.
• Today, nearly 20% of newly diagnosed HIV-infected people and more than 50% of all HIV-infected people in the United States are over the age of 50.
• The age range for routine screening for HIV infection should be expanded.

HIGH-RISK GROUPS AMONG THE ELDERLY

Early in the HIV epidemic, older patients acquired HIV from blood transfusions received because of hemophilia and other disorders. However, this rapidly ceased after blood banks began screening blood products. Today, people over age 50 who acquire HIV have many of the same risk factors as younger people.

Men who have sex with men are the largest subgroup of HIV-infected people in the United States, even among those over age 50. In particular, white men who have sex with men now constitute the largest demographic group among the HIV-infected elderly.⁴

Intravenous drug users make up about 15% of older people with HIV.

Women who have sex with infected men or with men at risk of HIV infection make up the largest group of older women with HIV.⁴

Sex and the older person

Many older HIV-infected people remain sexually active and continue to engage in unprotected sexual intercourse far into advanced age. According to one survey, 53% of Americans ages 65 to 74 are engaging in sexual activity regularly; however, they are not using protective measures with up to 91% of casual partners and 70% of new partners.^9,10 Many widowed and divorced people are dating again, and they may be unfamiliar with condom use or may be reluctant to use condoms because condoms can often make it difficult to maintain an erection.

Drugs for erectile dysfunction are making it easier for the elderly to engage in both vaginal and anal intercourse, but often without a condom.⁹ Older women who no longer worry about getting pregnant may be less likely to insist their partners use a condom and to practice safe sex. In addition, age-related thinning and dryness can cause vaginal tears, increasing the risk of HIV transmission.¹¹

Take-home points

• People older than 50 have risk factors for HIV similar to those in younger people.
• Men who have sex with men compose the largest group of HIV-infected individuals in the elderly population.
• Unprotected sexual intercourse is common in the elderly for several reasons: unfamiliarity with condom use, difficulty maintaining an erection, lack of concern about possible pregnancy, and vaginal thinning and dryness in women.

UNDERDIAGNOSIS AND LATE DIAGNOSIS IN THE ELDERLY

The cumulative number of AIDS cases in adults age 50 and older increased nearly ninefold from 1990 to the end of 2009. Even more worrisome, one-half of HIV-positive adults over age 50 are diagnosed with AIDS simultaneously or within 1 year of their HIV diagnosis.⁴ This late diagnosis—and therefore late initiation of treatment—is associated with poorer health outcomes and more rapid disease progression.¹²

HIV infection in older adults often goes undiagnosed, for several reasons.

Providers may underestimate the risk in this population and therefore may not discuss HIV transmission or perform testing. Despite a US Centers for Disease Control and Prevention recommendation that people ages 13 to 64 be tested at least once, and more often if sexually active, only 35% of adults ages 45 to 64 have ever been tested for HIV infection.¹³

Age greater than 50 has been strongly associated with higher rates of non–AIDS-related cancers and cardiovascular disease

Older patients may not perceive themselves to be at risk of HIV infection because of lack of insight and information about its prevention and transmission. They are also less likely than younger adults to discuss their sexual habits or drug use with providers.¹⁴ In addition, compared with the young sexually active population, very little HIV prevention education is targeted to older people.¹⁵ Social stigmatization is also a concern for many HIV-infected elderly, as a perceived negative reputation within their community may prevent them from seeking care and disclosing their HIV status.

Take-home points

Reasons that HIV infection is underdiagnosed in the elderly include lack of:

• Provider recognition
• Insight and information about HIV prevention and transmission
• HIV-prevention education targeting the elderly
• Disclosure because of the social stigma of HIV infection.

HIV ACCELERATES AGING, AGING REDUCES IMMUNITY

Many HIV-positive people can expect to live as long as people in the general population, but those who are diagnosed late and thus are started on antiretroviral therapy later in the course of their infection have a reduced life expectancy. Longevity depends on both restoring the CD4 count to near-normal and suppressing the viral load to undetectable levels.^3,16 This is especially important for older adults, as HIV may accelerate aging, and aging itself may speed the progression of HIV disease, so that therapy may result in delayed or only partial restoration of immunity.

Older age at the time of HIV infection is a strong predictor of accelerated HIV disease progression in the absence of therapy.¹⁷ Left untreated, older patients with HIV lose CD4 cells and progress to AIDS and death faster than younger patients. The deleterious effects of chronic immune activation in the course of HIV infection, combined with the immune senescence of aging, are thought to promote this accelerated course.¹⁸

Recent data indicate that starting antiretroviral therapy early can help prevent the CD4-cell impairment that occurs with aging.¹⁹ However, in adults over age 50, the capacity to restore the CD4 count with antiretroviral therapy apears to be reduced, despite demonstrated viral load suppression and better adherence.²⁰ Although mean adherence rates appear higher in older HIV-infected patients, they are worse in those with neurocognitive impairment, highlighting the importance of evaluating neurocognition in this population.²¹

Decreased immune recovery and the subsequent increased risk of serious AIDS events are factors that now favor starting antiretroviral therapy in all HIV patients over age 50, regardless of CD4 count.

Take-home points

• Without treatment, HIV infection in older patients progresses more rapidly to AIDS and death than in younger patients.
• HIV-positive people over age 50 who have never received antiretroviral therapy should be strongly considered for it, regardless of the CD4 count.

SO MANY DRUGS, SO MANY INTERACTIONS

Since HIV patients are now living longer thanks to antiretroviral therapy, they are now experiencing more disease- and treatment-related problems. This has led to an increased likelihood of polypharmacy, defined here as the use of six or more medications.

In general, polypharmacy in the elderly is associated with adverse drug events, drug interactions, inappropriate medication use, delirium, falls, fractures, and poor medication adherence.^22,23 But it becomes even more of a problem in HIV-infected elderly patients, as various drug interactions can alter the effectiveness of the antiretroviral regimen and can result in drug toxicity.

The most common classes of medications used in the elderly are antihypertensives, lipid-lowering agents, antiplatelet medications, antidepressants, anxiolytics, sedatives, and analgesics, and many of these have notable interactions with current antiretroviral regimens.^24,25 Most medications, including antiretrovirals, are cleared by the liver or kidneys, and the function of these organs often decreases with age, resulting in impaired elimination and in drug accumulation.

Information on drug interactions is readily available from the US Department of Health and Human Services,²⁶ drug interaction databases,^27,28 and drug interaction software. The combination of antiretroviral therapy and preexisting polypharmacy significantly increases the risk of serious interactions, which can lead to drug toxicity, poorer adherence with antiretroviral therapy, loss of efficacy of the coadministered medication, or resurgence of HIV infection due to drug-drug interactions affecting the metabolism and ultimate efficacy of the antiretroviral therapy. An increased awareness of common drug-drug interactions can prevent coadministration of potentially harmful medications in elderly HIV patients.

Important interactions between antiretroviral drugs and other drug classes are summarized in Table 1.^25–28 Most notably:

• Simvastatin and lovastatin are contraindicated with any protease inhibitor.
• Proton pump inhibitors are not recommended for patients taking ritonavir-boosted atazanavir. If a proton pump inhibitor is necessary, the daily dose should not exceed 20 mg of omeprazole or its equivalent in patients who have never taken a protease inhibitor, and it should be taken 12 hours before boosted atazanavir.²⁶
• Corticosteroids, whether systemic, inhaled, or intranasal (eg, fluticasone, budesonide), should be avoided in combination with any protease inhibitor, as they can cause iatrogenic Cushing syndrome and also pose the risk of adrenal crisis during acute illness.²⁷

Take-home points

• In cases of preexisting polypharmacy, antiretroviral therapy can lead to significant drug toxicity, poor adherence to medications, and resurgence of HIV infection.
• Increased provider awareness of common drug-drug interactions can prevent the prescribing of potentially harmful drug combinations to HIV-infected elderly patients.

COMORBIDITIES

In recent years, more than half of the deaths in HIV patients on antiretroviral therapy have been from noninfectious comorbidities such as cardiovascular disease, bone disease, and renal failure, which often coexist and are associated with advanced age.²⁹ In fact, both older age and each additional year of antiretroviral therapy are independent predictors of polypathology (simultaneous occurrence of two or more defined diseases).³⁰ The Antiretroviral Therapy Cohort Collaboration found that age greater than 50 was strongly associated with increasing rates of non–AIDS-related malignancy and cardiovascular disease.³¹

CARDIOVASCULAR DISEASE

With the increasing life expectancy of HIV-infected adults on antiretroviral therapy, cardiovascular disease has become an important concern. HIV-infected adults appear to have a significantly greater risk of myocardial infarction and coronary artery disease than age-matched HIV-negative individuals.³² Strikingly, being older than 50 itself increases the risk of hospitalization for cardiovascular disease fivefold (incidence rate ratio 5.01, 95% confidence interval 3.41–7.38).³³ In addition, HIV infection is associated with a risk of acute myocardial infarction 50% higher than that explained by recognized risk factors.³⁴

This high prevalence of coronary artery disease is likely from a combination of factors, including increasing age and the chronic inflammation and immune activation associated with HIV infection.³⁵ An association between untreated HIV disease and markers of risk for cardiovascular disease has been identified.^36,37

HIV is associated with a 50% higher risk of acute myocardial infarction beyond traditional risk factors

In addition, antiretroviral therapy is associated with dyslipidemia, which is most pronounced with protease inhibitor regimens. Whether specific lipid changes associated with individual antiretroviral drugs affect cardiovascular risk remains uncertain. In the Data Collection on Adverse Events of Anti-HIV Drugs studies,³⁸ only cumulative exposure to indinavir, lopinavir-ritonavir, and didanosine was associated with an increased risk of myocardial infarction.³⁸

Traditional risk factors such as obesity, tobacco use, and genetic predisposition also apply to HIV-infected people.³⁹ In fact, the prevalence of traditional risk factors such as smoking and dyslipidemia is generally higher in HIV-infected people than in the general population, although this situation may be improving.⁴⁰

Science needs to elucidate the relationship between traditional and nontraditional risk factors for cardiovascular disease in older HIV-infected adults. In the meantime, older patients with HIV require aggressive management of modifiable risk factors.

Tools for assessing cardiovascular risk include the Framingham risk score⁴¹ and the Data Collection on Adverse Events of Anti-HIV Drugs 5-year risk calculator.⁴² The European AIDS Clinical Society guidelines recommend considering changing the antiretroviral regimen if the patient’s 10-year risk of cardiovascular disease is more than 20%.⁴³ Recommended strategies for reducing cardiovascular risk in elderly patients with HIV infection include counseling about smoking cessation and weight loss at every clinic visit and optimally controlling dyslipidemia and hypertension using nationally accepted standardized guidelines.⁴⁴

Take-home points

• HIV infection is associated with a 50% higher risk of acute myocardial infarction beyond that explained by traditional risk factors.
• Chronic inflammation, immune activation, and dyslipidemia associated with antiretroviral therapy all contribute to cardiovascular disease in HIV-infected patients.
• HIV-infected elderly patients require aggressive management of modifiable risk factors for cardiovascular disease.

ENDOCRINE DISEASE

Diabetes mellitus

The estimated prevalence of diabetes mellitus is 3% in HIV-infected people who have never received antiretroviral therapy, but glucose intolerance increases to the range of 10% to 25% in those who have started it.⁴⁵ Glucose disorders are associated with traditional risk factors as well as with HIV-associated factors such as lipodystrophy and antiretroviral therapy, specifically long-term use of protease inhibitors.⁴⁶ Although increasing age and obesity clearly play a role in the development of diabetes mellitus in this population, HIV-specific factors may also allow diabetes to develop at a lower level of adiposity than in people without HIV infection.⁴⁷

Strategies for preventing type 2 diabetes mellitus in HIV-infected patients focus on avoiding excessive weight gain, especially after starting antiretroviral therapy; regularly screening for diabetes using hemoglobin A_1c, both before and after starting antiretroviral therapy; and continuing to check hemoglobin A_1c every 6 months. The target hemoglobin A_1c should be less than 7.0%. This threshold should be increased to 8% in frail elderly adults if their anticipated life expectancy is less than 5 years, given their higher risk of hypoglycemia, polypharmacy, and drug interactions.⁴⁸ In addition, as in HIV-negative patients, diabetes screening should be performed if systolic blood pressure exceeds 135/80 mm Hg.

Insulin sensitizers such as metformin and thiazolidinediones should be considered for treating diabetes in HIV-infected patients if no contraindications exist. Consideration may also be given to switching the antiretroviral regimen from a protease inhibitor-based regimen to a nonnucleoside reverse transcriptase inhibitor-based regimen.⁴⁸

Take-home points

• Glucose intolerance has been associated with HIV-specific factors, including lipodystrophy and antiretroviral therapy.
• Avoiding excessive weight gain, use of insulin-sensitizing medications, and alteration in antiretroviral regimens should be considered for the treatment of diabetes mellitus in HIV infection.

Osteoporosis

Osteoporotic bone disease disproportionately affects patients with advanced HIV infection compared with patients of similar age.⁴⁹ Bone mineral density is lower and the fracture rate is higher in HIV-infected individuals.

The pathogenesis of bone disease appears to be multifactorial. Traditional risk factors include hypogonadism, smoking, alcohol use, and low body weight, while HIV-related risk factors include chronic immune activation and antiretroviral therapy.⁵⁰

Several antiretroviral regimens have been linked to clinically significant bone loss, including both tenofovir-based and protease inhibitor-based regimens.⁵¹ Most studies have shown that bone mineral density decreases by 2% to 6% in the first 2 years after starting these regimens⁵²; however, long-term effects on bone loss are unknown.

Questions remain. For example, what are the exact mechanisms that lead to the acute decrease in bone mineral density after starting antiretroviral therapy? And why is vitamin D deficiency is so prevalent in HIV infection, with low vitamin D levels seen in up to 60% to 75% of elderly HIV-infected patients?⁵³

Osteoporosis and vitamin D deficiency appear to be more prevalent with HIV infection

Both the Work Group for the HIV and Aging Consensus Project⁵⁴ and the European AIDS Clinical Society⁴³ recommend screening for and treating causes of secondary low bone mineral density in HIV-infected men over age 50 and postmenopausal HIV-infected women. These causes include vitamin D deficiency. As of 2013, the National Osteoporosis Foundation guidelines include HIV infection and antiretroviral therapy as osteoporosis risk factors that should trigger screening for low bone mineral density with dual-energy x-ray absorptiometry (DXA).⁵⁵

As in the general population, the preferred treatment for low bone mineral density in people with HIV is a bisphosphonate, in addition to ensuring adequate calcium and vitamin D intake. It is important to repeat DXA imaging every 2 years and to reassess the need for continued bisphosphonate therapy after 3 to 5 years because of a possible increased risk of fracture with prolonged use.

Take-home points

• Osteoporosis and vitamin D deficiency both appear to be more prevalent with HIV infection.
• HIV infection and antiretroviral therapy are risk factors that should prompt DXA screening to evaluate for osteoporosis.

NEUROCOGNITIVE DISORDERS

HIV-associated neurocognitive disorders are common, with an estimated 50% of HIV-infected patients experiencing some degree of cognitive loss and some progressing to dementia.⁵⁶ Unfortunately, studies suggest that cognitive disorders can occur despite good HIV control with antiretroviral therapy, with one report demonstrating that 84% of patients with cognitive complaints and 64% without complaints were affected by an HIV-associated neurocognitive disorder.⁵⁷

HIV-associated dementia is often subcortical, with fluctuating symptoms such as psychomotor retardation, difficulty multitasking, and apathy. In contrast to dementia syndromes such as Alzheimer disease, relentless progression is less common in HIV-infected patients who receive antiretroviral therapy.

The Mini-Mental State Examination should not be used to screen for HIV-associated neurocognitive disorders, as it does not assess the domains that are typically impaired. The Montreal Cognitive Assessment has been suggested as the best screening instrument in elderly HIV-infected patients; it is available at no cost at www.mocatest.org.⁵⁸

As HIV-associated neurocognitive disorder is a diagnosis of exclusion, an evaluation for alternative diagnoses such as syphilis, hypothyroidism, and depression is recommended. If an HIV-associated neurocognitive disorder is diagnosed, referral to specialty care should be considered, as interventions such as lumbar puncture to assess cerebrospinal fluid viral escape and changing the antiretroviral regimen to improve central nervous system penetration are possible options under study.

Patients with poorly controlled HIV and a depressed CD4 count are at risk of a number of central nervous system complications in addition to HIV-associated neurocognitive disorders, eg, central nervous system toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and primary central nervous system lymphoma. Adherence to an effective antiretroviral regimen is the primary prevention strategy.

Take-home points

• HIV-associated neurocognitive disorders and dementia can occur despite appropriate HIV control and adherence to antiretroviral therapy.
• Adherence to antiretroviral therapy is the primary prevention against most central nervous system complications in HIV infection.

GERIATRIC SYNDROMES

The aging HIV-infected adult may also be at increased risk of geriatric syndromes.

HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail

In particular, a frailty-related phenotype of weight loss, exhaustion, slowness, and low physical activity was more common in HIV-infected elderly than in noninfected elderly.⁵⁹ HIV-infected men are 4.5 to 10 times more likely than age-matched controls to be frail, and the likelihood of frailty increases with age, duration of HIV infection, having a CD4 count lower than 350 × 10⁶/L, and having uncontrolled HIV replication.^60,61

Other geriatric syndromes such as falls, urinary incontinence, and functional impairment have been identified in 25% to 56% of older HIV-infected patients.⁶² Indeed, the combination of HIV and older age may adversely affect performance of instrumental activities of daily living.⁶³ Also, as previously mentioned, nondisclosure, fear of HIV-related social stigmatization, and a desire to be self-reliant are all factors that perpetuate the social isolation that is common among the HIV-infected elderly.

For these reasons, a comprehensive approach involving a geriatrician, an infectious disease specialist, and community social workers is needed to manage the care of this aging population.

Take-home point

• Geriatric syndromes have an important impact on health in aging HIV patients.

CANCER SCREENING IN HIV PATIENTS

People with HIV have an elevated risk of cancer. Specifically, compared with the general population, their risk is:

• 3,640 times higher for Kaposi sarcoma
• 77 times higher for non-Hodgkin lymphomas
• 6 times higher for cervical cancer.^64,65

These cancers are considered “AIDS-defining,” and fortunately, the development of effective antiretroviral therapy in the 1990s has led to a marked reduction in their incidence. However, the aging HIV population is now experiencing a rise in the incidence of non–AIDS-defining cancers, such as cancers of the lung, liver, kidney, anus, head and neck, and skin, as well as Hodgkin lymphoma.⁶⁶ Table 2 shows the standardized incidence ratio of selected non–AIDS-defining cancers in HIV-infected patients as reported in several large international studies.^65,67,68 The etiology for the increased risk of non–AIDS-defining cancers in the HIV-infected population is not clear, but possible explanations include the virus itself, antiretroviral therapy, and co-infection with other viruses such as hepatitis B, hepatitis C, and Epstein-Barr virus.

Guidelines for cancer screening vary by organization, and the American Cancer Society, the National Cancer Institute, and the US Preventive Services Task Force do not have formal screening guidelines for the most common non–AIDS-defining cancers. The European AIDS Clinical Society, however, has proposed some screening recommendations for selected malignancies.⁴³

In general, screening recommendations are similar to those for HIV-negative patients. A specific difference for HIV-infected patients is in cervical cancer screening. HIV-infected women should undergo a Papanicolaou smear at 6-month intervals during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter. There is no consensus as to whether human papillomavirus testing should be performed routinely on HIV-infected women.

At the time of this writing, there are no recommendations for routine screening for anal cancer, although some specialists recommend anal cytologic screening for HIV-positive men and women, and an annual digital anal examination may be useful to detect masses that could be anal cancer.⁶⁹

Take-home points

• The incidence of non–AIDS-defining cancers is rising in the aging HIV population.
• There are currently no formal recommendations for routine screening for anal cancer.

FINAL WORD

Because patients with HIV are living longer as a result of newer effective combination antiretroviral therapies, physicians face a new challenge of managing conditions in these patients that are traditionally associated with aging. Providers will need to improve their understanding of drug-drug interactions and polypharmacy issues and be able to address the complex medical and psychosocial issues in this growing population. As patients with HIV on effective antiretroviral therapy grow older, the burden of comorbid medical disease will continue to increase.